Here are the last 20 additions to the PBrain (total entries as of now = 3750)


Diuretic Treatment in Heart Failure (3731)
Ellison et al NEJM 377:1964 11-16-2017

Most accepted pharmacologic treatments for heart failure are supported by evidence from large clinical trials. In contrast, evidence from large, well-controlled clinical trials to guide the use of diuretics, among the most frequently used drugs in heart failure, is generally lacking. Fluid retention and congestion are hallmarks of heart failure, and they are associated with both severe symptoms and poor outcomes.1 Given the centrality of congestion to both symptoms and outcomes, diuretics remain cornerstones of management of heart failure.2 Although routine diuretic treatment of heart failure may appear to be uncomplicated, questions abound about how best to use diuretics, particularly in patients with acute decompensated heart failure and diuretic resistance. In this review, we discuss current pharmacologic principles of diuretic therapy, integrate data from recent research, and suggest evidence-based approaches to diuretic treatment of heart failure.

Full article


Hidradenitis Suppurativa: Advances in Diagnosis and Treatment (3732)
Saunte JAMA 318:2019 11-28-2017

Findings The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). HS is more common than was previously thought based on epidemiological analysis (0.05%-4.10%). Disability from HS can be significant. Patients with HS may have significant comorbidities (eg, obesity, metabolic syndrome, diabetes, and arthritis) and increased all-cause mortality (incidence rate ratio, 1.35 [95% CI, 1.15-1.59]). Antibiotic treatment with combinations of clindamycin and rifampicin, or ertapenem followed by combination rifampicin, moxifloxacin, and metronidazole for 6 months is effective. Adalimumab is effective in a significant proportion of patients and treatment with IL-1 and IL-12 receptor subunit beta 1 (Rb1) antibodies may also be useful. Tissue-sparing surgical techniques and carbon dioxide laser treatments also are available, but the evidence on clinical outcomes with these approaches is limited.

Conclusions and Relevance Hidradenitis suppurativa is more common than previously thought and may be treated by an array of pharmacological and surgical techniques. Hidradenitis suppurativa should be considered in the differential diagnosis of nodular lesions or sinus tracts present in the axillae, groin, perineal, and mammillary fold regions.

Full article


Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine (3733)
Friedman BW et al Neurology 10-18-2017

Intravenous hydromorphone is a poor choice for first-line migraine treatment in the emergency department.

Unfortunately, despite extensive evidence specifically demonstrating lack of efficacy, parenteral opioids are commonly used to treat migraine headaches in the emergency department (ED). In a randomized double-blind trial, researchers compared the efficacy of intravenous hydromorphone (1 mg) versus IV prochlorperazine (10 mg) plus diphenhydramine (25 mg) in 127 adults with a diagnosis of migraine and no recent opioid use. Eligible patients presented to two New York City EDs with moderate to severe headache pain.

Patients were offered a second dose of medication 1 hour after the first. Symptoms were assessed on a 4-item headache pain scale (severe, moderate, mild, none) in the ED every hour for up to 4 hours, and by phone call at 48 hours. The primary outcome was sustained headache relief, defined as a reduction in pain to mild or none that was sustained at 48 hours after a single dose of medication.

A second dose was requested by 8% of prochlorperazine and 31% of hydromorphone recipients. The primary outcome was achieved in 60% of patients who received one dose of prochlorperazine, compared with 31% of those who received one dose of hydromorphone. Among patients who received one or two doses of medication, sustained relief was reported by 60% in the prochlorperazine group versus 41% in the hydromorphone group. The study was ended early because "overwhelming superiority" of prochlorperazine for the primary outcome was demonstrated.

Comment: This study confirms others: opioids are not effective for the treatment of migraine headache and should not be used.


Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: Two open-label, randomised controlled trials (3734)
Stoffel NU et al Lancet Haematol 10-09-2017

Oral iron therapy is plagued by relatively poor absorption and gastrointestinal side effects. In a previous 2-day study, researchers demonstrated that fractional iron absorption is suppressed by high doses of oral iron (compared with lower doses) and by twice-daily dosing (compared with once-daily dosing; NEJM JW Gen Med Dec 1 2015 and Blood 2015; 126:1981). Now, the researchers have extended their previous observations.

They recruited healthy young Swiss women with low or low-normal iron stores (serum ferritin levels, ≤25 μg/L) and normal or only mildly low hemoglobin levels. In one experiment, 40 participants were randomized to receive 60 mg of iron (as ferrous sulfate) either every morning for 14 days or on alternate mornings for 28 days. At the end of these dosing periods, both fractional absorption and cumulative total absorption of iron were significantly greater in the alternate-day group than in the daily group.

In a second experiment, 20 women received either 120 mg of iron once daily or 60 mg twice daily for 3 days; after a 2-week washout period, each participant crossed over to the other regimen. The two regimens did not differ in fractional or total iron absorption, but with both regimens, absorption was higher on the first day than on the second and third days.

Comment: Alternate-day oral iron dosing is associated with better fractional absorption of iron than is daily dosing; the presumed mechanism is that iron intake raises levels of hepcidin (which blocks the absorption of iron given the following day). This study was too small and too short to allow reliable assessment of side effects, but gastrointestinal tolerability likely would be enhanced with alternate-day dosing. The next step will be to compare daily and alternate-day regimens in patients with substantial iron deficiency anemia.


Oral human papillomavirus infection: Differences in prevalence between sexes and concordance with genital human papillomavirus infection, NHANES 2011 to 2014 (3735)
Sonawane K et al Ann Intern Med 10-17-2017

Oral human papillomavirus is more prevalent in men than women, leading to a higher incidence of oropharyngeal squamous cell carcinoma.

Human papilloma virus (HPV) causes cancer at genital, oral, and anal sites. Although there is a higher reported prevalence of all HPV-related cancer in women, the prevalence of oropharyngeal squamous cell carcinoma (OPSCC) is about four times greater in men.

Using data from the National Health and Nutrition Examination, investigators found that the incidence of OPSCC has increased in men by 2.89% annually from 2002 to 2012, while increasing only 0.57% annually in women, and has exceeded the incidence of cervical cancer in women. The prevalence of oral HPV in men rose to 11.5%, equating to 11 million infected men nationwide, while the prevalence in women was 3.2%, equating to 3.2 million women; the prevalence of strains causing most cancers was higher in men by an even greater proportion.

Prevalence peaks in men were bimodal in the age groups of 30 to 39 and 50 to 54 years. Non-Hispanic black men had the highest prevalence overall prevalence and highest prevalence of high-risk infection. Other risk factors for overall and high-risk infection included cigarette and marijuana use (previous marijuana use in men, current use in women) and sexual practices in men and women, including having had many lifetime or recent sex partners. There was high concurrence between oral and genital infection and presence of high-risk infection in both men and women. The prevalence of high-risk infection was greatest (22.2%) in men with 2 or more same sex, oral sex partners.

Comment: These are very strong data showing increasing prevalence of oral human HPV, especially among men, with resultant development of OPSCC. The authors appropriately raise the issue of health policy changes to try to prevent infection and oropharyngeal cancer in men. One policy change that might be evaluated, as suggested by an editorial, is vaccination of middle-aged men.


Synopsis of the 2017 U.S. Department of Veterans Affairs/U.S. Department of Defense clinical practice guideline: Management of type 2 diabetes mellitus (3736)
Conlin PR et al Ann Intern Med 10-24-2017

Background: The VA and DoD assembled a multidisciplinary group of expert stakeholders - primary care physicians, endocrinologists, nurse practitioners, medical nutritionists, pharmacists, diabetes educators, and patient representatives (each without industry conflicts of interest) - to design a clinical practice guideline for managing patients with type 2 diabetes.

Key Recommendations:

Comment: The VA/DoD type 2 diabetes clinical practice guideline differs from other recently published guidelines because it establishes HbA1c target ranges, rather than thresholds, to avoid inappropriate intensification of therapy without consideration of benefits and risks. Target ranges also reflect patients' disease complications, comorbid conditions and their severity, therapy preferences, social factors, and life expectancy. Generally, other recommendations in this guideline are consistent with previously published guidelines.


Corticosteroids for treatment of sore throat: Systematic review and meta-analysis of randomised trials (3737)
Sadeghirad B et al BMJ 358:j3887 09-20-2017

In a meta-analysis, pain resolution occurred about 11 hours sooner when patients received single-dose dexamethasone.

Evidence suggests that corticosteroid treatment relieves pain in patients with sore throats (NEJM JW Gen Med Jun 1 2017 and JAMA 2017; 317:1535). In this systematic review and meta-analysis, researchers determined benefits and harms of adding corticosteroids to standard clinical care of children and adults (age, ≥5 years) with clinical signs of acute tonsillitis, pharyngitis, or clinical syndrome of sore throat who presented to emergency departments or primary care.

Researchers evaluated 10 randomized controlled trials (1426 patients) in which corticosteroids were compared with placebo or standard care. Single-dose oral dexamethasone was the most common intervention (10 mg for adults; 0.6 mg/kg [maximum, 10 mg] for children). Protocols for antibiotic and analgesic use varied among trials. Patients who received corticosteroids were significantly more likely to experience complete resolution of pain after 24 and 48 hours than were controls. Mean time to onset of pain relief was 5 hours sooner and mean time to complete resolution of pain was 11 hours sooner in participants who received corticosteroids than in controls. Adverse events were similar in corticosteroid and noncorticosteroid groups.

Comment: In this study, single-dose corticosteroid treatment hastened pain relief in children and adults with sore throat without causing adverse effects. However, most sore throat is due to acute pharyngitis caused by self-limited viral infections that resolve with self-care and over-the-counter medications. Thus, prescribing corticosteroids for all cases of sore throat seems inappropriate. Rather, corticosteroids might be a useful adjunct in treating patients with severe sore throat.


Percutaneous coronary intervention in stable angina (ORBITA): A double-blind, randomised controlled trial (3738)
Al-Lamee R et al Lancet 11-02-2017

Observational studies and the biologic plausibility linking coronary obstruction to angina have stimulated the use of percutaneous coronary intervention (PCI) in patients with angina and severe obstruction. Until now, no randomized studies have examined this link. In this first, blinded, sham-controlled, randomized study, investigators examined effects of PCI in 200 patients with stable chronic ischemic symptoms who were receiving intensive medical therapy (NCT02062593).

All patients had severe (≥70%) stenosis in a major epicardial coronary artery and underwent an intensive 6-week medication optimization period, including up-titration from about 1 to 3 medications, with multiple weekly physician consultations. Afterwards they were randomized in the catheterization laboratory to PCI or a sham procedure.

Six weeks later, the groups showed no significant differences on the primary endpoint, incremental improvement in exercise treadmill time (PCI, 28 seconds; sham surgery, 12 seconds). Groups also did not differ in improvements in time to 1-mm ST depression, peak oxygen uptake, Seattle Angina Questionnaire physical function or angina frequency, and quality-of-life score. PCI was associated with a small, significantly greater improvement in ischemia, as measured by wall-motion index score on dobutamine stress echocardiography (difference, –0.09).

Comment: Outcomes from this fascinating trial are surprising to interventionalists but are not "unbelievable," as suggested in the New York Times. In my view, they emphasize the great benefits of antianginal medication, which should continue to be first-line therapy. This small (though well-done) study enrolled very stable patients with angina lasting ~9 months, employed very intensive medical optimization, but had only 6 weeks of follow-up. As the authors note, the findings do not imply that patients should never undergo PCI for stable angina and do not apply to acute coronary syndromes, for which PCI has well-proven benefits.

Will I think twice before stenting the next proximal left anterior descending artery with 80% stenosis? Yes. Will I never stent such a patient? No. Should the guidelines be changed (as editorialists suggest)? Not yet. Howard C. Herrmann, MD


Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: A systematic review and meta-analysis (3739)
Brunstrom M and Carlberg B JAMA Intern Med 11-13-2017

High blood pressure (BP), particularly high systolic BP, is the strongest predictor of cardiovascular (CV)-related mortality, but the systolic BP level at which BP-lowering treatment should be initiated is somewhat controversial. In this meta-analysis, researchers examined data from 74 mostly industry-funded randomized trials in which pharmacologic treatment was compared with placebo, or different BP goals were compared with each other. Analysis involved about 306,000 participants and 1.2 million person-years of follow-up. Two thirds of the trials were classified as primary prevention (i.e., <50% of participants had known CV disease).

For primary prevention in patients with baseline systolic BPs of 140 to 159 mm Hg, treatment was associated with relative risk reductions of 13% for all-cause death and 12% for adverse CV events (i.e., CV-related mortality, major CV events, coronary heart disease, stroke, heart failure, and end-stage renal disease). Corresponding relative risk reductions in patients with baseline systolic BPs of ≥160 mm Hg were 7% and 22%. Treatment did not lower risk for either all-cause death or adverse CV events when baseline systolic BPs were <140 mm Hg. For secondary prevention, treatment in those with baseline systolic BPs <140 mm Hg was associated with lower risk for major adverse CV events but not all-cause or CV-related death.

Comment: The new hypertension guideline from the American College of Cardiology, the American Heart Association, and other societies recommends drug therapy for selected patients with no history of CV disease whose baseline systolic BPs are 130 to 139 mm Hg - lower than the traditional threshold of 140 mm Hg (NEJM JW Gen Med Dec 15 2017 and J Am Coll Cardiol 2017 Nov 13; [e-pub]). However, this meta-analysis does not support that recommendation: In primary prevention populations, treating patients whose systolic BPs were <140 mm Hg did not improve their CV outcomes. Thomas L. Schwenk, MD


Effectiveness of &#946;-lactam monotherapy vs macrolide combination therapy for children hospitalized with pneumonia (3740)
Williams DJ et al JAMA Pediatr 10-30-2017

Children admitted with community-acquired pneumonia are treated empirically with antibiotics, as the causative organism is rarely identified. Beta-lactam antibiotics are recommended to cover common bacterial pathogens, specifically Streptococcus pneumoniae but have no activity against atypical bacteria such as Mycoplasma pneumoniae and Chlamydophila pneumoniae.

To compare the effectiveness of beta-lactam monotherapy and beta-lactam combined with a macrolide in this setting, investigators prospectively assessed outcomes of over 1400 children admitted with radiographically confirmed pneumonia at three U.S. children's hospitals. Approximately 70% received beta-lactam monotherapy and 30% a beta-lactam-macrolide combination. In 74% of children, a virus was identified during their evaluation; in 5%, both viral and bacterial pathogens were identified; and in 9%, an atypical bacterium was detected (95% of these were M. pneumoniae).

In multivariate analysis, length of stay was similar between groups, and this was also true in a propensity-matched subcohort (over 550 patients) and in four subgroups of children considered most likely to benefit from macrolide coverage (age ≥5 years, atypical bacteria detected, intensive care admission, and acute wheezing). There were also no differences between the monotherapy and combination therapy groups in rates of admission to the intensive care unit (35% and 38%) or hospital readmission (5% and 2%).

Comment: These results add to a growing body of evidence suggesting that the benefits of macrolide antibiotics, even in proven atypical pneumonia, are limited. Also, almost three quarters of children in the study had a viral pathogen identified, raising the question of whether antibiotics, either monotherapy or combination therapy, are being overprescribed for treatment of children with pneumonia. In an accompanying editorial, the author challenges us to reconsider routine macrolide therapy for older children with pneumonia, while admitting that we still do not know if macrolides afford a benefit. This study provides additional information indicating that they may not. Deborah Lehman, MD


Acetaminophen or nonsteroidal anti-inflammatory drugs in acute musculoskeletal trauma: A multicenter, double-blind, randomized, clinical trial (3741)
Ridderikhof ML et al Ann Emerg Med 10-13-2017

Treating pain with nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious renal, gastrointestinal, and cardiovascular adverse effects. To determine whether acetaminophen is noninferior to NSAIDs in reducing pain, investigators in the Netherlands conducted a multicenter, randomized, double-blind trial in which 547 adults with acute minor extremity trauma received acetaminophen (4000 mg/day), the NSAID diclofenac (150 mg/day), or both for 3 days. All patients received omeprazole (20 mg/day) for 3 days.

The main outcome was decrease in pain measured on a numeric rating scale 90 minutes after the first dose. Also assessed were adverse events and patient satisfaction.

Acetaminophen was noninferior to the other regimens across all outcome measures, with a difference in pain score of zero.

Comment: Simple on its face, this paper rewards closer reading and is a model for clinical trial design. The authors conservatively recommend that any of the three strategies be used for management of pain due to minor musculoskeletal trauma, based on the finding of equivalence. I would take that a step farther and say out loud what their paper implies: These patients should use acetaminophen (or the European equivalent, paracetamol), not NSAIDs. Daniel J. Pallin, MD, MPH


Is intravenous administration of iodixanol associated with increased risk of acute kidney injury, dialysis, or mortality? A propensity score-adjusted study (3742)
McDonald JS et al Radiology 285:414 11-01-2017

In studies published several years ago by researchers at Mayo Clinic Rochester, intravenous iodinated contrast use in computed tomography (CT) scanning was not associated with acute kidney injury (AKI; NEJM JW Gen Med May 1 2014 and Radiology 2014; 271:65; NEJM JW Gen Med Dec 15 2014 and Radiology 2014; 273:714). Now, this team has performed a retrospective study of data from a new cohort of 5758 adults with chronic kidney disease (CKD; stages 1−5) who underwent either noncontrast CT or iodixanol-enhanced contrast CT and who had pre- and post-CT serum creatinine measurements. The researchers chose to confine this cohort to recipients of iodixanol, the iso-osmolar agent that generally was being used for patients perceived to be at high risk for postcontrast AKI.

Propensity-score matching yielded contrast-exposed and noncontrast groups (≈1500 patients in each group) who were statistically very similar on a broad range of clinical and demographic variables, including baseline renal function. Contrast exposure was not associated with excess AKI incidence, need for dialysis, or mortality - regardless of baseline renal function. Although relatively few patients with CKD stages 4 and 5 could be propensity-matched (76 contrast-exposed patients vs. 198 noncontrast patients), no hint of contrast-associated worsening of renal function was apparent even in these patients with advanced renal disease. An additional analysis of data from Mayo Clinic sites in Florida and Arizona yielded similar findings.

COMMENT: A growing body of evidence - albeit observational - suggests that intravenous contrast in CT scanning does not cause kidney injury. When clinical need for contrast is compelling (e.g., to rapidly diagnose pulmonary embolism), abnormal renal function should not preclude performing contrast-enhanced CT using a low-osmolar or iso-osmolar agent. Allan S. Brett, MD


Chronic Kidney Disease: Detection and Evaluation (3743)
Gaitonde et al AFP 96:776 12-15-2017

Chronic kidney disease affects 47 million people in the United States and is associated with significant health care costs, morbidity, and mortality. Because this disease can silently progress to advanced stages, early detection is critical for initiating timely interventions. Multiple guidelines recommend at least annual screening with serum creatinine, urine albumin/creatinine ratio, and urinalysis for patients with risk factors, particularly diabetes mellitus, hypertension, and a history of cardiovascular disease. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for chronic kidney disease in the general population, and the American College of Physicians recommends against screening asymptomatic adults without risk factors. Persistently elevated serum creatinine and albuminuria are diagnostic and prognostic hallmarks of chronic kidney disease. Lower levels of albuminuria are associated with adverse renal and cardiovascular outcomes. Serum cystatin C is a novel biomarker that is most useful when a false-positive decreased estimated glomerular filtration rate calculated from serum creatinine is suspected. New guidelines incorporate albuminuria into the classification framework for chronic kidney disease and elaborate on identification of the disease, the frequency of follow-up, and recommendations for nephrology referral. Nephrology consultation is indicated for patients with an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2, persistent urine albumin/creatinine ratio greater than 300 mg per g or urine protein/creatinine ratio greater than 500 mg per g, or if there is evidence of a rapid loss of kidney function. A multidisciplinary approach between primary care physicians, nephrologists, and other subspecialists for implementing early interventions, providing education, and planning for advanced renal disease is key for effective management.

Full article


Contemporary hormonal contraception and the risk of breast cancer (3744)
Morch LS et al NEJM 377:2228 12-07-2017

Many women and clinicians are concerned that hormonal contraception might raise risk for breast cancer. In a prospective cohort study, investigators used Danish national data to assess the association between use of hormonal contraception and risk for invasive breast cancer in women aged 15 to 49. Some 1.8 million women were followed for a mean of 10.9 years (1995 to 2012); 11,517 breast cancers were diagnosed. Findings were adjusted for duration of hormonal contraceptive use, age, calendar year, education, parity, polycystic ovary syndrome, endometriosis, and family history of breast or ovarian cancer.

Most hormonal contraceptives were oral formulations, followed by the progestin-releasing intrauterine device (IUD). Relative risk for breast cancer in current or recent users of any hormonal contraceptives compared with never-users was 1.20 (95% confidence interval, 1.14 to 1.26), an absolute risk of 13 additional cases of breast cancer per 100,000 person-years. Current or recent use of the progestin-releasing IUD was associated with an RR of 1.21 (95% CI, 1.11 to 1.33). Breast cancer diagnoses were uncommon among users of contraceptive implants or injections.

Comment: Given that >80% of invasive breast cancers are diagnosed in women older than 49 (for U.S. data, see American Cancer Society), I was surprised that these authors limited their analysis to women between 15 and 49 (despite using a database that tracks all Danish women aged 15 to 79). Clinical breast examinations, screening mammograms, and lactation history all contribute to the diagnosis of breast cancer; thus, I was also surprised that the authors did not adjust their findings for these potential confounders. Epidemiologists caution that, in cohort studies, RRs of less than 2 or 3 should not be interpreted as suggesting causation (Obstet Gynecol 2012; 120:920). It's therefore baffling that neither the investigators nor an editorialist mentioned what constitutes a fundamental limitation of this report. Lastly, an NIH-funded case-control study conducted by CDC investigators - considered by many to be among the definitive studies on this topic - found no suggestion of excess risk for breast cancer with use of oral contraceptives (N Engl J Med 2002; 346:2025). The findings of this Danish study will not alter the way in which I counsel patients about the benefits and risks of hormonal birth control: While we cannot rule out the possibility of a small increase in risk for breast cancer, the best available data suggest that use of hormonal contraceptives does not have an impact on this risk. Andrew M. Kaunitz, MD

Full article

Hunter DJ (editorial): Oral contraceptives and the small increased risk of breast cancer -- NEJM 2017 Dec 7; 377:2276


Shingrix: An Adjuvanted, Recombinant Herpes Zoster Vaccine (3745)
Med Ltr Med Ltr 59:195 12-04-2017

Although not directly compared to one another in clinical trials, adverse reactions appear to occur more often with Shingrix than with Zostavax. Common adverse effects of the new vaccine include myalgia (45%), fatigue (45%), headache (38%), shivering (27%), fever (21%), GI symptoms (17%), and injection-site pain (78%), redness (38%), and swelling (26%). Severe local reactions preventing normal daily activities occurred in 17% of persons who received Shingrix and persisted for a mean of 2 days. Serious adverse events, including new-onset immune-mediated disease and death, occurred at similar rates in the vaccine and placebo groups. Long-term data on the safety of Shingrix are lacking. It is about 91-97% effective - vs Zostavax efficacy of 70% at best (in 50-59 year olds) and of 18% at worst (in those over age 80). Shingrix efficacy remains 91% in those over age 80.

Full article


Evaluation and Management of Female Sexual Dysfunction (3746)
Dawson et al JFP 66:722 12-01-2017

The authors don't provide any simple solutions - because there aren't any! But they do provide a wide range of potential treatment options.

Full article


Hypothyroidism Summary (3747)
Kney Various 12-31-2017

Bottomline about treating subclinical hypothyroidism:

Full article

Key points from PL, 12/17:


Paroxysmal Nocturnal Hemoglobinuria (3748)
Sykes et al NEJM 377:2581 12-28-2017

Case study from NEJM. I will almost never see this disorder, but the presentation and discussion were interesting.


Favism and Glucose-6-Phosphate Dehydrogenas Deficiency (3749)
Kyzzatti et al NEJM 378:60 01-04-2018

This is a fascinating article which goes from basic biochemistry to real-life medicine - explaining why fava beans cause hemolytic anemia in people with G6PD deficiency, and why there is variability in the expression of this problem depending upon the fava bean age/cooking method and the G6PD variant carried by the indivicual.

Full article


Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct (3750)
Nogueira et al NEJM 378:11 01-04-2018

A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00).

CONCLUSIONS: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.

Full article

Editorial

From Journal Watch:

Endovascular thrombectomy (EVT) has been demonstrated to improve the outcome for select patients with large-vessel occlusion (LVO) who can be treated within 6 hours. Instead of using a rigid time window, a more physiologic approach is to use a "tissue-based clock." In this paradigm, patients with small infarct cores and extensive areas of brain tissue at risk for infarction can be treated without the constraint of a rigid time window.

To evaluate the use of EVT in select patients with LVO and radiologic data suggesting a small infarct core and greater amount of tissue at risk ("radiologic mismatch"), researchers randomized 206 patients (mean age, 70) who were last known to be well 6 to 24 hours previously, including patients who woke up with stroke symptoms. Patients were assigned to thrombectomy plus standard supportive care or to supportive care alone. The primary endpoint of the manufacturer-sponsored trial was a modified Rankin Scale (mRS) score of 0 to 2 (indicating functional independence) at 90 days, or a utility-weighted Rankin score.

Participants had occlusion of the distal internal carotid or proximal middle cerebral artery and had severe strokes (median NIH stroke scale score, 17). Median time from the last known well point was 12.8 hours. The trial was stopped early when the superiority of EVT became evident. (mRS score 0−2, 49% EVT group vs. 13% control group; mean utility-weighted mRS score, 5.5 EVT group vs. 3.4 control group). There was no difference in symptomatic brain hemorrhage (6% EVT vs. 3% control) or all-cause death at 90 days (19% EVT vs. 18% control).

Comment: These findings beautifully illustrate the value of tissue-based patient selection for acute stroke thrombectomy. The benefit was robust for EVT in delayed time windows. Hospital systems will need to carefully scrutinize how many patients with "wake-up strokes" or strokes of unknown onset time meet the study criteria. Only a minority of patients are likely to be candidates for EVT in the delayed time window. Clinicians should reserve the treatment for clinically moderate or severe stroke patients, as in the trial. Finally, local monitoring of thrombectomy outcomes is crucial at each hospital that provides EVT for acute stroke.


Here are the last 10 additions to the PBrain by date


Favism and Glucose-6-Phosphate Dehydrogenas Deficiency (3749)
Kyzzatti et al NEJM 378:60 01-04-2018

This is a fascinating article which goes from basic biochemistry to real-life medicine - explaining why fava beans cause hemolytic anemia in people with G6PD deficiency, and why there is variability in the expression of this problem depending upon the fava bean age/cooking method and the G6PD variant carried by the indivicual.

Full article


Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct (3750)
Nogueira et al NEJM 378:11 01-04-2018

A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00).

CONCLUSIONS: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.

Full article

Editorial

From Journal Watch:

Endovascular thrombectomy (EVT) has been demonstrated to improve the outcome for select patients with large-vessel occlusion (LVO) who can be treated within 6 hours. Instead of using a rigid time window, a more physiologic approach is to use a "tissue-based clock." In this paradigm, patients with small infarct cores and extensive areas of brain tissue at risk for infarction can be treated without the constraint of a rigid time window.

To evaluate the use of EVT in select patients with LVO and radiologic data suggesting a small infarct core and greater amount of tissue at risk ("radiologic mismatch"), researchers randomized 206 patients (mean age, 70) who were last known to be well 6 to 24 hours previously, including patients who woke up with stroke symptoms. Patients were assigned to thrombectomy plus standard supportive care or to supportive care alone. The primary endpoint of the manufacturer-sponsored trial was a modified Rankin Scale (mRS) score of 0 to 2 (indicating functional independence) at 90 days, or a utility-weighted Rankin score.

Participants had occlusion of the distal internal carotid or proximal middle cerebral artery and had severe strokes (median NIH stroke scale score, 17). Median time from the last known well point was 12.8 hours. The trial was stopped early when the superiority of EVT became evident. (mRS score 0−2, 49% EVT group vs. 13% control group; mean utility-weighted mRS score, 5.5 EVT group vs. 3.4 control group). There was no difference in symptomatic brain hemorrhage (6% EVT vs. 3% control) or all-cause death at 90 days (19% EVT vs. 18% control).

Comment: These findings beautifully illustrate the value of tissue-based patient selection for acute stroke thrombectomy. The benefit was robust for EVT in delayed time windows. Hospital systems will need to carefully scrutinize how many patients with "wake-up strokes" or strokes of unknown onset time meet the study criteria. Only a minority of patients are likely to be candidates for EVT in the delayed time window. Clinicians should reserve the treatment for clinically moderate or severe stroke patients, as in the trial. Finally, local monitoring of thrombectomy outcomes is crucial at each hospital that provides EVT for acute stroke.


Hypothyroidism Summary (3747)
Kney Various 12-31-2017

Bottomline about treating subclinical hypothyroidism:

Full article

Key points from PL, 12/17:


Paroxysmal Nocturnal Hemoglobinuria (3748)
Sykes et al NEJM 377:2581 12-28-2017

Case study from NEJM. I will almost never see this disorder, but the presentation and discussion were interesting.


Chronic Kidney Disease: Detection and Evaluation (3743)
Gaitonde et al AFP 96:776 12-15-2017

Chronic kidney disease affects 47 million people in the United States and is associated with significant health care costs, morbidity, and mortality. Because this disease can silently progress to advanced stages, early detection is critical for initiating timely interventions. Multiple guidelines recommend at least annual screening with serum creatinine, urine albumin/creatinine ratio, and urinalysis for patients with risk factors, particularly diabetes mellitus, hypertension, and a history of cardiovascular disease. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for chronic kidney disease in the general population, and the American College of Physicians recommends against screening asymptomatic adults without risk factors. Persistently elevated serum creatinine and albuminuria are diagnostic and prognostic hallmarks of chronic kidney disease. Lower levels of albuminuria are associated with adverse renal and cardiovascular outcomes. Serum cystatin C is a novel biomarker that is most useful when a false-positive decreased estimated glomerular filtration rate calculated from serum creatinine is suspected. New guidelines incorporate albuminuria into the classification framework for chronic kidney disease and elaborate on identification of the disease, the frequency of follow-up, and recommendations for nephrology referral. Nephrology consultation is indicated for patients with an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2, persistent urine albumin/creatinine ratio greater than 300 mg per g or urine protein/creatinine ratio greater than 500 mg per g, or if there is evidence of a rapid loss of kidney function. A multidisciplinary approach between primary care physicians, nephrologists, and other subspecialists for implementing early interventions, providing education, and planning for advanced renal disease is key for effective management.

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Contemporary hormonal contraception and the risk of breast cancer (3744)
Morch LS et al NEJM 377:2228 12-07-2017

Many women and clinicians are concerned that hormonal contraception might raise risk for breast cancer. In a prospective cohort study, investigators used Danish national data to assess the association between use of hormonal contraception and risk for invasive breast cancer in women aged 15 to 49. Some 1.8 million women were followed for a mean of 10.9 years (1995 to 2012); 11,517 breast cancers were diagnosed. Findings were adjusted for duration of hormonal contraceptive use, age, calendar year, education, parity, polycystic ovary syndrome, endometriosis, and family history of breast or ovarian cancer.

Most hormonal contraceptives were oral formulations, followed by the progestin-releasing intrauterine device (IUD). Relative risk for breast cancer in current or recent users of any hormonal contraceptives compared with never-users was 1.20 (95% confidence interval, 1.14 to 1.26), an absolute risk of 13 additional cases of breast cancer per 100,000 person-years. Current or recent use of the progestin-releasing IUD was associated with an RR of 1.21 (95% CI, 1.11 to 1.33). Breast cancer diagnoses were uncommon among users of contraceptive implants or injections.

Comment: Given that >80% of invasive breast cancers are diagnosed in women older than 49 (for U.S. data, see American Cancer Society), I was surprised that these authors limited their analysis to women between 15 and 49 (despite using a database that tracks all Danish women aged 15 to 79). Clinical breast examinations, screening mammograms, and lactation history all contribute to the diagnosis of breast cancer; thus, I was also surprised that the authors did not adjust their findings for these potential confounders. Epidemiologists caution that, in cohort studies, RRs of less than 2 or 3 should not be interpreted as suggesting causation (Obstet Gynecol 2012; 120:920). It's therefore baffling that neither the investigators nor an editorialist mentioned what constitutes a fundamental limitation of this report. Lastly, an NIH-funded case-control study conducted by CDC investigators - considered by many to be among the definitive studies on this topic - found no suggestion of excess risk for breast cancer with use of oral contraceptives (N Engl J Med 2002; 346:2025). The findings of this Danish study will not alter the way in which I counsel patients about the benefits and risks of hormonal birth control: While we cannot rule out the possibility of a small increase in risk for breast cancer, the best available data suggest that use of hormonal contraceptives does not have an impact on this risk. Andrew M. Kaunitz, MD

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Hunter DJ (editorial): Oral contraceptives and the small increased risk of breast cancer -- NEJM 2017 Dec 7; 377:2276


Shingrix: An Adjuvanted, Recombinant Herpes Zoster Vaccine (3745)
Med Ltr Med Ltr 59:195 12-04-2017

Although not directly compared to one another in clinical trials, adverse reactions appear to occur more often with Shingrix than with Zostavax. Common adverse effects of the new vaccine include myalgia (45%), fatigue (45%), headache (38%), shivering (27%), fever (21%), GI symptoms (17%), and injection-site pain (78%), redness (38%), and swelling (26%). Severe local reactions preventing normal daily activities occurred in 17% of persons who received Shingrix and persisted for a mean of 2 days. Serious adverse events, including new-onset immune-mediated disease and death, occurred at similar rates in the vaccine and placebo groups. Long-term data on the safety of Shingrix are lacking. It is about 91-97% effective - vs Zostavax efficacy of 70% at best (in 50-59 year olds) and of 18% at worst (in those over age 80). Shingrix efficacy remains 91% in those over age 80.

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Evaluation and Management of Female Sexual Dysfunction (3746)
Dawson et al JFP 66:722 12-01-2017

The authors don't provide any simple solutions - because there aren't any! But they do provide a wide range of potential treatment options.

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Hidradenitis Suppurativa: Advances in Diagnosis and Treatment (3732)
Saunte JAMA 318:2019 11-28-2017

Findings The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). HS is more common than was previously thought based on epidemiological analysis (0.05%-4.10%). Disability from HS can be significant. Patients with HS may have significant comorbidities (eg, obesity, metabolic syndrome, diabetes, and arthritis) and increased all-cause mortality (incidence rate ratio, 1.35 [95% CI, 1.15-1.59]). Antibiotic treatment with combinations of clindamycin and rifampicin, or ertapenem followed by combination rifampicin, moxifloxacin, and metronidazole for 6 months is effective. Adalimumab is effective in a significant proportion of patients and treatment with IL-1 and IL-12 receptor subunit beta 1 (Rb1) antibodies may also be useful. Tissue-sparing surgical techniques and carbon dioxide laser treatments also are available, but the evidence on clinical outcomes with these approaches is limited.

Conclusions and Relevance Hidradenitis suppurativa is more common than previously thought and may be treated by an array of pharmacological and surgical techniques. Hidradenitis suppurativa should be considered in the differential diagnosis of nodular lesions or sinus tracts present in the axillae, groin, perineal, and mammillary fold regions.

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Management of Acute Hip Fracture (3729)
Bhandari et al NEJM 377:2053 11-23-2017

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