This year I focus on four interesting and clinically relevant studies:

• an article by Huang and colleagues addressing the important issue of how best to reduce the frequency of methicillin-resistant Staphylococcus aureus (MRSA) infection in critically ill patients hospitalized in the intensive care unit (ICU)
• a study by Duggal and colleagues assessing the value of perioperative oxygen ­supplementation to reduce the frequency of postcesarean infection
• an investigation of diagnostic criteria for urinary tract infection (UTI) by Hooton and colleagues
• an exploration of the association between intra-amniotic inflammation, as distinct from bacterial colonization, and adverse fetal outcomes.

For ICU patients, universal decolonization reduces nosocomial infection more than targeted decolonization

Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255–2265.

Infection in general, and nosocomial infection in particular, is common among patients hospitalized in the ICU. Such patients often are severely immunosuppressed and debilitated. They are likely to have multiple indwelling catheters and to require mechanical ventilation—interventions that predispose to life-threatening infection. The longer the duration of care in the ICU, the greater the risk of infection, especially infection caused by organisms that have acquired resistance to multiple antibiotics.

In this cluster-randomized trial, Huang and colleagues compared targeted and universal decolonization of patients treated in an ICU to determine which approach was more effective at preventing nosocomial infection, particularly MRSA infection. They found universal decolonization to be superior to targeted decolonization in reducing these infections.

Details of the studyInvestigators conducted their study in 74 ICUs in 43 hospitals. Each hospital was ­randomly assigned to one of three interventions:

• Group 1: MRSA screening followed by isolation of colonized patients
• Group 2: MRSA screening followed by isolation and decolonization of MRSA carriers
• Group 3: Universal decolonization (no screening).

The decolonization regimen consisted of twice-daily administration of intranasal mupirocin for 5 days and daily bathing with chlorhexidine-impregnated cloths for the duration of the ICU stay.

The study’s two endpoints were 1) the modeled hazard ratios for MRSA clinical isolates and 2) the hazard ratios for bloodstream infection with any pathogen.

During the intervention period, fewer MRSA isolates were found in the universal decolonization group, compared with the other two groups (P<.01). In addition, the number of bloodstream infections in the universal decolonization group was significantly lower than in the other two groups (P<.001). Fifty-four patients (number needed to treat) needed to undergo decolonization to prevent one bloodstream infection.

What this EVIDENCE means for practiceThe relevance of this investigation for those of us in the field of obstetrics and gynecology is simple and clear: If we have to transfer a patient to an ICU (such as an HIV-infected patient with a serious post­cesarean infection, or an oncology patient with a badly infected surgical wound), she should immediately be started on a regimen of twice-daily nasal mupirocin and daily bathing with chlorhexidine. This straightforward intervention will be of great value in reducing the incidence of bacteremia caused by a particularly dangerous pathogen.

Related article: Update on infectious disease. Patrick Duff, MD (July 2013)

The jury is still out on supplemental oxygen to reduce surgical site infection

Duggal N, Poddatorri V, Noroozkhani S, Siddik-Ahman RI, Caughey AB. Perioperative oxygen supplementation and surgical site infection after cesarean delivery. Obstet Gynecol. 2013;122(1):79–84.

In a widely read study published in 2000 in the New England Journal of Medicine, Greif and colleagues demonstrated that, in patients undergoing colorectal surgery, the rate of postoperative wound infection was significantly reduced from 11.2% in patients given 30% supplemental oxygen during surgery to 5.2% in those given 80% supplemental oxygen.¹ The oxygen was continued for 2 hours after surgery.

In a later study among general surgery patients, Pryor and colleagues were unable to replicate this finding.² It was in this setting that Duggal and colleagues undertook their investigation among women undergoing cesarean delivery. These investigators, too, were unable to replicate the 2000 finding of Greif and colleagues.

Related article: Update: Infectious Disease.  Patrick Duff, MD (June 2012)

Details of the studyOver 4 years, from 2006 to 2010, Duggal and colleagues conducted a prospective, randomized, double-blinded controlled trial among patients undergoing scheduled, urgent, or emergent cesarean delivery. All patients were given prophylactic antibiotics, usually cefazolin 2 g intravenously after the infant’s umbilical cord was clamped. Surgical technique was reasonably well standardized and included closure of the deep subcutaneous layer of tissue using 2-0 plain gut sutures.

Patients were randomly assigned to receive supplemental oxygen via face mask, at 30% or 80% concentration, during surgery and for 1 hour postoperatively. They were evaluated postoperatively at 2 and 6 weeks. The primary outcome measure was a composite of surgical site infection, endometritis, or both.

A total of 415 women received 30% oxygen and 416 were given 80% oxygen. The two groups were well matched for important confounding variables such as age, race, pari­ty, body mass index, number of prior cesarean deliveries, diabetes, cardiopulmonary disease, anemia, smoking, and chronic steroid use.

The groups did not differ in the frequency of surgical site infection or endometritis, which occurred at a rate of 2.4% in the group receiving 30% oxygen, compared with 2.9% in the group given 80% oxygen.

Rationale for oxygen supplementationAdequate tissue oxygenation has been observed to enhance the bactericidal function of neutrophils. So why were Duggal and colleagues unable to demonstrate a beneficial effect for oxygen therapy?

The most likely explanations:

• Their obstetric patients were less seriously ill than the general surgery patients undergoing colorectal surgery in the study by Greif and colleagues.
• Given the low overall rate of infection, their sample size may have been too small to show a statistically significant difference in outcome (Type II statistical error).

In point of fact, more than 80% of patients in both groups had scheduled cesarean deliveries, presumably prior to the onset of labor and ruptured membranes. The outcome may have been different had the groups included a majority of patients undergoing surgery after labor and ruptured membranes.

What this EVIDENCE means for practiceUntil additional studies are performed, I cannot recommend routine use of perioperative hyperoxygenation as a method of reducing the rate of surgical site infection and/or endometritis. However, we have very good scientific evidence indicating that the following measures significantly reduce the rate of endometritis after both scheduled and unscheduled cesarean delivery:
• administration of prophylactic antibiotics prior to the start of surgery
• removal of the placenta by gentle traction on the umbilical cord rather than by manual extraction.^3,4
Similarly, we have sound evidence demonstrating that the following measures significantly reduce the rate of surgical site infection:
• clipping, rather than shaving, the hair at the surgical site just prior to the incision
• preoperative cleansing of the surgical area with chlorhexidine
• administration of prophylactic antibiotics prior to the start of surgery closure of the lower half of the subcutaneous tissue (if it exceeds 2 cm in thickness) using a relatively noninflammatory suture such as polyglactin or polyglycolic acid.

The presence of E coli in a midstream urine specimen is highly predictive of UTI

Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med. 2013;369(20):1883–1891.

Urinary tract infections (UTI) are among the most common infections experienced by women of all ages. Asymptomatic bacteriuria affects 5% to 10% of all sexually active women. During the course of their lifetime, at least 50% of women develop some form of UTI.

Pyelonephritis is not nearly as common as asymptomatic bacteriuria or cystitis, but this infection can be especially dangerous in older, debilitated women who reside in nursing homes and require indwelling catheters.

The most common organisms that cause UTIs in women are the aerobic gram-negative bacilli, principally Escherichia coli, Klebsiella species, and Proteus species. Other Gram-negative bacilli such as Pseudomonas species, Serratia, or Enterobacter are not common uropathogens except in immunosuppressed hosts or patients who have long-term indwelling catheters. Gram-positive organisms such as group B streptococci, enterococci, and staphylococcal species are occasional pathogens but, as Hooton and colleagues demonstrate in this study, perhaps not quite as important as we once thought.

Related articles:
• Update on infectious disease. Alan T. N. Tita, MD, PhD (June 2011)
• Have you tried these innovative alternatives to antibiotics for UTI prevention? Patrick A. Nosti, MD; Kate C. Arnold; Cheryl B. Iglesia, MD (February 2013)

Details of the studyUsing an elegantly simple design, the Hooton team studied women aged 18 to 49 years who had symptoms suggestive of acute cystitis. They collected two urine specimens from each woman for culture—one was collected using the midstream, clean-catch technique and the other by catheterization. They then compared microbial species and colony counts in the paired specimens to determine the positive and negative predictive values of midstream culture results, using the catheterized culture results as the reference standard.

The 226 women in the study experienced 236 clinical episodes suggestive of acute cystitis. One hundred forty-two (70%) of the catheterized specimens were positive for infection; of these, four specimens yielded more than one uropathogen. One hundred fifty-seven (78%) of the midstream specimens were positive for infection.

The presence of E coli in the midstream culture was highly predictive of a positive culture for E coli by catheterization, even when the cutoff was only 100 colonies/mL on the midstream specimen (positive predictive value, 93%). However, neither the presence of enterococci nor the presence of group B streptococci, at any colony count, was predictive of a positive culture by catheterization. Interestingly, among 41 patients who had either enterococci or group B streptococci in their midstream culture, E coli was present in the catheterizedculture in 61% of cases, suggesting that infection with E coli may be the more important cause of the patient’s symptoms.

Hooton and colleagues concluded that the presence of E coli on a midstream culture, even in low colony counts, is predictive of true bladder infection, as determined by catheterization. However, enterococci and group B streptococci were more likely to be vaginal contaminants or associated with coinfection with E coli, or bot.

What this EVIDENCE means for practiceThe findings of Hooton and colleagues have several key implications for practicing clinicians:
• When either a pregnant or nonpregnant patient experiences her first episode of acute cystitis, the overwhelming probability is that E coli is the infecting pathogen. We can reduce costs by empirically treating the initial infection, thereby avoiding the expense of a urine culture.
• For patients with recurrent infections or for immunocompromised patients, a culture and sensitivity test should be performed because other uropathogens are more likely to be involved and may have less predictable antibiotic susceptibility patterns.
• Contamination of supposed “clean-catch” specimens is very common, and the cultures resulting from these specimens can mislead us in our decisions about antibiotic therapy. Enterococci and group B streptococci are more likely than not to be contaminants from the vaginal flora rather than true infecting pathogens. When they are present in the bladder, they are usually associated with E coli. Accordingly, E coli should be the principal target of anti­biotic therapy.
• To avoid concerns about contamination of specimens in acutely symptomatic patients, obtain the urine specimen by catheter. In the catheterized specimen, the cutoff for true bladder infection should be ≥100 colonies/mL. The cutoff of ≥100,000 colonies/mLis applicable only for clean-catch specimens obtained from asymptomatic patients.
• Clinical laboratories should embrace the new cutoff and report even seemingly low colony counts when the urine sample has been obtained by catheterization.

In preterm labor, amniotic fluid infection without inflammation does not necessarily predict a poor fetal outcome

Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125.e1–e15.

In this very important clinical investigation, Combs and colleagues collected amniotic fluid from 305 women with preterm labor. They then measured the amniotic fluid concentration of interleukin-6 (IL-6) and assessed for the presence of microbial invasion of the amniotic cavity (MIAC) by either culture or detection of microbial 16S ribosomal DNA. Based on these test results, investigators divided the patients into five groups:

• Infection—defined as positive MIAC and IL-6 >11.3 ng/mL
• Severe inflammation—negative MIAC and IL-6 >11.3 ng/mL
• Mild inflammation—no MIAC and IL-6 from 2.6 to 11.2 ng/mL
• Colonization—positive MIAC and IL-6 <2.6 ng/mL
• Negative—no MIAC and IL-6 <2.6 ng/mL.

The end points of the investigation were latency period and composite perinatal morbidity and mortality. Perinatal morbidity included respiratory distress syndrome, grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, and culture-proven neonatal sepsis.

Related article: Does treating asymptomatic bacterial vaginosis reduce preterm delivery? Hyagriv N. Simhan, MD, MSCR (Examining the Evidence; April 2008)

Interestingly, the infection and severe inflammation groups had similar short latency periods (median of <1 and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively).

The colonization and negative groups also had similar latency periods (median of 23.5 and 25 days, respectively) and similar rates of composite morbidity and mortality (21% and 25%, respectively).

The mild inflammation group had intermediate outcomes.

When Combs and colleagues used multivariate analysis to adjust for gestational age at enrollment, amniotic fluid IL-6 concentrations greater than 11.3 ng/mL and in the range of 2.6 to 11.3 ng/mL—but not MIAC—were associated with increased composite perinatal morbidity and mortality.

What this EVIDENCE means for practiceThis study offers several critically important take-home messages:
• Bacterial colonization of the amniotic fluid, without actual inflammation, is not necessarily associated with an ominous outcome for the fetus
• Varying degrees of inflammation exist
• The more intense the inflammation, the worse the outcome for the baby
• The logical clinical application of this investigation is to modify our practice so that, when we perform an amniocentesis for patients with preterm labor, we look not only for bacterial growth but for the presence of key inflammatory mediators in the amniotic fluid, such as IL-6
• A rapidly available, inexpensive, and easy-to-perform assay for IL-6 would be invaluable in improving our ability to assess patients for subclinical infection and inflammation
• An important question, of course, is whether early implementation of specific anti-inflammatory therapy could alter the prognosis for the fetus in selected cases.

WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

This year I focus on four interesting and clinically relevant studies:

• an article by Huang and colleagues addressing the important issue of how best to reduce the frequency of methicillin-resistant Staphylococcus aureus (MRSA) infection in critically ill patients hospitalized in the intensive care unit (ICU)
• a study by Duggal and colleagues assessing the value of perioperative oxygen ­supplementation to reduce the frequency of postcesarean infection
• an investigation of diagnostic criteria for urinary tract infection (UTI) by Hooton and colleagues
• an exploration of the association between intra-amniotic inflammation, as distinct from bacterial colonization, and adverse fetal outcomes.

For ICU patients, universal decolonization reduces nosocomial infection more than targeted decolonization

Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255–2265.

Infection in general, and nosocomial infection in particular, is common among patients hospitalized in the ICU. Such patients often are severely immunosuppressed and debilitated. They are likely to have multiple indwelling catheters and to require mechanical ventilation—interventions that predispose to life-threatening infection. The longer the duration of care in the ICU, the greater the risk of infection, especially infection caused by organisms that have acquired resistance to multiple antibiotics.

In this cluster-randomized trial, Huang and colleagues compared targeted and universal decolonization of patients treated in an ICU to determine which approach was more effective at preventing nosocomial infection, particularly MRSA infection. They found universal decolonization to be superior to targeted decolonization in reducing these infections.

Details of the studyInvestigators conducted their study in 74 ICUs in 43 hospitals. Each hospital was ­randomly assigned to one of three interventions:

• Group 1: MRSA screening followed by isolation of colonized patients
• Group 2: MRSA screening followed by isolation and decolonization of MRSA carriers
• Group 3: Universal decolonization (no screening).

The decolonization regimen consisted of twice-daily administration of intranasal mupirocin for 5 days and daily bathing with chlorhexidine-impregnated cloths for the duration of the ICU stay.

The study’s two endpoints were 1) the modeled hazard ratios for MRSA clinical isolates and 2) the hazard ratios for bloodstream infection with any pathogen.

During the intervention period, fewer MRSA isolates were found in the universal decolonization group, compared with the other two groups (P<.01). In addition, the number of bloodstream infections in the universal decolonization group was significantly lower than in the other two groups (P<.001). Fifty-four patients (number needed to treat) needed to undergo decolonization to prevent one bloodstream infection.

What this EVIDENCE means for practiceThe relevance of this investigation for those of us in the field of obstetrics and gynecology is simple and clear: If we have to transfer a patient to an ICU (such as an HIV-infected patient with a serious post­cesarean infection, or an oncology patient with a badly infected surgical wound), she should immediately be started on a regimen of twice-daily nasal mupirocin and daily bathing with chlorhexidine. This straightforward intervention will be of great value in reducing the incidence of bacteremia caused by a particularly dangerous pathogen.

Related article: Update on infectious disease. Patrick Duff, MD (July 2013)

The jury is still out on supplemental oxygen to reduce surgical site infection

Duggal N, Poddatorri V, Noroozkhani S, Siddik-Ahman RI, Caughey AB. Perioperative oxygen supplementation and surgical site infection after cesarean delivery. Obstet Gynecol. 2013;122(1):79–84.

In a widely read study published in 2000 in the New England Journal of Medicine, Greif and colleagues demonstrated that, in patients undergoing colorectal surgery, the rate of postoperative wound infection was significantly reduced from 11.2% in patients given 30% supplemental oxygen during surgery to 5.2% in those given 80% supplemental oxygen.¹ The oxygen was continued for 2 hours after surgery.

In a later study among general surgery patients, Pryor and colleagues were unable to replicate this finding.² It was in this setting that Duggal and colleagues undertook their investigation among women undergoing cesarean delivery. These investigators, too, were unable to replicate the 2000 finding of Greif and colleagues.

Related article: Update: Infectious Disease.  Patrick Duff, MD (June 2012)

Details of the studyOver 4 years, from 2006 to 2010, Duggal and colleagues conducted a prospective, randomized, double-blinded controlled trial among patients undergoing scheduled, urgent, or emergent cesarean delivery. All patients were given prophylactic antibiotics, usually cefazolin 2 g intravenously after the infant’s umbilical cord was clamped. Surgical technique was reasonably well standardized and included closure of the deep subcutaneous layer of tissue using 2-0 plain gut sutures.

Patients were randomly assigned to receive supplemental oxygen via face mask, at 30% or 80% concentration, during surgery and for 1 hour postoperatively. They were evaluated postoperatively at 2 and 6 weeks. The primary outcome measure was a composite of surgical site infection, endometritis, or both.

A total of 415 women received 30% oxygen and 416 were given 80% oxygen. The two groups were well matched for important confounding variables such as age, race, pari­ty, body mass index, number of prior cesarean deliveries, diabetes, cardiopulmonary disease, anemia, smoking, and chronic steroid use.

The groups did not differ in the frequency of surgical site infection or endometritis, which occurred at a rate of 2.4% in the group receiving 30% oxygen, compared with 2.9% in the group given 80% oxygen.

Rationale for oxygen supplementationAdequate tissue oxygenation has been observed to enhance the bactericidal function of neutrophils. So why were Duggal and colleagues unable to demonstrate a beneficial effect for oxygen therapy?

The most likely explanations:

• Their obstetric patients were less seriously ill than the general surgery patients undergoing colorectal surgery in the study by Greif and colleagues.
• Given the low overall rate of infection, their sample size may have been too small to show a statistically significant difference in outcome (Type II statistical error).

In point of fact, more than 80% of patients in both groups had scheduled cesarean deliveries, presumably prior to the onset of labor and ruptured membranes. The outcome may have been different had the groups included a majority of patients undergoing surgery after labor and ruptured membranes.

What this EVIDENCE means for practiceUntil additional studies are performed, I cannot recommend routine use of perioperative hyperoxygenation as a method of reducing the rate of surgical site infection and/or endometritis. However, we have very good scientific evidence indicating that the following measures significantly reduce the rate of endometritis after both scheduled and unscheduled cesarean delivery:
• administration of prophylactic antibiotics prior to the start of surgery
• removal of the placenta by gentle traction on the umbilical cord rather than by manual extraction.^3,4
Similarly, we have sound evidence demonstrating that the following measures significantly reduce the rate of surgical site infection:
• clipping, rather than shaving, the hair at the surgical site just prior to the incision
• preoperative cleansing of the surgical area with chlorhexidine
• administration of prophylactic antibiotics prior to the start of surgery closure of the lower half of the subcutaneous tissue (if it exceeds 2 cm in thickness) using a relatively noninflammatory suture such as polyglactin or polyglycolic acid.

The presence of E coli in a midstream urine specimen is highly predictive of UTI

Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med. 2013;369(20):1883–1891.

Urinary tract infections (UTI) are among the most common infections experienced by women of all ages. Asymptomatic bacteriuria affects 5% to 10% of all sexually active women. During the course of their lifetime, at least 50% of women develop some form of UTI.

Pyelonephritis is not nearly as common as asymptomatic bacteriuria or cystitis, but this infection can be especially dangerous in older, debilitated women who reside in nursing homes and require indwelling catheters.

The most common organisms that cause UTIs in women are the aerobic gram-negative bacilli, principally Escherichia coli, Klebsiella species, and Proteus species. Other Gram-negative bacilli such as Pseudomonas species, Serratia, or Enterobacter are not common uropathogens except in immunosuppressed hosts or patients who have long-term indwelling catheters. Gram-positive organisms such as group B streptococci, enterococci, and staphylococcal species are occasional pathogens but, as Hooton and colleagues demonstrate in this study, perhaps not quite as important as we once thought.

Related articles:
• Update on infectious disease. Alan T. N. Tita, MD, PhD (June 2011)
• Have you tried these innovative alternatives to antibiotics for UTI prevention? Patrick A. Nosti, MD; Kate C. Arnold; Cheryl B. Iglesia, MD (February 2013)

Details of the studyUsing an elegantly simple design, the Hooton team studied women aged 18 to 49 years who had symptoms suggestive of acute cystitis. They collected two urine specimens from each woman for culture—one was collected using the midstream, clean-catch technique and the other by catheterization. They then compared microbial species and colony counts in the paired specimens to determine the positive and negative predictive values of midstream culture results, using the catheterized culture results as the reference standard.

The 226 women in the study experienced 236 clinical episodes suggestive of acute cystitis. One hundred forty-two (70%) of the catheterized specimens were positive for infection; of these, four specimens yielded more than one uropathogen. One hundred fifty-seven (78%) of the midstream specimens were positive for infection.

The presence of E coli in the midstream culture was highly predictive of a positive culture for E coli by catheterization, even when the cutoff was only 100 colonies/mL on the midstream specimen (positive predictive value, 93%). However, neither the presence of enterococci nor the presence of group B streptococci, at any colony count, was predictive of a positive culture by catheterization. Interestingly, among 41 patients who had either enterococci or group B streptococci in their midstream culture, E coli was present in the catheterizedculture in 61% of cases, suggesting that infection with E coli may be the more important cause of the patient’s symptoms.

Hooton and colleagues concluded that the presence of E coli on a midstream culture, even in low colony counts, is predictive of true bladder infection, as determined by catheterization. However, enterococci and group B streptococci were more likely to be vaginal contaminants or associated with coinfection with E coli, or bot.

What this EVIDENCE means for practiceThe findings of Hooton and colleagues have several key implications for practicing clinicians:
• When either a pregnant or nonpregnant patient experiences her first episode of acute cystitis, the overwhelming probability is that E coli is the infecting pathogen. We can reduce costs by empirically treating the initial infection, thereby avoiding the expense of a urine culture.
• For patients with recurrent infections or for immunocompromised patients, a culture and sensitivity test should be performed because other uropathogens are more likely to be involved and may have less predictable antibiotic susceptibility patterns.
• Contamination of supposed “clean-catch” specimens is very common, and the cultures resulting from these specimens can mislead us in our decisions about antibiotic therapy. Enterococci and group B streptococci are more likely than not to be contaminants from the vaginal flora rather than true infecting pathogens. When they are present in the bladder, they are usually associated with E coli. Accordingly, E coli should be the principal target of anti­biotic therapy.
• To avoid concerns about contamination of specimens in acutely symptomatic patients, obtain the urine specimen by catheter. In the catheterized specimen, the cutoff for true bladder infection should be ≥100 colonies/mL. The cutoff of ≥100,000 colonies/mLis applicable only for clean-catch specimens obtained from asymptomatic patients.
• Clinical laboratories should embrace the new cutoff and report even seemingly low colony counts when the urine sample has been obtained by catheterization.

In preterm labor, amniotic fluid infection without inflammation does not necessarily predict a poor fetal outcome

Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125.e1–e15.

In this very important clinical investigation, Combs and colleagues collected amniotic fluid from 305 women with preterm labor. They then measured the amniotic fluid concentration of interleukin-6 (IL-6) and assessed for the presence of microbial invasion of the amniotic cavity (MIAC) by either culture or detection of microbial 16S ribosomal DNA. Based on these test results, investigators divided the patients into five groups:

• Infection—defined as positive MIAC and IL-6 >11.3 ng/mL
• Severe inflammation—negative MIAC and IL-6 >11.3 ng/mL
• Mild inflammation—no MIAC and IL-6 from 2.6 to 11.2 ng/mL
• Colonization—positive MIAC and IL-6 <2.6 ng/mL
• Negative—no MIAC and IL-6 <2.6 ng/mL.

The end points of the investigation were latency period and composite perinatal morbidity and mortality. Perinatal morbidity included respiratory distress syndrome, grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, and culture-proven neonatal sepsis.

Related article: Does treating asymptomatic bacterial vaginosis reduce preterm delivery? Hyagriv N. Simhan, MD, MSCR (Examining the Evidence; April 2008)

Interestingly, the infection and severe inflammation groups had similar short latency periods (median of <1 and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively).

The colonization and negative groups also had similar latency periods (median of 23.5 and 25 days, respectively) and similar rates of composite morbidity and mortality (21% and 25%, respectively).

The mild inflammation group had intermediate outcomes.

When Combs and colleagues used multivariate analysis to adjust for gestational age at enrollment, amniotic fluid IL-6 concentrations greater than 11.3 ng/mL and in the range of 2.6 to 11.3 ng/mL—but not MIAC—were associated with increased composite perinatal morbidity and mortality.

What this EVIDENCE means for practiceThis study offers several critically important take-home messages:
• Bacterial colonization of the amniotic fluid, without actual inflammation, is not necessarily associated with an ominous outcome for the fetus
• Varying degrees of inflammation exist
• The more intense the inflammation, the worse the outcome for the baby
• The logical clinical application of this investigation is to modify our practice so that, when we perform an amniocentesis for patients with preterm labor, we look not only for bacterial growth but for the presence of key inflammatory mediators in the amniotic fluid, such as IL-6
• A rapidly available, inexpensive, and easy-to-perform assay for IL-6 would be invaluable in improving our ability to assess patients for subclinical infection and inflammation
• An important question, of course, is whether early implementation of specific anti-inflammatory therapy could alter the prognosis for the fetus in selected cases.

WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

This year I focus on four interesting and clinically relevant studies:

• an article by Huang and colleagues addressing the important issue of how best to reduce the frequency of methicillin-resistant Staphylococcus aureus (MRSA) infection in critically ill patients hospitalized in the intensive care unit (ICU)
• a study by Duggal and colleagues assessing the value of perioperative oxygen ­supplementation to reduce the frequency of postcesarean infection
• an investigation of diagnostic criteria for urinary tract infection (UTI) by Hooton and colleagues
• an exploration of the association between intra-amniotic inflammation, as distinct from bacterial colonization, and adverse fetal outcomes.

For ICU patients, universal decolonization reduces nosocomial infection more than targeted decolonization

Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 2013;368(24):2255–2265.

Infection in general, and nosocomial infection in particular, is common among patients hospitalized in the ICU. Such patients often are severely immunosuppressed and debilitated. They are likely to have multiple indwelling catheters and to require mechanical ventilation—interventions that predispose to life-threatening infection. The longer the duration of care in the ICU, the greater the risk of infection, especially infection caused by organisms that have acquired resistance to multiple antibiotics.

In this cluster-randomized trial, Huang and colleagues compared targeted and universal decolonization of patients treated in an ICU to determine which approach was more effective at preventing nosocomial infection, particularly MRSA infection. They found universal decolonization to be superior to targeted decolonization in reducing these infections.

Details of the studyInvestigators conducted their study in 74 ICUs in 43 hospitals. Each hospital was ­randomly assigned to one of three interventions:

• Group 1: MRSA screening followed by isolation of colonized patients
• Group 2: MRSA screening followed by isolation and decolonization of MRSA carriers
• Group 3: Universal decolonization (no screening).

The decolonization regimen consisted of twice-daily administration of intranasal mupirocin for 5 days and daily bathing with chlorhexidine-impregnated cloths for the duration of the ICU stay.

The study’s two endpoints were 1) the modeled hazard ratios for MRSA clinical isolates and 2) the hazard ratios for bloodstream infection with any pathogen.

During the intervention period, fewer MRSA isolates were found in the universal decolonization group, compared with the other two groups (P<.01). In addition, the number of bloodstream infections in the universal decolonization group was significantly lower than in the other two groups (P<.001). Fifty-four patients (number needed to treat) needed to undergo decolonization to prevent one bloodstream infection.

What this EVIDENCE means for practiceThe relevance of this investigation for those of us in the field of obstetrics and gynecology is simple and clear: If we have to transfer a patient to an ICU (such as an HIV-infected patient with a serious post­cesarean infection, or an oncology patient with a badly infected surgical wound), she should immediately be started on a regimen of twice-daily nasal mupirocin and daily bathing with chlorhexidine. This straightforward intervention will be of great value in reducing the incidence of bacteremia caused by a particularly dangerous pathogen.

Related article: Update on infectious disease. Patrick Duff, MD (July 2013)

The jury is still out on supplemental oxygen to reduce surgical site infection

Duggal N, Poddatorri V, Noroozkhani S, Siddik-Ahman RI, Caughey AB. Perioperative oxygen supplementation and surgical site infection after cesarean delivery. Obstet Gynecol. 2013;122(1):79–84.

In a widely read study published in 2000 in the New England Journal of Medicine, Greif and colleagues demonstrated that, in patients undergoing colorectal surgery, the rate of postoperative wound infection was significantly reduced from 11.2% in patients given 30% supplemental oxygen during surgery to 5.2% in those given 80% supplemental oxygen.¹ The oxygen was continued for 2 hours after surgery.

In a later study among general surgery patients, Pryor and colleagues were unable to replicate this finding.² It was in this setting that Duggal and colleagues undertook their investigation among women undergoing cesarean delivery. These investigators, too, were unable to replicate the 2000 finding of Greif and colleagues.

Related article: Update: Infectious Disease.  Patrick Duff, MD (June 2012)

Details of the studyOver 4 years, from 2006 to 2010, Duggal and colleagues conducted a prospective, randomized, double-blinded controlled trial among patients undergoing scheduled, urgent, or emergent cesarean delivery. All patients were given prophylactic antibiotics, usually cefazolin 2 g intravenously after the infant’s umbilical cord was clamped. Surgical technique was reasonably well standardized and included closure of the deep subcutaneous layer of tissue using 2-0 plain gut sutures.

Patients were randomly assigned to receive supplemental oxygen via face mask, at 30% or 80% concentration, during surgery and for 1 hour postoperatively. They were evaluated postoperatively at 2 and 6 weeks. The primary outcome measure was a composite of surgical site infection, endometritis, or both.

A total of 415 women received 30% oxygen and 416 were given 80% oxygen. The two groups were well matched for important confounding variables such as age, race, pari­ty, body mass index, number of prior cesarean deliveries, diabetes, cardiopulmonary disease, anemia, smoking, and chronic steroid use.

The groups did not differ in the frequency of surgical site infection or endometritis, which occurred at a rate of 2.4% in the group receiving 30% oxygen, compared with 2.9% in the group given 80% oxygen.

Rationale for oxygen supplementationAdequate tissue oxygenation has been observed to enhance the bactericidal function of neutrophils. So why were Duggal and colleagues unable to demonstrate a beneficial effect for oxygen therapy?

The most likely explanations:

• Their obstetric patients were less seriously ill than the general surgery patients undergoing colorectal surgery in the study by Greif and colleagues.
• Given the low overall rate of infection, their sample size may have been too small to show a statistically significant difference in outcome (Type II statistical error).

In point of fact, more than 80% of patients in both groups had scheduled cesarean deliveries, presumably prior to the onset of labor and ruptured membranes. The outcome may have been different had the groups included a majority of patients undergoing surgery after labor and ruptured membranes.

What this EVIDENCE means for practiceUntil additional studies are performed, I cannot recommend routine use of perioperative hyperoxygenation as a method of reducing the rate of surgical site infection and/or endometritis. However, we have very good scientific evidence indicating that the following measures significantly reduce the rate of endometritis after both scheduled and unscheduled cesarean delivery:
• administration of prophylactic antibiotics prior to the start of surgery
• removal of the placenta by gentle traction on the umbilical cord rather than by manual extraction.^3,4
Similarly, we have sound evidence demonstrating that the following measures significantly reduce the rate of surgical site infection:
• clipping, rather than shaving, the hair at the surgical site just prior to the incision
• preoperative cleansing of the surgical area with chlorhexidine
• administration of prophylactic antibiotics prior to the start of surgery closure of the lower half of the subcutaneous tissue (if it exceeds 2 cm in thickness) using a relatively noninflammatory suture such as polyglactin or polyglycolic acid.

The presence of E coli in a midstream urine specimen is highly predictive of UTI

Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med. 2013;369(20):1883–1891.

Urinary tract infections (UTI) are among the most common infections experienced by women of all ages. Asymptomatic bacteriuria affects 5% to 10% of all sexually active women. During the course of their lifetime, at least 50% of women develop some form of UTI.

Pyelonephritis is not nearly as common as asymptomatic bacteriuria or cystitis, but this infection can be especially dangerous in older, debilitated women who reside in nursing homes and require indwelling catheters.

The most common organisms that cause UTIs in women are the aerobic gram-negative bacilli, principally Escherichia coli, Klebsiella species, and Proteus species. Other Gram-negative bacilli such as Pseudomonas species, Serratia, or Enterobacter are not common uropathogens except in immunosuppressed hosts or patients who have long-term indwelling catheters. Gram-positive organisms such as group B streptococci, enterococci, and staphylococcal species are occasional pathogens but, as Hooton and colleagues demonstrate in this study, perhaps not quite as important as we once thought.

Related articles:
• Update on infectious disease. Alan T. N. Tita, MD, PhD (June 2011)
• Have you tried these innovative alternatives to antibiotics for UTI prevention? Patrick A. Nosti, MD; Kate C. Arnold; Cheryl B. Iglesia, MD (February 2013)

Details of the studyUsing an elegantly simple design, the Hooton team studied women aged 18 to 49 years who had symptoms suggestive of acute cystitis. They collected two urine specimens from each woman for culture—one was collected using the midstream, clean-catch technique and the other by catheterization. They then compared microbial species and colony counts in the paired specimens to determine the positive and negative predictive values of midstream culture results, using the catheterized culture results as the reference standard.

The 226 women in the study experienced 236 clinical episodes suggestive of acute cystitis. One hundred forty-two (70%) of the catheterized specimens were positive for infection; of these, four specimens yielded more than one uropathogen. One hundred fifty-seven (78%) of the midstream specimens were positive for infection.

The presence of E coli in the midstream culture was highly predictive of a positive culture for E coli by catheterization, even when the cutoff was only 100 colonies/mL on the midstream specimen (positive predictive value, 93%). However, neither the presence of enterococci nor the presence of group B streptococci, at any colony count, was predictive of a positive culture by catheterization. Interestingly, among 41 patients who had either enterococci or group B streptococci in their midstream culture, E coli was present in the catheterizedculture in 61% of cases, suggesting that infection with E coli may be the more important cause of the patient’s symptoms.

Hooton and colleagues concluded that the presence of E coli on a midstream culture, even in low colony counts, is predictive of true bladder infection, as determined by catheterization. However, enterococci and group B streptococci were more likely to be vaginal contaminants or associated with coinfection with E coli, or bot.

What this EVIDENCE means for practiceThe findings of Hooton and colleagues have several key implications for practicing clinicians:
• When either a pregnant or nonpregnant patient experiences her first episode of acute cystitis, the overwhelming probability is that E coli is the infecting pathogen. We can reduce costs by empirically treating the initial infection, thereby avoiding the expense of a urine culture.
• For patients with recurrent infections or for immunocompromised patients, a culture and sensitivity test should be performed because other uropathogens are more likely to be involved and may have less predictable antibiotic susceptibility patterns.
• Contamination of supposed “clean-catch” specimens is very common, and the cultures resulting from these specimens can mislead us in our decisions about antibiotic therapy. Enterococci and group B streptococci are more likely than not to be contaminants from the vaginal flora rather than true infecting pathogens. When they are present in the bladder, they are usually associated with E coli. Accordingly, E coli should be the principal target of anti­biotic therapy.
• To avoid concerns about contamination of specimens in acutely symptomatic patients, obtain the urine specimen by catheter. In the catheterized specimen, the cutoff for true bladder infection should be ≥100 colonies/mL. The cutoff of ≥100,000 colonies/mLis applicable only for clean-catch specimens obtained from asymptomatic patients.
• Clinical laboratories should embrace the new cutoff and report even seemingly low colony counts when the urine sample has been obtained by catheterization.

In preterm labor, amniotic fluid infection without inflammation does not necessarily predict a poor fetal outcome

Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125.e1–e15.

In this very important clinical investigation, Combs and colleagues collected amniotic fluid from 305 women with preterm labor. They then measured the amniotic fluid concentration of interleukin-6 (IL-6) and assessed for the presence of microbial invasion of the amniotic cavity (MIAC) by either culture or detection of microbial 16S ribosomal DNA. Based on these test results, investigators divided the patients into five groups:

• Infection—defined as positive MIAC and IL-6 >11.3 ng/mL
• Severe inflammation—negative MIAC and IL-6 >11.3 ng/mL
• Mild inflammation—no MIAC and IL-6 from 2.6 to 11.2 ng/mL
• Colonization—positive MIAC and IL-6 <2.6 ng/mL
• Negative—no MIAC and IL-6 <2.6 ng/mL.

The end points of the investigation were latency period and composite perinatal morbidity and mortality. Perinatal morbidity included respiratory distress syndrome, grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, and culture-proven neonatal sepsis.

Related article: Does treating asymptomatic bacterial vaginosis reduce preterm delivery? Hyagriv N. Simhan, MD, MSCR (Examining the Evidence; April 2008)

Interestingly, the infection and severe inflammation groups had similar short latency periods (median of <1 and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively).

The colonization and negative groups also had similar latency periods (median of 23.5 and 25 days, respectively) and similar rates of composite morbidity and mortality (21% and 25%, respectively).

The mild inflammation group had intermediate outcomes.

When Combs and colleagues used multivariate analysis to adjust for gestational age at enrollment, amniotic fluid IL-6 concentrations greater than 11.3 ng/mL and in the range of 2.6 to 11.3 ng/mL—but not MIAC—were associated with increased composite perinatal morbidity and mortality.

What this EVIDENCE means for practiceThis study offers several critically important take-home messages:
• Bacterial colonization of the amniotic fluid, without actual inflammation, is not necessarily associated with an ominous outcome for the fetus
• Varying degrees of inflammation exist
• The more intense the inflammation, the worse the outcome for the baby
• The logical clinical application of this investigation is to modify our practice so that, when we perform an amniocentesis for patients with preterm labor, we look not only for bacterial growth but for the presence of key inflammatory mediators in the amniotic fluid, such as IL-6
• A rapidly available, inexpensive, and easy-to-perform assay for IL-6 would be invaluable in improving our ability to assess patients for subclinical infection and inflammation
• An important question, of course, is whether early implementation of specific anti-inflammatory therapy could alter the prognosis for the fetus in selected cases.

WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

This study from a large Danish population appears to suggest that the prenatal use of acetaminophen may increase the risk of ADHD and HKD. It is yet another study in which the data indicate and the authors claim that use of a particular drug during pregnancy is responsible for this condition. However, despite the extremely large sample size (which increases the likelihood of positive findings), the hazard ratios were only marginally significant, suggesting that the relevance of the conclusions is questionable.

Details of the study
The 64,322 live-born children and mothers in the Danish National Birth Cohort from 1996 to 2002 were evaluated three ways:

• through parental reports of behavioral problems in children at age 7 using the Strengths and Difficulties Questionnaire
• through retrieval of HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011
• through prescriptions for ADHD (primarily methylphenidate [Ritalin]) for children from the Danish Prescription Registry.

Liew and colleagues then estimated hazard ratios for receiving a diagnosis of HKD or using a medication for ADHD, as well as risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

Stronger associations between prenatal acetaminophen use and HKD or ADHD were found when the mother used the medication in more than one trimester. Exposure-response trends increased with the frequency of acetaminophen use during pregnancy for all three outcomes (HKD diagnosis, ADHD-like behaviors, and ADHD medication use; P trend <.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, or the mother’s mental health status.

Related articles:
• How can pregnant women safely relieve low-back pain? Roselyn Jan W. Clemente-Fuentes, MD; Heather Pickett, DO; Misty Carney, MLIS; and Paul Crawford, MD (January 2014)
• Perinatal depression: What you can do to reduce its long-term effects. Janelle Yates (February 2014)
• Low-dose aspirin and preeclampsia prevention: Ready for prime time, but as a “re-run” or as a “new series”? John T. Repke, MD (Guest Editorial; June 2014)

Why these findings are less than compelling
Acetaminophen is the most commonly used medication during pregnancy, although few investigators have analyzed neurobehavioral complications in children exposed to this drug in utero. Another recent epidemiologic study from Norway also suggests that long-term exposure (>28 days) to acetaminophen increases the risk of poor gross motor functioning, poor communication skills, and externalizing and internalizing behavior problems.³

The rationale behind an association between acetaminophen and ADHD and HKD is that the medication is an endocrine-disrupting agent. The evidence of this status comes primarily from in vitro experiments from one group of researchers, which may not represent in vivo conditions.^4,5

Epidemiologic studies frequently are confounded by poor design and methodology. It also should be noted that correlation is not necessarily the same as causation. In this study, the design and methodology were appropriate considering the data available. Researchers often use large databases like this to research “hot topics” such as the association between ADHD and prenatal acetaminophen use. In this study, acetaminophen cannot be associated definitively with an increased risk of ADHD or HKD. Further research is needed, with greater attention to possible confounding factors, such as why these women consumed chronic doses and for what conditions.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
For the time being, you should probably counsel your patients to use acetaminophen sparingly during pregnancy, and certainly not on a daily basis. We also should encourage nonpharmacologic pain management, such as cognitive behavioral therapy, when appropriate, and caution patients against long-term use of analgesics, when possible, during gestation and lactation.
Thomas W. Hale, RPH, PhD; Aarienne Einarson, RN; and Teresa Baker, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

This study from a large Danish population appears to suggest that the prenatal use of acetaminophen may increase the risk of ADHD and HKD. It is yet another study in which the data indicate and the authors claim that use of a particular drug during pregnancy is responsible for this condition. However, despite the extremely large sample size (which increases the likelihood of positive findings), the hazard ratios were only marginally significant, suggesting that the relevance of the conclusions is questionable.

Details of the study
The 64,322 live-born children and mothers in the Danish National Birth Cohort from 1996 to 2002 were evaluated three ways:

• through parental reports of behavioral problems in children at age 7 using the Strengths and Difficulties Questionnaire
• through retrieval of HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011
• through prescriptions for ADHD (primarily methylphenidate [Ritalin]) for children from the Danish Prescription Registry.

Liew and colleagues then estimated hazard ratios for receiving a diagnosis of HKD or using a medication for ADHD, as well as risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

Stronger associations between prenatal acetaminophen use and HKD or ADHD were found when the mother used the medication in more than one trimester. Exposure-response trends increased with the frequency of acetaminophen use during pregnancy for all three outcomes (HKD diagnosis, ADHD-like behaviors, and ADHD medication use; P trend <.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, or the mother’s mental health status.

Related articles:
• How can pregnant women safely relieve low-back pain? Roselyn Jan W. Clemente-Fuentes, MD; Heather Pickett, DO; Misty Carney, MLIS; and Paul Crawford, MD (January 2014)
• Perinatal depression: What you can do to reduce its long-term effects. Janelle Yates (February 2014)
• Low-dose aspirin and preeclampsia prevention: Ready for prime time, but as a “re-run” or as a “new series”? John T. Repke, MD (Guest Editorial; June 2014)

Why these findings are less than compelling
Acetaminophen is the most commonly used medication during pregnancy, although few investigators have analyzed neurobehavioral complications in children exposed to this drug in utero. Another recent epidemiologic study from Norway also suggests that long-term exposure (>28 days) to acetaminophen increases the risk of poor gross motor functioning, poor communication skills, and externalizing and internalizing behavior problems.³

The rationale behind an association between acetaminophen and ADHD and HKD is that the medication is an endocrine-disrupting agent. The evidence of this status comes primarily from in vitro experiments from one group of researchers, which may not represent in vivo conditions.^4,5

Epidemiologic studies frequently are confounded by poor design and methodology. It also should be noted that correlation is not necessarily the same as causation. In this study, the design and methodology were appropriate considering the data available. Researchers often use large databases like this to research “hot topics” such as the association between ADHD and prenatal acetaminophen use. In this study, acetaminophen cannot be associated definitively with an increased risk of ADHD or HKD. Further research is needed, with greater attention to possible confounding factors, such as why these women consumed chronic doses and for what conditions.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
For the time being, you should probably counsel your patients to use acetaminophen sparingly during pregnancy, and certainly not on a daily basis. We also should encourage nonpharmacologic pain management, such as cognitive behavioral therapy, when appropriate, and caution patients against long-term use of analgesics, when possible, during gestation and lactation.
Thomas W. Hale, RPH, PhD; Aarienne Einarson, RN; and Teresa Baker, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

This study from a large Danish population appears to suggest that the prenatal use of acetaminophen may increase the risk of ADHD and HKD. It is yet another study in which the data indicate and the authors claim that use of a particular drug during pregnancy is responsible for this condition. However, despite the extremely large sample size (which increases the likelihood of positive findings), the hazard ratios were only marginally significant, suggesting that the relevance of the conclusions is questionable.

Details of the study
The 64,322 live-born children and mothers in the Danish National Birth Cohort from 1996 to 2002 were evaluated three ways:

• through parental reports of behavioral problems in children at age 7 using the Strengths and Difficulties Questionnaire
• through retrieval of HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011
• through prescriptions for ADHD (primarily methylphenidate [Ritalin]) for children from the Danish Prescription Registry.

Liew and colleagues then estimated hazard ratios for receiving a diagnosis of HKD or using a medication for ADHD, as well as risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

Stronger associations between prenatal acetaminophen use and HKD or ADHD were found when the mother used the medication in more than one trimester. Exposure-response trends increased with the frequency of acetaminophen use during pregnancy for all three outcomes (HKD diagnosis, ADHD-like behaviors, and ADHD medication use; P trend <.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, or the mother’s mental health status.

Related articles:
• How can pregnant women safely relieve low-back pain? Roselyn Jan W. Clemente-Fuentes, MD; Heather Pickett, DO; Misty Carney, MLIS; and Paul Crawford, MD (January 2014)
• Perinatal depression: What you can do to reduce its long-term effects. Janelle Yates (February 2014)
• Low-dose aspirin and preeclampsia prevention: Ready for prime time, but as a “re-run” or as a “new series”? John T. Repke, MD (Guest Editorial; June 2014)

Why these findings are less than compelling
Acetaminophen is the most commonly used medication during pregnancy, although few investigators have analyzed neurobehavioral complications in children exposed to this drug in utero. Another recent epidemiologic study from Norway also suggests that long-term exposure (>28 days) to acetaminophen increases the risk of poor gross motor functioning, poor communication skills, and externalizing and internalizing behavior problems.³

The rationale behind an association between acetaminophen and ADHD and HKD is that the medication is an endocrine-disrupting agent. The evidence of this status comes primarily from in vitro experiments from one group of researchers, which may not represent in vivo conditions.^4,5

Epidemiologic studies frequently are confounded by poor design and methodology. It also should be noted that correlation is not necessarily the same as causation. In this study, the design and methodology were appropriate considering the data available. Researchers often use large databases like this to research “hot topics” such as the association between ADHD and prenatal acetaminophen use. In this study, acetaminophen cannot be associated definitively with an increased risk of ADHD or HKD. Further research is needed, with greater attention to possible confounding factors, such as why these women consumed chronic doses and for what conditions.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
For the time being, you should probably counsel your patients to use acetaminophen sparingly during pregnancy, and certainly not on a daily basis. We also should encourage nonpharmacologic pain management, such as cognitive behavioral therapy, when appropriate, and caution patients against long-term use of analgesics, when possible, during gestation and lactation.
Thomas W. Hale, RPH, PhD; Aarienne Einarson, RN; and Teresa Baker, MD

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your Letter to the Editor to: [email protected]

The 2014 Medscape Compensation Report surveyed more than 24,000 physicians in 25 specialties. Five percent of respondents were ObGyns, whose mean income rose slightly to $243,000 in 2013 from $242,000 in 2012, up from $220,000 in 2011.^1–3 The highest ObGyn earners lived in the Great Lakes and North Central regions.¹

Survey findings
Men make more than women. In 2013, male ObGyns reported earning $256,000; female ObGyns reported $229,000 in mean income. However, women felt more satisfied with their salary (47% of women vs 38% of men). Regardless of gender, ObGyns were slightly less happy with their income than all physicians (50% satisfied).¹

Among all female physicians, more were employed than self-employed; the opposite was true for male physicians.⁴ Half of all graduating physicians are now female, and demographics show that 62% of all female physicians are younger than age 45.¹

Practice settings are key to income. Sixty percent of ObGyns indicated they would choose medicine again as a career; 43% would choose their own specialty. However, only 25% of ObGyns would make the same decision about practice setting.¹

In 2013, employed and self-employed ObGyns reported nearly the same mean income: $243,000 versus $246,000, respectively. However, when broken down by specific practice setting, the highest earners were ObGyns who worked for health-care organizations, at $273,000. Additional 2013 mean earnings ranked by work setting were¹:

• multispecialty office-based group practices, $271,000
• single-specialty office-based group practices, $255,000
• hospitals, $228,000
• solo office-based practices, $212,000
• outpatient clinics, $207,000.

In 2013, 49% of employed physicians worked in hospitals or in groups owned by a hospital, while 21% were employed by private groups. Other employment situations included community health centers, corporate laboratories, correction institutions, military bases, and nursing homes.⁴

ACO participation grows. In 2013, 37% of ObGyns either participated in an Accountable Care Organization (ACO) or planned on joining an ACO within the next year.¹ This was an increase from 25% in 2012.^2,3

In the most recent report, 2% chose concierge practices (also known as direct primary care) and 5% opted for cash-only practices.¹ In 2012, only 1% of ObGyns opted for concierge practices, and 3% for cash-only practices.^2,3

Related article: Is private ObGyn practice on its way out? Lucia DiVenere, MA (October 2011)

Employment over private practice? In 2013, physicians were enticed to seek employment by the financial challenges of private practice (38%); not having to be concerned about administrative issues (29%); and working shorter and more regular hours (19%). Other reported benefits of employment were academic opportunities, better life−work balance, more vacation time, and no loss of income during vacation. More than half (53%) of employed physicians who were previously self-employed felt that patient care was superior now that they were employed, and 37% thought it was about the same.⁴

Related article: Mean income for ObGyns increased in 2012. Deborah Reale (News for your Practice; August 2013)

Career satisfaction
ObGyns were close to the bottom among all physicians (48%) when it came to overall career satisfaction, tied with nephrologists, surgeons, and pulmonologists. The most satisfied physicians were dermatologists (65%); the least satisfied were plastic surgeons (45%).¹

What drives you? In 2013, more ObGyns (41%) than all physicians (33%) reported that the most rewarding part of their job was their relationships with patients. Thirty percent of ObGyns chose being good at their jobs; 8% chose making good money; and 2% found nothing rewarding about the job.¹

How much patient time do you spend? The majority (58%) of ObGyns reported spending more than 40 hours per week with patients and 16 minutes or less (66%) per patient.¹ In 2012, 60% of ObGyn respondents reported spending 16 minutes or less per patient.^2,3

Anticipating the effects of the Affordable Care Act
Under the Affordable Care Act (ACA), an organization’s revenue will still be determined largely by the volume generated by ­physicians. The percentage of ObGyns who saw 50 to 124 patients per week increased from 57% in 2012 to 69% in 2013 (TABLE).^1,2

In 2013, 53% of ObGyns still were undecided about health-insurance exchange participation—the same percentage as all survey respondents. Among ObGyns, 30% would participate, and 17% would not participate.¹

Related article: As the Affordable Care Act comes of age, a look behind the headlines. Lucia DiVenere, MA (Practice Management; January 2014)

Almost half (49%) of ObGyns expect their income under the ACA to decrease. About 45% of ObGyns did not foresee any change, and 5% believed their incomes would increase (1% didn’t know) under the ACA. ObGyns also anticipated a higher workload, a decline in quality of patient care and access, and reduced ability to make decisions.¹

Almost one-third of ObGyns dropped poorly paying insurers. In 2013, 29% of ObGyns said they regularly drop insurers who pay poorly, but 46% said they keep their insurers year after year. In 2012, 26% of ObGyns said they drop insurers who pay the least or create the most trouble; 29% said they keep all insurers.^2,3 Private insurance paid for 63% of patient visits to ObGyns in 2013.¹

Fewer ObGyns indicated they would see Medicare and Medicaid patients. In 2013, 20% of self-employed and 5% of employed ObGyns said that they plan to stop taking new Medicare or Medicaid patients. More employed (72%) than self-employed (46%) ObGyns reported that they would continue seeing new and current Medicare and Medicaid patients.¹

Related article: Medicare and Medicaid are on the brink of insolvency, and you’re not just a bystander. Robert L. Barbieri, MD (Editorial; October 2011)

In 2012, 15% of ObGyn respondents planned to stop taking new Medicare or Medicaid patients, but 53% of ObGyn respondents said they would continue to see current patients and would take on new Medicare or Medicaid patients.^2,3

TELL US WHAT YOU THINK! Share your thoughts on this article. Send your Letter to the Editor to: [email protected] 

The 2014 Medscape Compensation Report surveyed more than 24,000 physicians in 25 specialties. Five percent of respondents were ObGyns, whose mean income rose slightly to $243,000 in 2013 from $242,000 in 2012, up from $220,000 in 2011.^1–3 The highest ObGyn earners lived in the Great Lakes and North Central regions.¹

Survey findings
Men make more than women. In 2013, male ObGyns reported earning $256,000; female ObGyns reported $229,000 in mean income. However, women felt more satisfied with their salary (47% of women vs 38% of men). Regardless of gender, ObGyns were slightly less happy with their income than all physicians (50% satisfied).¹

Among all female physicians, more were employed than self-employed; the opposite was true for male physicians.⁴ Half of all graduating physicians are now female, and demographics show that 62% of all female physicians are younger than age 45.¹

Practice settings are key to income. Sixty percent of ObGyns indicated they would choose medicine again as a career; 43% would choose their own specialty. However, only 25% of ObGyns would make the same decision about practice setting.¹

In 2013, employed and self-employed ObGyns reported nearly the same mean income: $243,000 versus $246,000, respectively. However, when broken down by specific practice setting, the highest earners were ObGyns who worked for health-care organizations, at $273,000. Additional 2013 mean earnings ranked by work setting were¹:

• multispecialty office-based group practices, $271,000
• single-specialty office-based group practices, $255,000
• hospitals, $228,000
• solo office-based practices, $212,000
• outpatient clinics, $207,000.

In 2013, 49% of employed physicians worked in hospitals or in groups owned by a hospital, while 21% were employed by private groups. Other employment situations included community health centers, corporate laboratories, correction institutions, military bases, and nursing homes.⁴

ACO participation grows. In 2013, 37% of ObGyns either participated in an Accountable Care Organization (ACO) or planned on joining an ACO within the next year.¹ This was an increase from 25% in 2012.^2,3

In the most recent report, 2% chose concierge practices (also known as direct primary care) and 5% opted for cash-only practices.¹ In 2012, only 1% of ObGyns opted for concierge practices, and 3% for cash-only practices.^2,3

Related article: Is private ObGyn practice on its way out? Lucia DiVenere, MA (October 2011)

Employment over private practice? In 2013, physicians were enticed to seek employment by the financial challenges of private practice (38%); not having to be concerned about administrative issues (29%); and working shorter and more regular hours (19%). Other reported benefits of employment were academic opportunities, better life−work balance, more vacation time, and no loss of income during vacation. More than half (53%) of employed physicians who were previously self-employed felt that patient care was superior now that they were employed, and 37% thought it was about the same.⁴

Related article: Mean income for ObGyns increased in 2012. Deborah Reale (News for your Practice; August 2013)

Career satisfaction
ObGyns were close to the bottom among all physicians (48%) when it came to overall career satisfaction, tied with nephrologists, surgeons, and pulmonologists. The most satisfied physicians were dermatologists (65%); the least satisfied were plastic surgeons (45%).¹

What drives you? In 2013, more ObGyns (41%) than all physicians (33%) reported that the most rewarding part of their job was their relationships with patients. Thirty percent of ObGyns chose being good at their jobs; 8% chose making good money; and 2% found nothing rewarding about the job.¹

How much patient time do you spend? The majority (58%) of ObGyns reported spending more than 40 hours per week with patients and 16 minutes or less (66%) per patient.¹ In 2012, 60% of ObGyn respondents reported spending 16 minutes or less per patient.^2,3

Anticipating the effects of the Affordable Care Act
Under the Affordable Care Act (ACA), an organization’s revenue will still be determined largely by the volume generated by ­physicians. The percentage of ObGyns who saw 50 to 124 patients per week increased from 57% in 2012 to 69% in 2013 (TABLE).^1,2

In 2013, 53% of ObGyns still were undecided about health-insurance exchange participation—the same percentage as all survey respondents. Among ObGyns, 30% would participate, and 17% would not participate.¹

Related article: As the Affordable Care Act comes of age, a look behind the headlines. Lucia DiVenere, MA (Practice Management; January 2014)

Almost half (49%) of ObGyns expect their income under the ACA to decrease. About 45% of ObGyns did not foresee any change, and 5% believed their incomes would increase (1% didn’t know) under the ACA. ObGyns also anticipated a higher workload, a decline in quality of patient care and access, and reduced ability to make decisions.¹

Almost one-third of ObGyns dropped poorly paying insurers. In 2013, 29% of ObGyns said they regularly drop insurers who pay poorly, but 46% said they keep their insurers year after year. In 2012, 26% of ObGyns said they drop insurers who pay the least or create the most trouble; 29% said they keep all insurers.^2,3 Private insurance paid for 63% of patient visits to ObGyns in 2013.¹

Fewer ObGyns indicated they would see Medicare and Medicaid patients. In 2013, 20% of self-employed and 5% of employed ObGyns said that they plan to stop taking new Medicare or Medicaid patients. More employed (72%) than self-employed (46%) ObGyns reported that they would continue seeing new and current Medicare and Medicaid patients.¹

Related article: Medicare and Medicaid are on the brink of insolvency, and you’re not just a bystander. Robert L. Barbieri, MD (Editorial; October 2011)

In 2012, 15% of ObGyn respondents planned to stop taking new Medicare or Medicaid patients, but 53% of ObGyn respondents said they would continue to see current patients and would take on new Medicare or Medicaid patients.^2,3

TELL US WHAT YOU THINK! Share your thoughts on this article. Send your Letter to the Editor to: [email protected] 

The 2014 Medscape Compensation Report surveyed more than 24,000 physicians in 25 specialties. Five percent of respondents were ObGyns, whose mean income rose slightly to $243,000 in 2013 from $242,000 in 2012, up from $220,000 in 2011.^1–3 The highest ObGyn earners lived in the Great Lakes and North Central regions.¹

Survey findings
Men make more than women. In 2013, male ObGyns reported earning $256,000; female ObGyns reported $229,000 in mean income. However, women felt more satisfied with their salary (47% of women vs 38% of men). Regardless of gender, ObGyns were slightly less happy with their income than all physicians (50% satisfied).¹

Among all female physicians, more were employed than self-employed; the opposite was true for male physicians.⁴ Half of all graduating physicians are now female, and demographics show that 62% of all female physicians are younger than age 45.¹

Practice settings are key to income. Sixty percent of ObGyns indicated they would choose medicine again as a career; 43% would choose their own specialty. However, only 25% of ObGyns would make the same decision about practice setting.¹

In 2013, employed and self-employed ObGyns reported nearly the same mean income: $243,000 versus $246,000, respectively. However, when broken down by specific practice setting, the highest earners were ObGyns who worked for health-care organizations, at $273,000. Additional 2013 mean earnings ranked by work setting were¹:

• multispecialty office-based group practices, $271,000
• single-specialty office-based group practices, $255,000
• hospitals, $228,000
• solo office-based practices, $212,000
• outpatient clinics, $207,000.

In 2013, 49% of employed physicians worked in hospitals or in groups owned by a hospital, while 21% were employed by private groups. Other employment situations included community health centers, corporate laboratories, correction institutions, military bases, and nursing homes.⁴

ACO participation grows. In 2013, 37% of ObGyns either participated in an Accountable Care Organization (ACO) or planned on joining an ACO within the next year.¹ This was an increase from 25% in 2012.^2,3

In the most recent report, 2% chose concierge practices (also known as direct primary care) and 5% opted for cash-only practices.¹ In 2012, only 1% of ObGyns opted for concierge practices, and 3% for cash-only practices.^2,3

Related article: Is private ObGyn practice on its way out? Lucia DiVenere, MA (October 2011)

Employment over private practice? In 2013, physicians were enticed to seek employment by the financial challenges of private practice (38%); not having to be concerned about administrative issues (29%); and working shorter and more regular hours (19%). Other reported benefits of employment were academic opportunities, better life−work balance, more vacation time, and no loss of income during vacation. More than half (53%) of employed physicians who were previously self-employed felt that patient care was superior now that they were employed, and 37% thought it was about the same.⁴

Related article: Mean income for ObGyns increased in 2012. Deborah Reale (News for your Practice; August 2013)

Career satisfaction
ObGyns were close to the bottom among all physicians (48%) when it came to overall career satisfaction, tied with nephrologists, surgeons, and pulmonologists. The most satisfied physicians were dermatologists (65%); the least satisfied were plastic surgeons (45%).¹

What drives you? In 2013, more ObGyns (41%) than all physicians (33%) reported that the most rewarding part of their job was their relationships with patients. Thirty percent of ObGyns chose being good at their jobs; 8% chose making good money; and 2% found nothing rewarding about the job.¹

How much patient time do you spend? The majority (58%) of ObGyns reported spending more than 40 hours per week with patients and 16 minutes or less (66%) per patient.¹ In 2012, 60% of ObGyn respondents reported spending 16 minutes or less per patient.^2,3

Anticipating the effects of the Affordable Care Act
Under the Affordable Care Act (ACA), an organization’s revenue will still be determined largely by the volume generated by ­physicians. The percentage of ObGyns who saw 50 to 124 patients per week increased from 57% in 2012 to 69% in 2013 (TABLE).^1,2

In 2013, 53% of ObGyns still were undecided about health-insurance exchange participation—the same percentage as all survey respondents. Among ObGyns, 30% would participate, and 17% would not participate.¹

Related article: As the Affordable Care Act comes of age, a look behind the headlines. Lucia DiVenere, MA (Practice Management; January 2014)

Almost half (49%) of ObGyns expect their income under the ACA to decrease. About 45% of ObGyns did not foresee any change, and 5% believed their incomes would increase (1% didn’t know) under the ACA. ObGyns also anticipated a higher workload, a decline in quality of patient care and access, and reduced ability to make decisions.¹

Almost one-third of ObGyns dropped poorly paying insurers. In 2013, 29% of ObGyns said they regularly drop insurers who pay poorly, but 46% said they keep their insurers year after year. In 2012, 26% of ObGyns said they drop insurers who pay the least or create the most trouble; 29% said they keep all insurers.^2,3 Private insurance paid for 63% of patient visits to ObGyns in 2013.¹

Fewer ObGyns indicated they would see Medicare and Medicaid patients. In 2013, 20% of self-employed and 5% of employed ObGyns said that they plan to stop taking new Medicare or Medicaid patients. More employed (72%) than self-employed (46%) ObGyns reported that they would continue seeing new and current Medicare and Medicaid patients.¹

Related article: Medicare and Medicaid are on the brink of insolvency, and you’re not just a bystander. Robert L. Barbieri, MD (Editorial; October 2011)

In 2012, 15% of ObGyn respondents planned to stop taking new Medicare or Medicaid patients, but 53% of ObGyn respondents said they would continue to see current patients and would take on new Medicare or Medicaid patients.^2,3

TELL US WHAT YOU THINK! Share your thoughts on this article. Send your Letter to the Editor to: [email protected] 

Blood from an SCD patient

pre-HSCT (top) and post-HSCT

Credit: NIH Molecular and

Clinical Hematology Branch

In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.

Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).

There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.

The team described the regimen and its effects in JAMA.

Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.

The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.

In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.

All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ⁰- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.

Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 10⁶ cells/kg) from HLA-matched siblings.

There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).

As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.

Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.

“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”

Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.

“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”

Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.

“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.

“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”

Blood from an SCD patient

pre-HSCT (top) and post-HSCT

Credit: NIH Molecular and

Clinical Hematology Branch

In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.

Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).

There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.

The team described the regimen and its effects in JAMA.

Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.

The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.

In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.

All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ⁰- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.

Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 10⁶ cells/kg) from HLA-matched siblings.

There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).

As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.

Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.

“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”

Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.

“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”

Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.

“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.

“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”

Blood from an SCD patient

pre-HSCT (top) and post-HSCT

Credit: NIH Molecular and

Clinical Hematology Branch

In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.

Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).

There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.

The team described the regimen and its effects in JAMA.

Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.

The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.

In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.

All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ⁰- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.

Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 10⁶ cells/kg) from HLA-matched siblings.

There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).

As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.

Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.

“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”

Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.

“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”

Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.

“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.

“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”

Yes, we have been here before. Another day, another delay in implementing International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). But, do not expect another postponement. If you are already conducting training sessions to move to the new system come next October, continue to do so. If you have not yet started, now is the time to start. ICD-10-CM is coming to your practice, and it will change everything.

“Why the switch?” you ask?
This change in our diagnostic coding system is required to allow coding for increased specificity in the reporting of diseases and recently recognized conditions as well as to maintain our status with respect to the rest of the world (which has been using ICD-10 for years). It also will be essential to use this coding system with the electronic medical record (EMR), so that meaningful use can be demonstrated more easily. Keep in mind that failure to show meaningful use will lead to penalties in the future. This new system offers improvements over ICD-9-CM in coding primary care encounters, external causes of injury, mental disorders, neoplasms, obstetric complications, and preventive health. It also allows physicians to demonstrate severity of illness in a way that is not possible with ICD-9-CM.

There will be 65,000 more codes than currently exist in ICD-9-CM. No physician will be able to keep all of these code numbers handy, but by making changes to clinician documentation and applying diagnostic coding guidelines correctly within the framework of the new system, the transition will not be onerous. And consider that, while the number of new codes is great, the number of codes used in the typical ObGyn practice will be a fraction of that number.

Related article: As ICD-10 conversion nears, keep these factors in mind to ensure proper reimbursements in 2014. Barbara S. Levy, MD (Audiocast, January 2014)

For ICD-10, documentation is paramount
The most important issue when considering overall coding and practice changes will be recognizing that clinician documentation will be the key to coding the highest level of specificity—and this high level of specificity may be required by most payers when ­deciding to reimburse for treatments rendered. Complete documentation sets the stage for the severity of illness and should in fact result in fewer denials for medical necessity.

For the new process to work efficiently, however, without a lot of delays due to coders and billers having to get more information from clinician offices before sending out claims, your understanding of and “buy-in” to the more clinically specific documentation will be essential.

To explain, under ICD-9-CM coding, simply documenting amenorrhea was acceptable. But when we switch to ICD-10-CM, documentation will need to specify whether the amenorrhea was primary or secondary. This more specific diagnostic coding will make a difference in the health statistics we collect. These data are used for research and to make decisions about allocation of resources—all essential components to excellent quality patient care.

The codes themselves will look different, which may be why some are resisting the change. Instead of the up to five digits required in ICD-9-CM, ICD-10-CM will require up to seven characters. All of the ICD-10-CM codes begin with a letter, may require a placeholder code of “x” as part of the code number, and the seventh character can be either a number or a letter. For instance, with some ICD-10-CM diagnoses reported by ObGyns, a seventh character might require documentation of the encounter as being initial, subsequent, or a sequel; in other cases, that seventh character will be used to identify which fetus has the problem identified by the diagnostic code.

Related article: The economics of surgical gynecology: How we can not only survive, but thrive, in the 21st Century. Q&A with Barbara S. Levy, MD (Practice Management; February 2013)

Your understanding, although not a necessity, is best for all involved
In truth, most clinicians are not familiar with code formats and code numbers within our current ICD-9-CM code set. The expectation that you will suddenly become fluent in ICD-10-CM “code speak” is not realistic. But an understanding of the new codes in relation to documentation expectations will go a long way to making this transition as smooth as possible. For instance, when a patient currently presents reporting vaginal pain that is found to be due to erosion of a previously placed mesh, the code 628.31 (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue) is  reported. But in ICD-10-CM, the documentation would need to include whether this was an initial encounter and the code would become T83.711A (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue, initial encounter).

Smart search. The good news is that most EMR products will have a “smart search” program available for clinicians to pick the correct code based on the search criteria. The bad news is that you will have to be a bit more exact in the search terms you use to make the process easy. For instance, the patient has pelvic pain but you search only on the term “pain.” That term by itself will result in about 100 codes to select from, and the order of the codes may mean that the correct code for pelvic pain is 25 codes down the list. However, if you instead search on the term “pelvic pain,” the one and only code for this condition will be listed and you can simply select it and move on.

Develop cheat sheets. Health-care professionals who are not using an EMR or some sort of computerized code search program will have a harder time, but the use of multiple paper “cheat sheets” for general gynecology, family planning, surgical cases, urology, infertility, obstetrics, etc., will ease that burden. Practice management staff can develop these forms, built on the codes that are currently being reported by the clinician. Place all of the options to replace the older code on the sheet so the correct selection can be made.

For instance, if the provider previously had reported vaginitis with one code, when we move to ICD-10-CM the code would expand to four code selections based on documentation of acute vaginitis, subacute and chronic vaginitis, acute vulvitis, or subacute and chronic vulvitis. If you only had documented vaginitis in the medical record, this gives you the opportunity to refine the documentation to something more specific that supports selection of the correct code and supports the medical need for management options.

Related article: Dos, don’ts, and dollars: Making the switch to an HER. Neil H. Baum, MD; Paul Kepper, MS. (Practice Management; November 2013)

Take advantage of the extra time
Now that we have a delay in the rollout, take this time to critically examine your documentation styles, and practice selecting ICD-10-CM codes before it counts toward payment or nonpayment of a claim. When the time comes, your practice will be fluent in the new system and there will be no delays in getting claims out the door or payment due to incorrect diagnostic coding. In other words, practice makes perfect.

In fact, some ObGyn practices that were ready for the new system have decided to switch to ICD-10-CM coding as of October 1, 2014. They will code each encounter by reporting both the ICD-9-CM code and the ICD-10-CM code on the revised CMS claim form or electronic billing format that permits dual diagnostic coding. This type of experience will ensure that all physicians and other health-care professionals in the practice have ample opportunity to improve their documentation and make any adjustments before the 2015 deadline.

Related article: The 2014 CPT and Medicare code changes affecting ObGyn practice. Melanie Witt, RN, CPC, COBGC, MA (Reimbursement Adviser; January 2014)

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

Yes, we have been here before. Another day, another delay in implementing International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). But, do not expect another postponement. If you are already conducting training sessions to move to the new system come next October, continue to do so. If you have not yet started, now is the time to start. ICD-10-CM is coming to your practice, and it will change everything.

“Why the switch?” you ask?
This change in our diagnostic coding system is required to allow coding for increased specificity in the reporting of diseases and recently recognized conditions as well as to maintain our status with respect to the rest of the world (which has been using ICD-10 for years). It also will be essential to use this coding system with the electronic medical record (EMR), so that meaningful use can be demonstrated more easily. Keep in mind that failure to show meaningful use will lead to penalties in the future. This new system offers improvements over ICD-9-CM in coding primary care encounters, external causes of injury, mental disorders, neoplasms, obstetric complications, and preventive health. It also allows physicians to demonstrate severity of illness in a way that is not possible with ICD-9-CM.

There will be 65,000 more codes than currently exist in ICD-9-CM. No physician will be able to keep all of these code numbers handy, but by making changes to clinician documentation and applying diagnostic coding guidelines correctly within the framework of the new system, the transition will not be onerous. And consider that, while the number of new codes is great, the number of codes used in the typical ObGyn practice will be a fraction of that number.

Related article: As ICD-10 conversion nears, keep these factors in mind to ensure proper reimbursements in 2014. Barbara S. Levy, MD (Audiocast, January 2014)

For ICD-10, documentation is paramount
The most important issue when considering overall coding and practice changes will be recognizing that clinician documentation will be the key to coding the highest level of specificity—and this high level of specificity may be required by most payers when ­deciding to reimburse for treatments rendered. Complete documentation sets the stage for the severity of illness and should in fact result in fewer denials for medical necessity.

For the new process to work efficiently, however, without a lot of delays due to coders and billers having to get more information from clinician offices before sending out claims, your understanding of and “buy-in” to the more clinically specific documentation will be essential.

To explain, under ICD-9-CM coding, simply documenting amenorrhea was acceptable. But when we switch to ICD-10-CM, documentation will need to specify whether the amenorrhea was primary or secondary. This more specific diagnostic coding will make a difference in the health statistics we collect. These data are used for research and to make decisions about allocation of resources—all essential components to excellent quality patient care.

The codes themselves will look different, which may be why some are resisting the change. Instead of the up to five digits required in ICD-9-CM, ICD-10-CM will require up to seven characters. All of the ICD-10-CM codes begin with a letter, may require a placeholder code of “x” as part of the code number, and the seventh character can be either a number or a letter. For instance, with some ICD-10-CM diagnoses reported by ObGyns, a seventh character might require documentation of the encounter as being initial, subsequent, or a sequel; in other cases, that seventh character will be used to identify which fetus has the problem identified by the diagnostic code.

Related article: The economics of surgical gynecology: How we can not only survive, but thrive, in the 21st Century. Q&A with Barbara S. Levy, MD (Practice Management; February 2013)

Your understanding, although not a necessity, is best for all involved
In truth, most clinicians are not familiar with code formats and code numbers within our current ICD-9-CM code set. The expectation that you will suddenly become fluent in ICD-10-CM “code speak” is not realistic. But an understanding of the new codes in relation to documentation expectations will go a long way to making this transition as smooth as possible. For instance, when a patient currently presents reporting vaginal pain that is found to be due to erosion of a previously placed mesh, the code 628.31 (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue) is  reported. But in ICD-10-CM, the documentation would need to include whether this was an initial encounter and the code would become T83.711A (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue, initial encounter).

Smart search. The good news is that most EMR products will have a “smart search” program available for clinicians to pick the correct code based on the search criteria. The bad news is that you will have to be a bit more exact in the search terms you use to make the process easy. For instance, the patient has pelvic pain but you search only on the term “pain.” That term by itself will result in about 100 codes to select from, and the order of the codes may mean that the correct code for pelvic pain is 25 codes down the list. However, if you instead search on the term “pelvic pain,” the one and only code for this condition will be listed and you can simply select it and move on.

Develop cheat sheets. Health-care professionals who are not using an EMR or some sort of computerized code search program will have a harder time, but the use of multiple paper “cheat sheets” for general gynecology, family planning, surgical cases, urology, infertility, obstetrics, etc., will ease that burden. Practice management staff can develop these forms, built on the codes that are currently being reported by the clinician. Place all of the options to replace the older code on the sheet so the correct selection can be made.

For instance, if the provider previously had reported vaginitis with one code, when we move to ICD-10-CM the code would expand to four code selections based on documentation of acute vaginitis, subacute and chronic vaginitis, acute vulvitis, or subacute and chronic vulvitis. If you only had documented vaginitis in the medical record, this gives you the opportunity to refine the documentation to something more specific that supports selection of the correct code and supports the medical need for management options.

Related article: Dos, don’ts, and dollars: Making the switch to an HER. Neil H. Baum, MD; Paul Kepper, MS. (Practice Management; November 2013)

Take advantage of the extra time
Now that we have a delay in the rollout, take this time to critically examine your documentation styles, and practice selecting ICD-10-CM codes before it counts toward payment or nonpayment of a claim. When the time comes, your practice will be fluent in the new system and there will be no delays in getting claims out the door or payment due to incorrect diagnostic coding. In other words, practice makes perfect.

In fact, some ObGyn practices that were ready for the new system have decided to switch to ICD-10-CM coding as of October 1, 2014. They will code each encounter by reporting both the ICD-9-CM code and the ICD-10-CM code on the revised CMS claim form or electronic billing format that permits dual diagnostic coding. This type of experience will ensure that all physicians and other health-care professionals in the practice have ample opportunity to improve their documentation and make any adjustments before the 2015 deadline.

Related article: The 2014 CPT and Medicare code changes affecting ObGyn practice. Melanie Witt, RN, CPC, COBGC, MA (Reimbursement Adviser; January 2014)

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

Yes, we have been here before. Another day, another delay in implementing International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). But, do not expect another postponement. If you are already conducting training sessions to move to the new system come next October, continue to do so. If you have not yet started, now is the time to start. ICD-10-CM is coming to your practice, and it will change everything.

“Why the switch?” you ask?
This change in our diagnostic coding system is required to allow coding for increased specificity in the reporting of diseases and recently recognized conditions as well as to maintain our status with respect to the rest of the world (which has been using ICD-10 for years). It also will be essential to use this coding system with the electronic medical record (EMR), so that meaningful use can be demonstrated more easily. Keep in mind that failure to show meaningful use will lead to penalties in the future. This new system offers improvements over ICD-9-CM in coding primary care encounters, external causes of injury, mental disorders, neoplasms, obstetric complications, and preventive health. It also allows physicians to demonstrate severity of illness in a way that is not possible with ICD-9-CM.

There will be 65,000 more codes than currently exist in ICD-9-CM. No physician will be able to keep all of these code numbers handy, but by making changes to clinician documentation and applying diagnostic coding guidelines correctly within the framework of the new system, the transition will not be onerous. And consider that, while the number of new codes is great, the number of codes used in the typical ObGyn practice will be a fraction of that number.

Related article: As ICD-10 conversion nears, keep these factors in mind to ensure proper reimbursements in 2014. Barbara S. Levy, MD (Audiocast, January 2014)

For ICD-10, documentation is paramount
The most important issue when considering overall coding and practice changes will be recognizing that clinician documentation will be the key to coding the highest level of specificity—and this high level of specificity may be required by most payers when ­deciding to reimburse for treatments rendered. Complete documentation sets the stage for the severity of illness and should in fact result in fewer denials for medical necessity.

For the new process to work efficiently, however, without a lot of delays due to coders and billers having to get more information from clinician offices before sending out claims, your understanding of and “buy-in” to the more clinically specific documentation will be essential.

To explain, under ICD-9-CM coding, simply documenting amenorrhea was acceptable. But when we switch to ICD-10-CM, documentation will need to specify whether the amenorrhea was primary or secondary. This more specific diagnostic coding will make a difference in the health statistics we collect. These data are used for research and to make decisions about allocation of resources—all essential components to excellent quality patient care.

The codes themselves will look different, which may be why some are resisting the change. Instead of the up to five digits required in ICD-9-CM, ICD-10-CM will require up to seven characters. All of the ICD-10-CM codes begin with a letter, may require a placeholder code of “x” as part of the code number, and the seventh character can be either a number or a letter. For instance, with some ICD-10-CM diagnoses reported by ObGyns, a seventh character might require documentation of the encounter as being initial, subsequent, or a sequel; in other cases, that seventh character will be used to identify which fetus has the problem identified by the diagnostic code.

Related article: The economics of surgical gynecology: How we can not only survive, but thrive, in the 21st Century. Q&A with Barbara S. Levy, MD (Practice Management; February 2013)

Your understanding, although not a necessity, is best for all involved
In truth, most clinicians are not familiar with code formats and code numbers within our current ICD-9-CM code set. The expectation that you will suddenly become fluent in ICD-10-CM “code speak” is not realistic. But an understanding of the new codes in relation to documentation expectations will go a long way to making this transition as smooth as possible. For instance, when a patient currently presents reporting vaginal pain that is found to be due to erosion of a previously placed mesh, the code 628.31 (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue) is  reported. But in ICD-10-CM, the documentation would need to include whether this was an initial encounter and the code would become T83.711A (Erosion of implanted vaginal mesh and other prosthetic materials to surrounding organ or tissue, initial encounter).

Smart search. The good news is that most EMR products will have a “smart search” program available for clinicians to pick the correct code based on the search criteria. The bad news is that you will have to be a bit more exact in the search terms you use to make the process easy. For instance, the patient has pelvic pain but you search only on the term “pain.” That term by itself will result in about 100 codes to select from, and the order of the codes may mean that the correct code for pelvic pain is 25 codes down the list. However, if you instead search on the term “pelvic pain,” the one and only code for this condition will be listed and you can simply select it and move on.

Develop cheat sheets. Health-care professionals who are not using an EMR or some sort of computerized code search program will have a harder time, but the use of multiple paper “cheat sheets” for general gynecology, family planning, surgical cases, urology, infertility, obstetrics, etc., will ease that burden. Practice management staff can develop these forms, built on the codes that are currently being reported by the clinician. Place all of the options to replace the older code on the sheet so the correct selection can be made.

For instance, if the provider previously had reported vaginitis with one code, when we move to ICD-10-CM the code would expand to four code selections based on documentation of acute vaginitis, subacute and chronic vaginitis, acute vulvitis, or subacute and chronic vulvitis. If you only had documented vaginitis in the medical record, this gives you the opportunity to refine the documentation to something more specific that supports selection of the correct code and supports the medical need for management options.

Related article: Dos, don’ts, and dollars: Making the switch to an HER. Neil H. Baum, MD; Paul Kepper, MS. (Practice Management; November 2013)

Take advantage of the extra time
Now that we have a delay in the rollout, take this time to critically examine your documentation styles, and practice selecting ICD-10-CM codes before it counts toward payment or nonpayment of a claim. When the time comes, your practice will be fluent in the new system and there will be no delays in getting claims out the door or payment due to incorrect diagnostic coding. In other words, practice makes perfect.

In fact, some ObGyn practices that were ready for the new system have decided to switch to ICD-10-CM coding as of October 1, 2014. They will code each encounter by reporting both the ICD-9-CM code and the ICD-10-CM code on the revised CMS claim form or electronic billing format that permits dual diagnostic coding. This type of experience will ensure that all physicians and other health-care professionals in the practice have ample opportunity to improve their documentation and make any adjustments before the 2015 deadline.

Related article: The 2014 CPT and Medicare code changes affecting ObGyn practice. Melanie Witt, RN, CPC, COBGC, MA (Reimbursement Adviser; January 2014)

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The alleged STAP cells

Credit: Haruko Obokata

The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.

In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.

Not long after the papers were published, however, members of the scientific community began to question the validity of the research.

They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.

In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.

But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.

Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.

As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.

Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research.

The alleged STAP cells

Credit: Haruko Obokata

The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.

In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.

Not long after the papers were published, however, members of the scientific community began to question the validity of the research.

They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.

In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.

But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.

Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.

As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.

Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research.

The alleged STAP cells

Credit: Haruko Obokata

The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.

In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.

Not long after the papers were published, however, members of the scientific community began to question the validity of the research.

They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.

In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.

But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.

Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.

As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.

Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research.

Syringe

Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.

The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.

The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.

However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.

To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.

Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.

Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:

Lot #       Description                                NDC                    Expiration

201125    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2014

201126    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Nov. 2014

201127    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Dec. 2014

201228    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    June 2015

201229    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    July 2015

201230    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2015

Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.

Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.

Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Syringe

Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.

The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.

The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.

However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.

To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.

Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.

Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:

Lot #       Description                                NDC                    Expiration

201125    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2014

201126    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Nov. 2014

201127    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Dec. 2014

201228    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    June 2015

201229    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    July 2015

201230    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2015

Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.

Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.

Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Syringe

Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.

The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.

The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.

However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.

To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.

Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.

Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:

Lot #       Description                                NDC                    Expiration

201125    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2014

201126    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Nov. 2014

201127    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Dec. 2014

201228    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    June 2015

201229    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    July 2015

201230    COUMADIN LINJ 5MG (6VL) US    0590-0324-35    Sept. 2015

Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.

Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.

Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).

The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).

According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.

Trial results

Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.

“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”

To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).

The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.

Safety

Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.

“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.

The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.

The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.

Efficacy

The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.

An exploratory endpoint was minimal residual disease (MRD) response (<10^-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.

In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.

Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.

The median relapse-free survival was 5.9 months.

“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”

“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”

Highlights from The Hospitalist this month include hospitalist reactions to the once-again delayed implementation of the coding classification system ICD-10. Robert Tennant, senior policy advisor at Medical Group Management Association, shares his organization’s perspective on the postponement. Dr. Amy Boutwell, a hospitalist at Newton-Wellesley Hospital and president of Collaborative Healthcare Strategies, discusses Medicare’s new hospital discharge rules and the opportunity they hold for hospitalists. Elsewhere in this issue, we have an update on SHM’s Leadership Academy scheduled for November 3–6 in Honolulu, Hawaii, and the latest in clinical research, including a review of best practices for end-of-life care and when to suspect Kawasaki disease in infants.

Click here to listen to the July highlights Podcast.

Highlights from The Hospitalist this month include hospitalist reactions to the once-again delayed implementation of the coding classification system ICD-10. Robert Tennant, senior policy advisor at Medical Group Management Association, shares his organization’s perspective on the postponement. Dr. Amy Boutwell, a hospitalist at Newton-Wellesley Hospital and president of Collaborative Healthcare Strategies, discusses Medicare’s new hospital discharge rules and the opportunity they hold for hospitalists. Elsewhere in this issue, we have an update on SHM’s Leadership Academy scheduled for November 3–6 in Honolulu, Hawaii, and the latest in clinical research, including a review of best practices for end-of-life care and when to suspect Kawasaki disease in infants.

Click here to listen to the July highlights Podcast.

Highlights from The Hospitalist this month include hospitalist reactions to the once-again delayed implementation of the coding classification system ICD-10. Robert Tennant, senior policy advisor at Medical Group Management Association, shares his organization’s perspective on the postponement. Dr. Amy Boutwell, a hospitalist at Newton-Wellesley Hospital and president of Collaborative Healthcare Strategies, discusses Medicare’s new hospital discharge rules and the opportunity they hold for hospitalists. Elsewhere in this issue, we have an update on SHM’s Leadership Academy scheduled for November 3–6 in Honolulu, Hawaii, and the latest in clinical research, including a review of best practices for end-of-life care and when to suspect Kawasaki disease in infants.

Click here to listen to the July highlights Podcast.

Dr. George

Dr. George is president of the central business unit for Brentwood, Tenn.-based Cogent Healthcare, the largest privately held hospital medicine company in the United States. She oversees multiple HM programs in the north central region of the U.S. Previously, she was medical director of hospitalist services for OSF St. Anthony Medical Center in Rockford, Ill.

Undergraduate education: Dr. George went straight from high school to a direct medical program and earned her MBA at the University of Tennessee in Knoxville.

Medical school: JJM Medical College in India.

Notable: She began her MBA at the University of Tennessee when she was 34 weeks pregnant, proving wrong the professors who thought she would not be able to finish the program. Actively involved in the SHM Leadership, RIV, and Annual Meeting committees, Dr. George is a frequent annual meeting presenter on women’s workforce issues.

FYI: Dr. George keeps busy with her two children, ages 15 and 9, supporting them in such extra-curricular pursuits as marching band, music lessons, tae kwon do, and chess. In her downtime, she likes to relax by watching movies and spending time with friends.

Quotable: “It is a tremendous honor to be a Fellow in Hospital Medicine; it demonstrates clearly to everyone my accomplishments as a hospitalist, and I am proud to have been a member of the inaugural class of fellows.”

Dr. George

Dr. George is president of the central business unit for Brentwood, Tenn.-based Cogent Healthcare, the largest privately held hospital medicine company in the United States. She oversees multiple HM programs in the north central region of the U.S. Previously, she was medical director of hospitalist services for OSF St. Anthony Medical Center in Rockford, Ill.

Undergraduate education: Dr. George went straight from high school to a direct medical program and earned her MBA at the University of Tennessee in Knoxville.

Medical school: JJM Medical College in India.

Notable: She began her MBA at the University of Tennessee when she was 34 weeks pregnant, proving wrong the professors who thought she would not be able to finish the program. Actively involved in the SHM Leadership, RIV, and Annual Meeting committees, Dr. George is a frequent annual meeting presenter on women’s workforce issues.

FYI: Dr. George keeps busy with her two children, ages 15 and 9, supporting them in such extra-curricular pursuits as marching band, music lessons, tae kwon do, and chess. In her downtime, she likes to relax by watching movies and spending time with friends.

Quotable: “It is a tremendous honor to be a Fellow in Hospital Medicine; it demonstrates clearly to everyone my accomplishments as a hospitalist, and I am proud to have been a member of the inaugural class of fellows.”

Dr. George

Dr. George is president of the central business unit for Brentwood, Tenn.-based Cogent Healthcare, the largest privately held hospital medicine company in the United States. She oversees multiple HM programs in the north central region of the U.S. Previously, she was medical director of hospitalist services for OSF St. Anthony Medical Center in Rockford, Ill.

Undergraduate education: Dr. George went straight from high school to a direct medical program and earned her MBA at the University of Tennessee in Knoxville.

Medical school: JJM Medical College in India.

Notable: She began her MBA at the University of Tennessee when she was 34 weeks pregnant, proving wrong the professors who thought she would not be able to finish the program. Actively involved in the SHM Leadership, RIV, and Annual Meeting committees, Dr. George is a frequent annual meeting presenter on women’s workforce issues.

FYI: Dr. George keeps busy with her two children, ages 15 and 9, supporting them in such extra-curricular pursuits as marching band, music lessons, tae kwon do, and chess. In her downtime, she likes to relax by watching movies and spending time with friends.

Quotable: “It is a tremendous honor to be a Fellow in Hospital Medicine; it demonstrates clearly to everyone my accomplishments as a hospitalist, and I am proud to have been a member of the inaugural class of fellows.”