Program Written Summary NEJM Journal Watch Volume 27, Issue 05 March 1, 2016 Digital Media $24.99 Audio CD $27.99 The following is a list of articles summarized on this issue of NEJM Journal Watch Audio General Medicine. Journal Watch Audio Program Info Accreditation Info Cultural & Linguistic Competency Resources GUIDELINE WATCH: 2016 U.S. ADULT IMMUNIZATION SCHEDULE The Advisory Committee on Immunization Practices has issued its 2016 recommendations for immunizing patients 19 or older. This years schedule incorporates a few new vaccines and changes in the rules for administering some older ones. Details appear in the February2 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M15-3005 ). Immunization tables and extensive footnotes are available on the website of the Centers for Disease Control and Prevention ( www. cdc .gov /vaccines/schedules/downloads/adult/adult-combined-schedule.pdf ), free of charge. Whatschanged? Two meningococcal vaccines that offer protection against group B meningococcal disease have been added to the schedule. Group B meningococcal vaccine is recommended for use in high-risk patients (those who were exposed in a type B outbreak or those with functional or anatomic asplenia). Either of the group B vaccines can be used, but they are not interchangeable (which means that patients must receive the same vaccine for all of their doses). A 9-valent human papillomavirus vaccine has been added to the schedule, joining bivalent and quadrivalent vaccines as an option for immunizing young adults between the ages of 19 and 26. Any of the vaccines can be used in women; only the 9-valent and the quadrivalent vaccines can be used in men. The sequence of 13-valent and 23-valent pneumococcal vaccination is complicated and depends on age and underlying medical conditions. This year, a longer recommended interval between 13-valent and 23-valent vaccination makes the nomogram a little easier to remember: In immunocompetent adults, at least a year should separate the two vaccines, no matter which is administered first; in immunocompromised adults, 23-valent vaccination should follow 13-valent vaccination by at least 2months, and 13-valent vaccination should follow 23-valent vaccination by at least a year. Adult immunizations are increasingly complex, and these guidelines do not help clinicians decide among specific vaccines when several options are available. But they do continue to offer useful and user-friendly graphics to outline which vaccines are recommended, optional, and contraindicated for adults with a range of chronic medical conditions. ENCOURAGING PROGRESS TOWARD IMMUNIZATION AGAINST EBOLA Three different species of Ebolavirus have caused repeated disease outbreaks in Africa. Monoclonal antibodies against the species that caused the outbreak in 2014 through 2015 might be beneficial against that species, but not against the others. In fact, the three species have enough antigenic diversity that developing a vaccine thats effective against all of them has been considered to be unlikely. In a multicenter study in the January28 issue of Cell ( http:// dx.doi.org /10.1016/ j. cell.2015.12.022 ), researchers in the United States report that they have identified two monoclonal antibodies that are produced naturally in humans infected with Ebolavirus ; in vitro, these antibodies neutralize all three species by targeting parts of the viral surface proteins that are conserved. In mice and guinea pigs, a single treatment with the antibodies, given within a day of experimental infection with each of the species of Ebolavirus , provided complete protection. Broadly neutralizing antibodies against conserved parts of viral surface proteins are proving to be effective in treating viruses that have remarkable antigenic diversity most importantly, HIV and influenza viruses ( www.jwatch.org /na34054 ). The same methods might work for Ebolavirus . Whether this form of passive immunization will be effective to treat human infection with Ebolavirus remains to be seen; if so, viral vectors carrying the genes that make the broadly neutralizing antibodies might be used to actively immunize people to prevent infection in areas where Ebolaviruses are endemic ( www.jwatch.org /jw201201310000005 ). OPT-IN AND OPT-OUT HIV TESTING, REVISITED In many patients, the prospect of HIV testing elicits emotional and often irrational reactions that can seriously interfere with their medical care. For years, researchers have tried to figure out how best to deflect these emotions and increase testing rates, but studies have yielded wildly inconsistent results. In a study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h6895 ), researchers tried to remove all confounders by evaluating three different HIV testing strategies among patients who visited a single emergency department in San Francisco between 2011 and 2013. All eligible patients were informed by study personnel, Were offering routine HIV tests to all of our patients. Its a rapid test with results available in one to two hours . To divert attention from the issue of HIV testing, the patients were also offered a generic questionnaire to complete about improving emergency care. The nearly 5000 patients who agreed to participate in the study were then randomized to one of three HIV testing strategies, namely: Opt-in ( You can let me, your nurse, or your doctor know if youd like a test today .) Active choice ( Would you like a test today ?) Opt-out ( You will be tested unless you decline .) The overall HIV test acceptance rate was 50%: 40% in the opt-in group, 50% in the active-choice group, and nearly 70% in the opt-out group. Opt-out testing had significantly higher acceptance rates than opt-in testing among patients in all HIV risk categories (and also for each of the researchers who offered the testing). The results were similar after adjusting for the patients reasons for visiting the emergency department in the first place. The Centers for Disease Control and Prevention have recommended the opt-out strategy for HIV testing since 2006, but most hospitals have yet to adopt it. This study clearly supports its use for increasing HIV testing rates, at least in settings where HIV and its complications are quite well known. Arguably, these results might need to be reconfirmed in places in which patients are less familiar with HIV, where a more educational and interactive strategy might be preferable. CLARITHROMYCIN IS ASSOCIATED WITH EXCESS CV RISK Its been suggested that clarithromycin is associated with an excess cardiovascular risk, but whether this risk is short-term or long-term is unclear. In a population-based study on the website of The BMJ ( http://bmj .com /content/352/bm j. h6926 ), researchers in Hong Kong compared cardiovascular outcomes among 100,000 adults who got oral clarithromycin with the outcomes among 200,000 adults who got oral amoxicillin (which is not associated with cardiovascular risk). The patients were matched by age, sex, and calendar year of antibiotic use. Propensity-adjusted analyses showed that, with current use, the risk for myocardial infarction was nearly 4 times higher and the risk for arrhythmia was 2 times higher among the clarithromycin users than among the amoxicillin users. All-cause and cardiac-related mortality was roughly doubled among the current clarithromycin users vs . the current amoxicillin users. These excess risks disappeared after 2weeks of clarithromycin use (after completing the antibiotic course). The risk for stroke was not elevated in the clarithromycin users at any time. Subgroup analyses showed that the risk with clarithromycin use was highest among the patients older than 75 and for those with hypertension-associated disease or diabetes. In this study, only current clarithromycin use was associated with an excess risk for myocardial infarction, cardiac arrhythmia, and death. Case reports have linked clarithromycin with QT prolongation and arrhythmia a possible mechanism for the excess cardiovascular risk. Overall, clinicians should exercise caution when considering clarithromycin, especially in patients with, or at high risk for, cardiovascular disease. IBUPROFEN FOR INITIAL TREATMENTOF WOMEN WITH UNCOMPLICATEDDYSURIA Usually, women with suspected uncomplicated urinary tract infections are treated with antibiotics, even though this condition is often self-limited. In fact, although its been shown that placebo or delayed antibiotics (compared with immediate antibiotics) prolonged the resolution of symptoms and bacterial clearance, no serious UTI-associated complications were seen in any of the treatment groups ( www.jwatch.org /id201003100000001 ). In a study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h6544 ), researchers in Germany asked whether managing the symptoms of uncomplicated UTI with ibuprofen could safely lower the rate of antibiotic prescriptions. The researchers randomized 500 women between the ages of 18 and 65 with suspected UTIs that were uncomplicated (defined as dysuria or frequency/urgency without upper-tract signs) to either 3 g /day of oral fosfomycin (trade name: Monurol) or 400mg of ibuprofen 3 times /day for 3days (plus placebo dummies). Urine cultures were positive in three quarters of the patients. In the ibuprofen group, a third of the patients ultimately got antibiotics for symptoms that persisted or worsened during a month of follow-up. In the fosfomycin group, all of the patients got the antibiotic initially, and 14% got second courses for UTIs during follow-up. The average durations of symptoms were significantly longer in the ibuprofen group than in the fosfomycin group (5.6 vs . 4.6days), but UTI relapses and complications (like recurrent UTIs, early relapse, a worsening of symptoms, or pyelonephritis) were similar in the two groups. Notably, a recurrence of UTI after week 2 was significantly less common in the ibuprofen group than in the fosfomycin group (6% vs . 11%). Managing suspected uncomplicated urinary tract infections with ibuprofen rather than fosfomycin lowered antibiotic use by two thirds, but was associated with a greater symptom burden. Although UTI relapses and complications were similar in the two groups, the study was not powered to detect important clinical differences. This study is not likely to persuade clinicians and patients at least in the United States to withhold antibiotic therapy when women present with classic symptoms suggesting lower-tract urinary infection. Even so, the findings could support withholding antibiotics and providing analgesia (not necessarily ibuprofen, but perhaps the urinary analgesic phenazopyridine) while awaiting culture results in selected cases. Examples might include women with a known intolerance or contraindications to the usual antibiotic choices and women with mild or atypical symptoms. TWO BEHAVIORAL INTERVENTIONS LESSEN INAPPROPRIATE ANTIBIOTICPRESCRIBING Efforts to curtail inappropriate and excessive antibiotic use, especially for acute respiratory infections, have been only modestly successful. In a study in the February9 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.0275 ), researchers examined three interventions designed to curb inappropriate prescribing, namely: An electronic medical recordbased prompt to consider nonantibiotic alternatives when acute respiratory infection was diagnosed An EMR-based prompt to enter a free-text justification for prescribing antibiotics Monthly emails to clinicians in which their prescribing performance was compared with that of so-called top performers (meaning clinicians with the lowest inappropriate prescribing rates) The researchers randomized 250 clinicians with an average age of 48 in 50 primary care practices to one of the three interventions, combinations of them, or no intervention. Prescribing rates for antibiotic-inappropriate acute respiratory infections were evaluated for 30,000 patient visits half during an 18-month baseline run-in period and half during the 18-month intervention period. During the intervention, inappropriate antibiotic prescribing dropped from 20% to 10% in the control practices, from 20% to 6% with suggested alternatives, from 20% to 5% with the justification requirement, and from 20% to 4% with peer comparison. The declines with the justification requirement and with peer comparison, compared with no intervention, were significant. In only one group the combined justification plus peer-comparison group the rate of return visits for possible bacterial infection exceeded that of the control group. The baseline rate of inappropriate prescribing in this study was already low compared with national data, and inappropriate prescribing declined further during the 18-month run-in, so these results might not be generalizable to other physician groups. Even so, interventions that focus on physicians professional pride and performance have promise and should be easily implemented in any practice that uses an electronic medical record ( http:// dx.doi.org /10.1001/jama.2016.0430 ). DUPILUMAB SHOWS PROMISE FOR MANAGING NASAL POLYPOSIS Chronic sinusitis can be categorized on the presence or the absence of nasal polyps. A systematic review from 2015 supported the daily use of saline irrigation plus topical intranasal corticosteroids as first-line therapy for all patients with chronic sinusitis, with short courses of systemic corticosteroids or doxycycline or daily leukotriene-antagonist therapy for patients with nasal polyps ( www.jwatch.org /na38917 ). Despite maximal medical therapy, many patients still suffer from substantial decreases in quality of life; although sinus surgery is helpful, it often does not provide complete relief, and polyps recur in about half of surgery patients. Because nasal polyposis is an eosinophilic disease associated with TH 2 -cytokines, researchers examined whether dupilumab, which is a monoclonal antibody against the interleukin-4 receptor, would be helpful. In a study in the February2 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.19330 ), 60 adults with chronic sinusitis and nasal polyposis got daily intranasal mometasone and were randomized to weekly subcutaneous injections of either dupilumab or placebo. At 4months, endoscopic nasal polyp scores, nasal symptoms, and quality-of-life scores had all improved significantly more in the dupilumab group than in the placebo group. Dupilumab is effective in atopic dermatitis and severe asthma, and this small proof-of-concept study shows that its also a promising agent for nasal polyposis. Its not yet approved by the Food and Drug Administration, and a big drawback will be its high price. Omalizumab (trade name: Xolair) and mepolizumab (trade name: Nucala), while FDA-approved for asthma, are also effective in patients with nasal polyps; these two drugs have high price tags aswell. This study was industry-funded. EXCESS INFECTION RISK WITH CERTAIN BIOLOGIC THERAPIES FOR RA Infection is the most common serious adverse event associated with biologic agents that are used to treat patients with rheumatoid arthritis. But these agents vary in their mechanisms of action on the immune system, and whether they confer different risks for infection is unclear. Using Medicare claims data, researchers retrospectively evaluated 30,000 patients with rheumatoid arthritis who got tumor necrosis factor inhibitors (namely, etanercept [trade name: Enbrel], infliximab [trade name: Remicade], adalimumab [trade name: Humira], certolizumab [trade name: Cimzia], or golimumab [trade name: Simponi]) or drugs with other mechanisms of action (like abatacept [trade name: Orencia], rituximab [trade name: Rituxan], or tocilizumab [trade name: Actemra]). Findings appear in the Januaryissue of Arthritis & Rheumatology ( http:// dx.doi.org /10.1002/art.39399 ). To ensure that patients in different drug groups were relatively comparable, the study included only the patients who were taking their second biologic agent (because non-TNF drugs are often begun only after treatment with a TNF inhibitor fails). Abatacept was the most commonly prescribed second biologic. During a year of follow-up, there were 2500 infections that needed hospitalization. Compared with abatacept (used as the reference standard), infections were significantly more likely to occur with infliximab, rituximab, and etanercept, after adjusting for infection risk scores and other confounders. This study implies that the risk for infection with a second biologic (after treatment failure with an initial biologic) is somewhat higher with infliximab, rituximab, and etanercept than with other alternatives. Because the most commonly used initial biologic agents are tumor necrosis factor inhibitors, an agent like abatacept with both a different mechanism of action and, possibly, a lower risk for serious infection might be a good choice for a second-line agent. REMARKABLE VARIABILITY IN POSTPRANDIAL BLOOD SUGAR SURGE There seems to be surprising variability in postprandial blood sugar levels following the same meal. In a study in the November19, 2015 issue of Cell ( http:// dx.doi.org /10.1016/ j. cell.2015.11.001 ), researchers in Israel explored this interesting phenomenon in 800 patients between the ages of 18 and 70 without diagnosed diabetes; three quarters of the patients were overweight or obese. The duration of the study was one week. The first meal of each day was provided by the study: All of the patients ate the same standardized meal. The patients used a smartphone app to document all additional meals by logging and photographing the food and to record physical activity, sleep, and other lifestyle behaviors. Anthropometric factors were recorded, and standard blood chemistries were performed. Feces were collected from each patient to characterize individual gut microbiomes. All of the patients wore continuous subcutaneous glucose monitors that reported glucose levels every 5minutes throughout the duration of the study (which translated into nearly 2 million measurements for all of the patients). In all, roughly 50,000 food encounters (including between-meal snacks) were studied. Using all of the collected data, the researchers developed an algorithm that accurately predicted the remarkably variable postprandial patterns. This algorithm was tested in a validation cohort of 100 new patients and was found to perform well. Were highlighting this audacious study primarily because it shows that a new kind of clinical research is possible with todays smartphones, constant physiological monitoring devices (namely, electronic skin ), and computers that can perform big data analytics. The researchers confirmation of the already-known variability in postprandial blood sugar trajectories is of only modest interest, and the clinical value of predicting the postprandial sugar trajectory of a patient without diabetes is unclear. ENDOBRONCHIAL COIL PLACEMENT CAN IMPROVE SYMPTOMS IN SEVERE EMPHYSEMA In highly selected patients with emphysema, lung-volumereduction surgery can improve quality of life and lengthen survival ( www.jwatch.org /jw200306030000001 ). To prevent surgical morbidity, researchers have pursued different bronchoscopic strategies for lung-volume reduction (like one-way valves, biologic sealants, and endobronchial coils www.jwatch.org /na39741 ). Although small studies of coils have suggested a benefit, results have not been definitive. In a study in the January12 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.17821 ), researchers in France randomized 100 patients with severe emphysema and marked hyperinflation (an average residual volume of 270% of predicted) to either usual care or bronchoscopic coil placement under general anesthesia (the average duration of the procedure was about an hour). The coil patients got an average of 10 coils per procedure. More coil patients had clinically meaningful improvements in 6-minute walk distance at 6months (36% vs . 18%), but not at a year. Plus, the patients in the coil group had significantly greater improvement from baseline in spirometric measures, dyspnea ratings, and quality-of-life scores at both time points. But the coil patients were more likely to develop pneumonia within a year (18% vs . 4%); about half had minor hemoptysis within a month after their procedures. The average 1-year difference in cost per patient was US$47,908. Currently, endobronchial coils are not approved by the Food and Drug Administration. Although some patients might benefit symptomatically from coil treatment, the short-term costs are quite high. Should coils become available, further study will be needed to define the best candidates for this and other bronchoscopic approaches to lung-volume reduction ( http:// dx.doi.org /10.1001/jama.2015.17714 ). OBESITY HYPOVENTILATION SYNDROME IS ASSOCIATED WITH SERIOUS POST-OP RESPIRATORY COMPLICATIONS Although obstructive sleep apnea is usually recognized, obesity hypoventilation syndrome remains underdiagnosed. Distinguishing between the two disorders is important: Patients with obstructive sleep apnea are treated with continuous positive airway pressure to stent open the upper airway, whereas patients with obesity hypoventilation syndrome require bilevel noninvasive positive pressure to support ventilation. The appropriate perioperative management of these distinct conditions might prevent postoperative complications. Using a single-center database, researchers examined noncardiac surgery patients with a body-mass index greater than 30kg/m 2 , obstructive sleep apnea diagnosed by polysomnography, and hypercapnia identified by arterial blood gas measurement on two occasions. The patients were categorized as having obesity hypoventilation syndrome if pulmonary function tests were available and showed no other lung disease (like chronic obstructive pulmonary disease); 160 patients with definite or probable obesity hypoventilation syndrome were compared with more than 300 patients with obstructive sleep apnea alone. Findings appear in the Januaryissue of Chest ( http:// dx.doi.org /10.1378/chest.14-3216 ). The patients with known or suspected obesity hypoventilation syndrome were significantly more likely than were the patients with obstructive sleep apnea alone to experience postoperative respiratory failure (21% vs . 2%; adjusted odds ratio, 11), to be transferred to the intensive care unit (21% vs . 6%; AOR, 11), and to have longer ICU and hospital lengths of stay. The risks for these complications were associated with the presence of hypercapnia, but not with body-mass index or apnea-hypopnea index. Given the association between obesity hypoventilation syndrome and an elevated risk for serious postoperative complications, looking for hypercapnia in obese preoperative patients with obstructive sleep apnea would be prudent. The researchers recommend preoperative serum bicarbonate assessment, with subsequent arterial carbon dioxide measurement if bicarbonate levels are greater than 27 mEq/L (this cutoff is highly sensitive, although nonspecific, for the syndrome). The prospective identification of obesity hypoventilation syndrome allows for planning perioperative management strategies to minimize complications. TEXT MESSAGING MIGHT IMPROVE MEDICATION ADHERENCE Long-term adherence to medication regimens for chronic disease management is about 50%. There may be improvements in adherence when mobile telephone text messaging is used for reminders and education. In a meta-analysis on the website of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.7667 ), researchers evaluated 16 randomized, controlled trials (including 2700 patients with a median age of 39) that employed text messaging to provide medication reminders for a range of chronic disease (like coronary artery disease, asthma, allergic rhinitis, and epilepsy). Five studies provided personalized messages, eight involved two-way communication, and eight sent daily reminders; the median trial duration was 3months, and adherence was measured mostly by self-report. The pooled analysis showed that text messaging increased the likelihood of adherence (odds ratio, 2.1) compared with usual care. This effect would translate into an absolute increase of about 18 percentage points over a baseline adherence rate of 50%. Subgroup analysis of the type of messaging revealed no differences. Editorialists note ( http:// dx.doi.org /10.1001/jamainternmed.2015.7853 ) several weaknesses of essentially all of the studies included in this meta-analysis: Adherence was measured by self-report, the trials were short, and actual improvements in chronic disease outcomes were not measured. Text messaging technology is intriguing, but it needs more thorough and rigorous evaluation before clinicians integrate it into practice. INTRACEREBRAL HEMORRHAGE WITH THE NEW DIRECT ORALANTICOAGULANTS In randomized trials, the incidence of intracerebral hemorrhage was significantly lower with the direct oral anticoagulants than with warfarin ( www.jwatch.org /na35816 ). But when this bleeding does happen during treatment with the newer agents or warfarin, are the clinical outcomes similar? To find out, researchers in the United Kingdom compared 50 patients who suffered intracerebral hemorrhages while taking warfarin with 11patients who suffered intracerebral hemorrhages while taking direct oral anticoagulants (6 on rivaroxaban [trade name: Xarelto], 3 on dabigatran [trade name: Pradaxa], and 2 on apixaban [trade name: Eliquis]). Patients with major head trauma or known structural reasons for intracerebral hemorrhage were excluded. The average international normalized ratio in the warfarin patients was 2.5. Findings appear in the January26 issue of Neurology ( http:// dx.doi.org /10.1212/WNL.0000000000002310 ). Median intracerebral hemorrhage volume was significantly larger with warfarin than with the direct oral anticoagulants (8.9mL vs . 2.4mL). In analyses adjusted for potentially confounding variables, the warfarin patients had significantly worse functional outcomes at hospital discharge than did the patients taking direct oral anticoagulants. Although this small study needs confirmation, it suggests that intracerebral hemorrhages are smaller and less clinically severe in patients taking direct oral anticoagulants than in patients taking warfarin. Because the frequency of intracerebral hemorrhage is also lower with the newer agents than with warfarin, the overall magnitude of this feared adverse effect taking both frequency and severity into account seems to be more favorable with the newer agents. ACUTE MI CARE STARTING AT AGE 80 Very few clinical trials focus on patients in their 80s and 90s, even though they constitute a growing percentage of patients hospitalized with cardiovascular disease. In an open-label study on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6 736(15)01166-6 ), researchers in Norway randomized 450 patients with an average age of 85 and with nonST-segment-elevation myocardial infarction to either an early invasive strategy (namely, angiography) or conservative therapy. Regarding revascularizations in the invasive group, half got percutaneous coronary interventions and 3% got coronary artery bypass grafting procedures. Median follow-up was 1.5years. The incidence of the primary endpoint which was a composite of MI, the need for urgent revascularization, stroke, and death was significantly lower in the invasive-therapy group than in the conservative-therapy group (41% vs . 61%), as was the incidence of each component of the endpoint. Each group had four patients with major bleeding episodes. The benefit of the invasive approach seemed to diminish with increasing age. The magnitude of benefit in this older population is even larger than in younger patients and should be replicated before the findings are fully accepted. Even so, despite this trials limitations (like a modest size and an open-label design), it shows that invasive therapy need not be withheld simply because of older age ( http:// dx.doi.org /10.1016/ S0140-6736(16)00036-2 ). SURGICAL DECOMPRESSION FOR DEGENERATIVE CERVICAL MYELOPATHY Degenerative cervical myelopathy remains the most common cause of chronic pain, gait difficulty, and falls in older patients. It results from cord compression caused by the degeneration of facet joints, disks, and vertebral bodies, and it can also involve ligamentous changes. Its been suggested that surgery might not be as effective or safe in older patients, perhaps due to a higher burden of preoperative comorbidities and the need for more-complex surgery due to more-severe degenerative changes. In a multicenter, international, prospective study on the website of the Journal of Neurology, Neurosurgery & Psychiatry ( http:// dx.doi.org /10.1136/ jnnp-2015-311074 ), researchers report the results of nearly 500 patients (about a quarter of whom were older than 65) who underwent surgical decompression for degenerative cervical myelopathy. The patients who were 65 or older had more-severe functional impairment from myelopathy, had more medical comorbidities, and were more likely to undergo posterior approachbased decompression. At a follow-up of 2years, younger patients had a higher level of functioning and less disability than older patients, even after adjusting for baseline differences and differences in operative technique. Even so, overall complication rates, surgical safety, and quality-of-life improvements were similar in both of the age groups. The older patients achieved significant improvement in functional status compared with preoperative baseline. This study suggests that, although surgical decompression might not yield the same level of benefit in older patients as it does in younger ones, it should still be considered in older patients, along with physical rehabilitation and medical therapy for symptom control. PLACE MATTERS: OUTCOMES FOR PLANNED OUT-OF-HOSPITAL BIRTHS Recently, the numbers of planned and actual births outside of hospital settings have increased, driven partly by some womens desire to avoid the medicalization of the process. But in studies of outcomes for women with planned home births, disentangling births planned for home (but delivered in hospitals) from those planned for the hospital has proven difficult. In a study in the December31, 2015 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMsa1501738 ), researchers in Oregon capitalized on statewide changes in birth certificate queries to examine outcomes by delivery plan at the onset of labor. Among almost 80,000 low-risk births from 2012 through 2013, 5% were planned as out of hospital; of these, 16% needed hospital transfer after labor began. The rates of perinatal death were 4 deaths per 1000 deliveries planned as out of hospital and 2 deaths per 1000 deliveries planned as in hospital. A planned out-of-hospital birth was associated with lower probabilities of labor induction and cesarean delivery. This observational study provides valuable tools for counseling patients who are considering out-of-hospital births. Although catastrophic pregnancy outcomes are rare, women contemplating out-of-hospital birth are at an elevated risk. Whether clinicians are involved in shared decision-making with patients or are viewing this issue through the lens of population health, the circumstances that make hospital birth unpalatable for many women need to be considered, namely unnecessary interventions, limits on patient- and family-centered options, and a disregard for important cultural norms concerning birth. KEY SCHIZOPHRENIA GENEDISCOVERED During the past 30years, many genetic loci and areas of the genome have been linked to schizophrenia. But because these early studies lacked size and statistical rigor, many putative associations have not been confirmed. That may no longer be the case. In a study in the February11 issue of Nature ( http:// dx.doi.org /10.1038/nature16549 ), researchers analyzed genetic linkage data from nearly 30,000 cases of schizophrenia and more than 35,000 controls in 20 countries and identified the gene for complement component 4 (known as C4) as being of critical importance in schizophrenia. The researchers then conducted biological studies to understand how C4 was involved. Human postmortem brain tissue showed that: 1.C4 protein is localized to synapses. 2.The brains of patients with schizophrenia have an excess production of C4. 3.Different alleles of the C4 gene produce different amounts of C4 protein. 4.Patients with schizophrenia have fewer synapses than do people without schizophrenia. Experiments in mice then showed that higher amounts of C4 lead to an excess pruning of synapses. This remarkable study identifies the complement system (which is a key part of innate immunity) as playing an important role in schizophrenia, by diminishing the number of synapses. It does not explain how the excess production of C4 lowers the number of synapses. We dont know whether schizophrenia might need some external cofactor (like a silent infection of the brain) to evoke C4 production. SHOULD SURGICAL RESIDENCY DUTY-HOUR RESTRICTIONS BE RELAXED? In the United States, residents are required to work no more than 80hours /week , with additional restrictions on the frequency of night calls, shift length, and the time between shifts. These restrictions (compared with unrestricted work hours) are intended to prevent fatigue-related medical errors, but a rigid adherence to duty-hour restrictions could potentially create harms by disrupting the residents ability to provide continuity of care. To examine these tradeoffs, researchers randomized 117 general surgery residency programs either to continue current duty-hour policies or to implement a flexible policy that retained the 80-hour maximum work week, but permitted longer shifts and less time between shifts. Findings appear on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1515724 ). During the 1-year trial, the rate of postoperative death or serious complications among the patients in the participating hospitals was exactly the same 9% in both the standard- and the flexible-policy groups. On structured surveys, the residents in the two groups reported similar levels of well-being and of overall satisfaction with their training. The standard-group residents were more likely than were the flexible-group residents to be dissatisfied with continuity of care and to feel a negative effect of duty-hour restrictions on training and operative experience. But the standard-group residents were also more likely to be satisfied with time available for rest and for friends and family. Reassuringly, allowing more-flexible work hours while preserving a maximum 80-hour work week did not compromise patient safety in this trial. The resident satisfaction survey results were not surprising: Flexibility was perceived to enhance training, at the expense of some negative effect on leisure time. Because patient outcomes were similar, and resident satisfaction captured the expected tradeoffs between standard and flexible policies, these results could be used to support either side of the debate on resident work hours. An editorialist comes down ( http:// dx.doi.org /10.1056/NEJMe1516572 ) on the side of preserving the current standard work-hour policy. DIRECT DEMONSTRATION OF ADVERSEEFFECTS OF NIGHT-SHIFTWORK ON DRIVING We know that drowsy drivers are more likely to have accidents, and drowsy driving is a particular problem for night-shift workers. Drowsy drivers are involved in about 20% of fatal crashes and have a fivefold higher risk for crashes or near-crashes. In a study in the January5 issue of the Proceedings of the National Academy of Sciences of the United States of America ( http:// dx.doi.org /10.1073/pnas.1510383112 ), researchers directly tested driving performance and sleep physiology in 16 night-shift workers who wore head electrodes that measured brain waves, eye movements, and blink duration, while they drove on a special testing track. Each worker was tested under two conditions: After 7hours of sleep and after a night shift. Following the night shifts, the patients drove less well (for example, there was more weaving between lanes), and the problems were evident as soon as they started driving. They were also sleepier, as determined by slow eye movements and blink duration. Near crashes happened in 40% of the tests following a night shift and in none of the tests following 7hours of sleep. About 10 million people in the United States work overnight or on rotating shifts. A third of these people have commutes from work to home of longer than 30minutes. So a substantial fraction of patients and many healthcare workers are at a considerable excess risk for auto accidents. Limiting the length of commutes or finding alternatives to driving are obvious solutions, but are also clearly difficult to achieve practically. FAMILY ASSESSMENTS OF END-OF-LIFE CARE IN CANCERPATIENTS Often, patients with advanced cancer get aggressive end-of-life care. To examine the associations between family satisfaction and aggressiveness of end-of-life care, researchers in the United States conducted a national interview study of the families of 1100 patients who had died from lung or colorectal cancer. Most of the interviewees were spouses or adult children who always or usually accompanied the patients to medical appointments, discussed important medical issues with the patients, and spent every day with the patients in the last week of life. The median time from death to the interview was about 5months. Details appear in the January19 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.18604 ). Most of the family members rated patients end-of-life care as excellent or very good. In adjusted analyses, family members more commonly rated end-of-life care as excellent for the patients who got more than 3days of hospice care vs . 3days or less or no hospice care, for the patients who did not die in the hospital vs . those who did, and for the patients who were not in intensive care units in the last month of life vs . those who were. But family members reported that patients end-of-life preferences had been followed about 80% of the time, regardless of the aggressiveness of their end-of-life care. The high frequency of excellent or very good ratings for end-of-life care is somewhat surprising, but reassuring, although we dont know how the patients themselves perceived their care. Because higher ratings by families correlated with less-intensive care, some treating clinicians likely failed to provide adequate guidance on deescalating care near the end of life. Even so, other influences like contemporary culture, family psychodynamics, and the often-fragmented healthcare system also shape the expectations and the satisfaction of dying patients and their families.
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