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NEJM Journal Watch

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Course Description

After hearing and assimilating this program, the listener will be better able to: ( 1 ) Increase his/her basic knowledge of important advances in medicine; ( 2 ) Identify a broad range of clinical research reported in the medical literature; ( 3 ) Synthesize research findings through one-on-one interviews with authors and editorialists; ( 4 ) Integrate new treatments reviewed in the summaries into current practice; ( 5 ) Challenge oneself with thoughtful, clinically relevant questions. Disclosure In adherence to the ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Jennifer Doudna reported being a cofounder and on the Scientific Advisory Board of Caribou Biosciences, Inc., which develops CRISPR-Cas technology for genome engineering for agricultural and biomedical applications; being a cofounder of Editas Medicine, a company that translates genome editing technology into human therapeutics; and being a cofounder and on the Scientific Advisory Board of Intellia Therapeutics. Dr. Tannaz Moin and the planning committee members reported that they had nothing to disclose. PLANTAR FASCIITIS: TWO NEW STUDIES Extracorporeal shock-wave therapy is used for treating patients with plantar fasciitis, but its efficacy hasnt been consistently determined. In a study in the May6 Journal of Bone & Joint Surgery ( http:// dx.doi.org /10.2106/JBJS.M.01331 ), researchers randomized 250 patients with plantar fasciitis to three sessions of either extracorporeal shock-wave therapy or a sham therapy (in which the transmission of shock waves was blocked). All of the patients had been symptomatic for at least 6months, despite having gotten multiple nonsurgical treatments. At 3months, the reduction in heel pain on a 10-point visual-analog scale which was the primary outcome was significantly greater in the shock-wave group than in the control group. Insoles and heel pads are commonly given to patients with plantar fasciitis. In a study in the May Journal of Rheumatology ( http:// dx.doi.org /10.3899/jrheum.140429 ), researchers randomized 70 patients (with symptoms lasting an average of a year) either to custom-made total-contact insoles (which were molded to the patients foot) or to flat, prefabricated insoles (this was the control intervention). During 6months of follow-up, the group that wore the custom insoles had statistically significant improvement, compared with the control group, in pain on walking, but not on scales that evaluated function and quality of life. In both of these studies, some patients with plantar fasciitis seemed to respond to the experimental interventions. The researchers describe both trials as double-blind , but we dont know how well blinding worked for the sham shock-wave procedure, and patients could certainly distinguish between custom-made molded insoles and flat ones. Although these approaches which can be costly might be worth trying in patients with chronic resistant symptoms, most patients with plantar fasciitis improve eventually, regardless of treatment. EPIDURAL STEROID INJECTION vs . GABAPENTIN FOR LUMBOSACRALRADICULAR PAIN There have been many comparison studies of epidural steroid injections or oral drugs with placebo for radicular pain. But in only a few trials has one active treatment been compared with another. In a multicenter, double-blind trial on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1748 ), researchers randomized 150 patients with lumbosacral radicular pain, secondary to a herniated disk or spinal stenosis either to single epidural steroid injections plus an oral placebo or to sham injections plus gabapentin. In all of the patients, the duration of pain was less than 4years, and leg pain was as severe as, or more severe than, back pain. A positive outcome was defined as a decrease of 2 or more points on a 10-point score of leg pain. At a month, average leg-pain scores (which was the primary outcome) had improved from a baseline of 5 in both of the groups, to 3.3 in the steroid injection group and 3.7 in the gabapentin group, with no significant differences between the two groups; the results were similar at 3months. For secondary outcomes, the epidural steroid group had greater improvements in scores of worst leg pain at a month, and the patients in this group were more likely to experience the composite outcome of a 2 or more point decrease in leg pain score and a positive global perceived effect, but the differences between the two groups were no longer significant at 3months. In this trial, outcomes were similar at 3months between epidural steroid injection and oral gabapentin for lumbosacral radicular pain, secondary to a herniated disk or spinal stenosis. But clinicians should keep in mind that the evidence to support either of these treatments is limited: In placebo-controlled trials, epidural steroids have provided only minimal short-term benefit at best ( www.jwatch.org /jw201212130000001 ), and for gabapentin, no large randomized trials have been conducted. NONSURGICAL AND SURGICALTREATMENTS FOR LUMBARSPINAL STENOSIS Two studies shed light on options for treating patients with lumbar spinal stenosis. In the first study, published in the April7 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-1420 ), researchers randomized 170 patients with lumbar spinal stenosis and neurogenic claudication to either surgical decompression or a formal physical therapy program. Intent-to-treat and sensitivity analyses revealed no significant differences in physical function (which was the primary outcome) or in pain, disability, symptoms, or expectations (these were secondary outcomes) between the two groups at any point during 2years of follow-up. Although 60% of the physical therapy patients crossed over to surgery during follow-up, the researchers state that statistical techniques show the equivalence of physical therapy and surgery. In the second study, which appears on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1603 ), researchers used data on nearly 900 patients from a spine surgery registry to compare the effectiveness of microdecompression vs . open laminectomy in patients with lumbar spinal stenosis. About 70% of the patients in each group experienced clinically meaningful improvement in disability. To minimize confounding, propensity-matched cohorts were used for statistical analyses. Microdecompression and laminectomy were equally effective for preventing disability, and there were no differences between the two groups for length of surgery, perioperative complications, or quality of life. Not surprisingly, length of hospitalization was significantly shorter in the microdecompression group. The results of these two studies provide guidance for patients with lumbar spinal stenosis and their clinicians. Physical therapy might be a reasonable initial option for patients with symptomatic lumbar spinal stenosis who are being considered for surgery. For patients who do undergo surgery, microdecompression might be a better option than open laminectomy. METFORMIN USE IN PATIENTS WITH PREDIABETES Back in 2002, the Diabetes Prevention Program Research Group reported that, in overweight adults with impaired glucose metabolism, the incidence of type2 diabetes was lowered by 60% with lifestyle intervention and by 30% with metformin, relative to placebo, during 3years of follow-up ( www.jwatch.org /jw200202190000001 ). Although lifestyle interventions have gotten considerable attention, we dont know much about the use of metformin to prevent diabetes. Until now. In a retrospective cohort study in the April21 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-1773 ), researchers examined health insurance claims data to determine metformin use among 17,000 patients between the ages of 19 and 58 with prediabetes between 2010 and 2012. During the study, less than 4% of the patients got prescriptions for metformin. Among those with body-mass indices greater than 35kg/m 2 or gestational diabetes, the prevalence of metformin prescription was 8%. Metformin prevents or delays the progression to diabetes in some patients with prediabetes. The researchers believe that their findings indicate a substantial underuse of metformin. But we dont know whether giving metformin to this population will eventually pay off in clinically meaningful reductions in microvascular or macrovascular complications. Plus, a recent re-analysis of Diabetes Prevention Program data suggested that metformin delayed the progression to formal diagnoses of diabetes in a relatively small subgroup of prediabetic patients who were at the highest baseline risk for progression ( www.jwatch.org /na37121 ). DOES ALCOHOL INTAKE PREVENT CHRONIC KIDNEY DISEASE? Its been suggested that moderate alcohol intake lowers cardiovascular risk. But whats the association between alcohol consumption and chronic kidney disease? In a prospective population-based cohort study in the Mayissue of Kidney International ( http:// dx.doi.org /10.1038/ki.2014.414 ), researchers in the Netherlands and the United States identified 5500 patients between the ages of 28 and 75 with no evidence of chronic kidney disease and followed them for an average of 10years. Alcohol intake was evaluated at baseline and periodically thereafter. During follow-up, 16% of the patients developed chronic kidney disease, defined as an estimated glomerular filtration rate lower than 60 mL/minute /1.73 m 2 or a 24-hour albumin excretion greater than 30mg. In analyses adjusted for potentially confounding variables, alcohol intake was inversely associated with the risk for chronic kidney disease: Compared with nondrinkers, those who drank 1 to 4 drinks /month , 2 to 7 drinks /week , 1 to 3 drinks /day , and more than 3 drinks /day had progressively lower hazard ratios for chronic kidney disease. This inverse association persisted in two separate sensitivity analyses: One for changes in drinking frequency during follow-up and one that excluded nondrinkers (to remove any bias that might happen if less healthy people avoided alcohol). The possibility of residual confounding is always a concern in studies like this; that is, maybe alcohol intake itself didnt protect the kidney, but instead was associated with another protective condition or behavior that did. Even so, the findings are provocative. The mechanism by which alcohol intake might protect against chronic kidney disease isnt known. BLEEDING RISK IN WARFARIN-TREATED PATIENTS WITH KIDNEY DISEASE According to official prescribing information for warfarin, no dosage adjustment is necessary for renal impairment. But its been shown that warfarin-treated patients with substantially impaired renal function need lower warfarin doses, are more likely to have international normalized ratios outside of the therapeutic range, and are at a higher risk for major hemorrhage ( http:// dx.doi.org /10.1681/ASN.2008070802 and www.jwatch.org /na36975 ). Now, in the May American Journal of Kidney Diseases ( http:// dx.doi.org /10.1053/ j. ajkd.2014.11.004 ), researchers have examined the interaction between supratherapeutic INR (4 or greater), renal function (evaluated using estimated glomerular filtration rate), and the risk for bleeding in nearly 1300 long-term users of warfarin. During an average follow-up of about 1.5years, more than 30,000 INR tests were done, and 140 patients experienced major hemorrhages. Compared with the patients who had normal renal function or mild kidney disease, those with advanced kidney disease were more likely to have INRs of 4 or greater and to have major bleeding events. But the association between renal disease and major bleeding depended on the INR at the time of bleeding. When the INR was less than 4, the risk for major bleeding was similar across all of the estimated glomerular filtration rate groups. In contrast, when the INR was 4 or greater, the risk for serious bleeding was several-fold higher among the patients with estimated glomerular filtration rates lower than 45 mL/minute /1.73 m 2 than among those with higher estimated filtration rates. The reversal of anticoagulation took longer in the patients with lower estimated glomerular filtration rates. In this study of patients treated with warfarin, moderate-to-severe kidney disease was associated with an elevated risk for major hemorrhage but only when international normalized ratios were 4 or greater. Although every patient with a supratherapeutic INR needs close follow-up, these results suggest that clinicians should be especially vigilant when the patient has advanced renal disease. INTERACTION OF FACTORSASSOCIATED WITH PEPTICULCER BLEEDING Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs, and low-dose aspirin can each cause peptic ulcer disease. To determine the potential interaction of these factors, researchers in Spain compared nearly 700 patients hospitalized with major peptic ulcer bleeding and the same number of controls matched by sex, age, and month of admission. H. pylori infection was identified by serology, and NSAID and aspirin use was determined by questionnaire. Findings appear in the Mayissue of The American Journal of Gastroenterology ( http:// dx.doi.org /10.1038/ajg.2015.98 ). H. pylori infection was significantly more common in the cases than in the controls, as was NSAID and low-dose aspirin use. The patients with simultaneous H. pylori infection and NSAID use had an eightfold higher risk for bleeding ulcers than the patients with neither risk factor; the patients with H. pylori infection who used aspirin had a nearly fourfold higher risk. Because the relative risk associated with simultaneous H. pylori infection and NSAID use was greater than the additive risk of each factor alone, the researchers suggested that a positive interaction exists between these factors. No positive interaction was seen between H. pylori infection and aspirin use. In this study, simultaneous infection with Helicobacter pylori plus the use of nonsteroidal anti-inflammatory drugs or aspirin carried a higher risk for peptic ulcer bleeding than did either NSAID or aspirin use alone. But the data suggesting that H. pylori infection and NSAID use confer greater-than-additive risk should be interpreted with caution because this study didnt control for potential confounding factors, including the assumption that a positive H. pylori serology implied current infection. These findings shouldnt change clinical practice: Patients at high risk who have to take NSAIDs or aspirin should also take prophylactic proton-pump inhibitors, and documented H. pylori infection should be eradicated to lower the risk for bleeding even more. DURATION OF TRIPLE THERAPY AFTER DES IN PATIENTS ALREADY ON ORALANTICOAGULATION For patients with a history of anticoagulation therapy and drug-eluting stent implantation, its been shown that oral anticoagulation plus clopidogrel has a similar ischemic benefit, with less bleeding, than does triple therapy (meaning, oral anticoagulation plus dual antiplatelet therapy www.jwatch.org /jc201302270000001 ). In a study in the April28 Journal of the American College of Cardiology ( http:// dx.doi.org /10.1016/ j. jacc.2015.02.050 ), researchers randomized 600 patients who got oral anticoagulation and aspirin after drug-eluting stent implantation to either 6weeks or 6months of clopidogrel. Most of these patients were taking oral anticoagulants for atrial fibrillation. The primary endpoint of death, myocardial infarction, definite stent thrombosis, stroke, and major bleeding at 9months was similar in the two groups (at around 9%). There were no differences in composite ischemic events or in major bleeding events alone, but in post-hoc analyses performed between 6weeks and 6months, shorter clopidogrel treatment was significantly associated with less bleeding. These findings support the current practice of many interventionalists to discontinue a second antiplatelet agent at 4 to 6weeks following drug-eluting stent implantation in patients who need oral anticoagulation. Plus, this study provides new evidence to support the discontinuation of clopidogrel instead of aspirin. Even so, the need to balance ischemic and bleeding risks in these patients is clear. Whether these findings, with statistical power only for composite endpoints, will prompt a change in the guidelines remains to be seen. TREAT PE WITH ANTICOAGULATIONALONE One strategy for managing severe acute venous thromboembolism is placing inferior vena cava filters as add-on therapy in patients who are candidates for anticoagulation. Because of the paucity of data on the long-term outcomes of this approach, guidelines vary. In a study in the April28 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.3780 ), researchers in France randomized 400 patients hospitalized with acute symptomatic pulmonary embolism that was associated with lower-limb venous thrombosis and 1 or more additional criterion for disease severity either to anticoagulation with retrievable inferior vena cava filter implantation or to anticoagulation alone. The disease-severity criteria were an age older than 75, active cancer, chronic cardiac or respiratory disease, recent ischemic stroke with leg paralysis, and right ventricular dysfunction or myocardial injury. The patients in both of the groups got full-dose, guideline-adherent anticoagulation for at least 6months. At 3 and 6months, there were no differences between the two groups in recurrent pulmonary embolism, recurrent deep vein thrombosis, major bleeding, or death from any cause. These findings dont support the use of retrievable inferior vena cava filters in patients with severe acute pulmonary embolism who can be treated with anticoagulation alone. These patients include those with submassive pulmonary embolism, defined as a systolic blood pressure greater than 90mmHg with either right ventricular dysfunction or myocardial necrosis; two thirds of the study patients in both of the treatment groups met these criteria. We dont know whether inferior vena cava filters add any benefit to anticoagulation in hemodynamically unstable patients with pulmonary embolism. WEEKEND ADMISSIONS ARE ASSOCIATED WITH HIGHER RISK FOR HOSPITAL-ACQUIRED CONDITIONS The United States Centers for Medicare and Medicaid Services label serious preventable hospital-acquired conditions as so-called never events . In a study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1460 ), researchers used a nationwide hospital database to compare the risks for 11 serious hospital-acquired conditions after weekend or weekday admissions. The database contained records on 350 million patients who were discharged from 2002 through 2010; 19% were admitted on weekends. The frequencies of these hospital-acquired conditions were 6% for weekend admissions and 4% for weekday admissions. The most common hospital-acquired conditions were falls or trauma, pressure ulcers, and catheter-associated urinary tract infections. After adjusting for multiple patient, hospital, and severity-of-admission factors, the probability of experiencing at least one hospital-acquired condition was 20% higher for the patients admitted on weekends than for those admitted on weekdays. Notably, the occurrence of at least one hospital-acquired condition was associated with significantly higher inpatient charges and a prolonged length of stay. In this nationwide study, serious hospital-acquired conditions so-called never events were more common after weekend admissions than after weekday admissions. Traditionally, hospitals have lower staffing and resources for diagnostic and therapeutic interventions on weekends than on weekdays. More staffing and resources on weekends, coupled with improved education and protocols to prevent never events , might attenuate these weekendweekday differences. CRISPR-Cas9 IS A POWERFUL NEW GENE-EDITING TECHNIQUE A relatively new gene editing technology called CRISPR-Cas9 is already profoundly affecting basic biological research and holds promise for treating human disease. In three recent papers, researchers report advances and grounds for concern. In the first article, which appears in the April9 issue of Nature ( http:// dx.doi.org /10.1038/nature14299 ), researchers report on a modification of the CRISPR technique that could escalate its potential for editing genes in living animals. The researchers targeted the pcsk9 gene, which is important in the metabolism of cholesterol and is inhibited by a new class of drugs ( www.jwatch.org /na37285 ). About 40% of the hepatocytes in living mice contained the edited gene, leading to prompt and marked reductions in total cholesterol. Apparently, the gene editing didnt induce any adverse effects. One theoretical use of CRISPR technology would be to edit defective genes in human zygotes and then implant those zygotes following in vitro fertilization procedures. In the second article, which appears in the Mayissue of Protein & Cell ( http:// dx.doi.org /10.1007/s13238-015-0153-5 ), researchers in China actually tested whether the technique could be used to edit genes in human zygotes. To avoid ethical issues, they used zygotes in which two sperm had entered a single egg because such zygotes cant produce viable fetuses. They found that, in these zygotes, the CRISPR technology was very inefficient and also produced off-target , potentially adverse, effects. In the third article, which appears in the April3 issue of Science ( http:// dx.doi.org /10.1126/science.aab1028 ), a group of distinguished biologists strongly urges that CRISPR technology not be used to attempt germline modification for clinical application in people; they argue that biologists first need to know much more about possible off-target effects (and on-target effects with unintended consequences). They urge the formation of multidisciplinary groups of biologists, clinicians, social scientists, legal scholars, ethicists, and representatives of government to chart a course. CRISPR-Cas9 technology is an extraordinarily important advance in biological research and is likely to become a therapeutic technique used in people. But applications of this technology for treating human disease, particularly interventions involving modification of the germline, need to be pursued very carefully. EARLY MOBILIZATION AFTER STROKE: HELPFUL OR HARMFUL? Many guidelines recommend the early mobilization of patients following a stroke. But the evidence base for this practice is fairly modest. In a study on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6736(15)60690-0 ), researchers randomized 2000 patients with ischemic or hemorrhagic strokes of mild-to-moderate severity to either early mobilization or usual care if the treatments could be started within 24hours after stroke onset. Treatment with tissue plasminogen activator was allowed. Early mobilization included three elements: 1.Initiation within 24hours 2.Sitting, standing, or walking 3.At least 3 additional out-of-bed sessions, compared with usual care Treatment lasted for two weeks or until hospital discharge. Time to first mobilization was 18hours in the early-mobilization group and 22hours in the usual-care group. The early-mobilization group, compared with the usual-care group, had more than twice the out-of-bed sessions /day and significantly more total time in out-of-bed activities during hospitalization. But at 3months, the early-mobilization group fared worse than the usual-care group in terms of disability. Advocates of early mobilization following a stroke feel that time is of the essence to capitalize on the brains plasticity and that a patient should be physically and mentally challenged poststroke. But this study suggests that the brain might need a cooling off period. Future studies should be aimed at defining the optimal dose and timing of therapies for recovery after a stroke. MRSA COLONIZATION FOLLOWING INFECTION VARIES Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus are increasingly common in outpatient settings. Patients with these infections might remain colonized with methicillin-resistant S. aureus long after their initial infections resolve and be at an elevated risk for recurrent infection. In a prospective cohort study in the May15 issue of Clinical Infectious Diseases ( http:// dx.doi.org /10.1093/cid/civ075 ), researchers examined the duration of colonization by following 240 pediatric and adult patients with confirmed and treated methicillin-resistant S. aureus skin and soft-tissue infections. Colonization was evaluated with self-obtained swabs of nares, axilla, and groin from patients and all members of their households every 2weeks for 6months. Overall, the median duration of colonization was 3weeks thats far shorter than determined in past studies. But the patients fell into two groups. One hundred and fifty werent colonized at study entry (which was about 2weeks after finishing treatment); these patients werent studied further. The remaining patients were colonized for a median duration of 5months; more than half of this group was still colonized at the end of the study. In multivariate analyses, treating index infections with clindamycin (rather than trimethoprim-sulfamethoxazole) was associated with a shorter duration of methicillin-resistant S. aureus carriage, as was younger patient age. Carriage among household members wasnt associated with a longer duration of colonization in the index patients, and treatment with topical antiseptics like mupirocin, chlorhexidine, and diluted bleach (which was prescribed for about 20% of the index patients) didnt seem to shorten the duration of colonization. Many studies have shown that carriage of methicillin-resistant Staphylococcus aureus lasts for months after infection, especially if household members are also carriers. This study suggests that patients with methicillin-resistant S. aureus infections include those who lose their carrier state quickly (or might never have been carriers at all) and those who remain carriers for extended periods. The association of clindamycin with rapid eradication of colonization hasnt been documented before and awaits confirmation. LUNG ULTRASOUND FOR DIAGNOSINGPNEUMONIA Lung ultrasound can detect pneumothorax and pulmonary edema, but data on its accuracy for diagnosing pneumonia are limited. In a prospective study in the Mayissue of The American Journal of Emergency Medicine ( http:// dx.doi.org /10.1016/ j. ajem.2015.01.035 ), researchers in Italy compared lung ultrasound to chest computed tomography and chest x-ray among adult patients with unexplained respiratory symptoms who presented to an academic emergency department. CT served as the gold standard for the diagnosis of an infiltrate, consistent with pneumonia. Bedside lung ultrasound was performed within 3hours of CT scans by either emergency physicians or internists, and chest x-ray was performed at the discretion of the treating clinicians. During the 8-month study, nearly 300 patients underwent CT and ultrasound; of these, 190 also underwent chest x-ray. Chest CT was positive for pneumonia in 90 patients. Sensitivity for diagnosing pneumonia was significantly higher with ultrasound than with x-ray, whereas specificity was similar. This intriguing study requires external validation, but suggests that ultrasound might be better than x-ray for diagnosing pneumonia thats a finding that would have major implications for diagnostic imaging. GUIDELINE WATCH: BEST PRACTICE ADVICE FOR CERVICALCANCER SCREENING IN AVERAGE-RISK WOMEN In the United States, routine screening for cervical cytologic abnormalities in asymptomatic women has lowered the incidence of cervical cancerrelated morbidity and mortality. Plus, the role of human papillomavirus in cervical cancer has led to new screening approaches that incorporate HPV testing. On the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-2426 ), the American College of Physicians has updated its best practice advice for cervical cancer screening in women at average risk. The key recommendations are: Women should be screened with cervical cytology every 3years beginning at the age of 21. After the age of 30, women can be screened with cytology and HPV testing every 5years. Before the age of 21, women shouldnt be screened at all. Before the age of 30, women shouldnt be screened with HPV testing. At the age of 65, screening can stop in women with three consecutive negative cytology results or two consecutive negative cytology results combined with a negative HPV test within the last 10years (with the most recent test within 5years). Women without a cervix shouldnt be screened. These recommendations on cervical cancer screening in women at average risk reflect a better understanding of the transient nature of most human papillomavirus infections and the harms of too-frequent screening, which include unnecessary diagnostic biopsies and excisional procedures, as well as expense and anxiety. The writing committee members acknowledge that changing annual screening habits might be difficult for providers and women alike. Generally, these guidelines harmonize with those of the United States Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and the American Cancer Society, with minor differences in whether HPV testing is presented as an option to everyone or only to the women who want less frequent testing. Optimal screening strategies are likely to shift again as more girls immunized against HPV reach the age at which screening is recommended, necessitating further updates to the guidelines. ANTIDEPRESSANT USE DURING EARLYPREGNANCY AND RISK FOR BIRTH DEFECTS The teratogenic effects of selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitor venlafaxine arent clear. In a multinational, population-based cohort study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1798 ), researchers evaluated maternal SSRI or venlafaxine use and the risk for birth defects in more than 2 million babies born between 1996 and 2010 in Nordic countries. To adjust for potential confounding from family-related factors, sibling-controlled analyses were performed using a cohort of sibling pairs (2300 babies) who were discordant for both maternal SSRI or venlafaxine use and birth defects. Among nearly 40,000 babies with first-trimester exposure to selective serotonin reuptake inhibitors, 4% had major birth defects, and 1.5% had cardiac-related birth defects; whereas, among 2 million unexposed babies, 3% had major birth defects, and 1.2% had cardiac-related birth defects. There was no significant association between the use of venlafaxine and birth defects. In the sibling-controlled analyses, SSRI or venlafaxine use wasnt associated with a higher prevalence of major birth defects or cardiac-related birth defects. In this large study, the maternal use of selective serotonin reuptake inhibitors during the first trimester of pregnancy was associated with modestly elevated risks for major birth defects and cardiac-related birth defects. But residual confounding likely accounts for these results, given that SSRI or venlafaxine use wasnt associated with a higher prevalence of these risks in sibling-controlled analyses. The researchers conclude that their findings argue against substantial teratogenic risk from SSRIs and suggest no teratogenic effect from venlafaxine. NEITHER VITAMIN D NOR EXERCISE AFFECTS OVERALL FALL RATES IN OLDER WOMEN Its been suggested that theres a benefit from vitamin D in preventing falls in older patients, but meta-analyses of clinical trials havent been conclusive. The effect of concomitant exercise is often hard to separate from that of vitamin D. In a study in the Mayissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.0225 ), researchers in Finland randomized 400 women with an average age of 74 to one of four groups, namely: 800 IU/ day of vitamin D plus exercise, placebo plus exercise, vitamin D without exercise, and placebo without exercise. Exercise consisted of structured classes twice /week for a year, then once /week for another year, with a focus on balance and strength training; the exercisers also got a home-training program. At baseline, the patients had a history of 1 or more falls during the past year, didnt take vitamin D supplements, and had no medical contraindication to exercise. Adherence to all of the interventions was high, and 90% of the patients finished the program. At 2years, intent-to-treat analyses showed no differences among the four groups in overall falls, but the rate of injurious falls was significantly lower in the exercise groups (with or without vitamin D) than in the nonexercise groups. Several measures of ambulation and physical function improved modestly with exercise vs . no exercise, but not with vitamin D vs . no vitamin D. These results weaken the speculation that vitamin D supplementation alone can prevent falls. Exercise, especially strength and balance training, continues to be important and should be promoted by clinicians. FEW COMMERCIAL DIETS SHOWEVIDENCE OF SUSTAINEDWEIGHTLOSS Last year, the market for commercial weight-loss programs was dominated by Weight Watchers, Nutrisystem, and Jenny Craig. In a systematic review in the April7 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-2238 ), researchers evaluated 45 studies (including 40 randomized trials lasting 3months or longer) in which commercial weight-loss programs were compared with control interventions (like printed materials only, sessions with a health professional, and behavioral counseling) or with no intervention. Compared with the control interventions, weight loss for commercial programs was: At least 3% greater at a year with Weight Watchers At least 5% greater at a year with Jenny Craig At least 4% greater at 3months (no trials were continued to a year) with Nutrisystem 1% to 3% greater at a year with Atkins At least 4% greater at 3months with very-low-calorie programs (like Health Management Resources, Medifast, and OPTIFAST) The results for SlimFast were mixed. Many of the trials were short (lasting less than a year), and attrition rates were high. The amount of money spent each year on weight-loss programs is staggering, although average weight loss is modest at best. If a commercial weight-loss program is advised, Weight Watchers and Jenny Craig might be preferable, given their effectiveness during at least a year. For other programs, including Nutrisystem, long-term studies are needed. These findings complement those of a meta-analysis published last year ( www.jwatch.org /na35594 ), in which low-fat and low-carbohydrate diets yielded similar weight-loss outcomes. IMAGING IN PATIENTS WITH STABLECHEST PAIN: WHATS THE BEST STRATEGY? There are many options for the evaluation of patients with stable chest pain. In an analysis in the April7 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-0027 ), researchers used a simulation model to evaluate the cost-effectiveness of different diagnostic strategies, including computed tomographic coronary angiography, cardiac stress imaging (that is to say, cardiac stress magnetic resonance imaging, stress single-photon emission CT, and stress echocardiography), and catheter-based coronary angiography, compared with no imaging (which was the baseline model). The results of initial testing were used to determine subsequent evaluation and treatment. The target population consisted of 60-year-old patients with stable chest pain and a 30% pre-imaging probability of coronary artery disease (meaning 50% or greater stenosis). The strategy that maximized quality-adjusted life-years and was the most cost-effective was to start with CT coronary angiography; to continue with cardiac stress testing, if angiography showed 50% or greater stenosis in 1 or more coronary vessels; and to conclude with catheter-based angiography, if stress imaging studies showed any degree of ischemia. This analysis suggests that computed tomographic coronary angiography is a cost-effective initial strategy in patients with stable chest pain. But these results should be interpreted in the context of the recently published PROMISE trial ( www.jwatch.org /na37279 ), which showed no differences in clinical outcomes between anatomic testing (namely, CT coronary angiography) and functional testing (namely, cardiac stress testing) as initial strategies in patients with stable chest pain. So the optimal initial testing strategy should be dictated by local experience and expertise. Finally, its important to note that one other plausible testing strategy an exercise test without imaging as the first-line test wasnt examined in this simulation analysis. DISCONTINUING STATINS FOR PATIENTS WITH TERMINAL ILLNESSES Often, its difficult for clinicians to discontinue preventive interventions (both therapeutic and diagnostic) in patients with terminal illnesses, but doing so might have important quality-of-life benefits. In a study in the Mayissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2015.0289 ), researchers randomized 400 patients with an average age of 74 who had predicted lifespans of less than a year and recent declines in functional status to either continue or discontinue statins. Nearly half of the patients had terminal cancer, 60% had known cardiovascular disease, and most had taken statins for more than 5years. The patients were followed for a median of 18weeks; about half died during follow-up. There were no significant differences between the two groups in the proportion of patients who died within 2months, the median time to death, or the incidence of adverse cardiovascular events. Overall quality-of-life scores were significantly higher in the discontinuation group than in the continuation group, although symptom-specific scores were similar. These results are encouraging for clinicians who wish to start discussions about the discontinuation of preventive therapies with patients whose predicted lifespans are markedly shortened. Patients can reasonably be told that their quality of life might improve without harm. But these findings dont address the difficulty of dealing with the symbolism of withdrawing medications when the benefits are distant and the patients death is near.

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Internal Medicine Gastroenterology Cardiology Rheumatology Emergency Medicine Infectious Diseases