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Original Research | 
Colleen R. Kelly, MD; Alexander Khoruts, MD; Christopher Staley, PhD; Michael J. Sadowsky, PhD; Mortadha Abd, MD; Mustafa Alani, MD; Brianna Bakow, BA; Patrizia Curran, MD; Joyce McKenney, MS; Allison Tisch, NP; Steven E. Reinert, MS; Jason T. Machan, PhD; and Lawrence J. Brandt, MD
Includes: Supplemental Content
Background:To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials. Objective:To determine the efficacy and safety of FMT for treatment of recurrent CDI. Design:Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494) Setting:Two academic medical centers. Patients:46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode. Intervention:Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy. Measurements:The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool. Results:In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors. Limitation:The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older. Conclusion:Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes. Primary Funding Source:National Institute of Diabetes and Digestive and Kidney Diseases.
Topics: transplantation, fecal transplant, microbiome, donors, clostridium difficile infection, feces, follow-up, vancomycin
Reviews | 
Dae Hyun Kim, MD, MPH, ScD; Caroline A. Kim, MD, MS, MPH; Sebastian Placide, BA; Lewis A. Lipsitz, MD; and Edward R. Marcantonio, MD, ScM
Includes: Supplemental Content
Background:Frailty assessment may inform surgical risk and prognosis not captured by conventional surgical risk scores. Purpose:To evaluate the evidence for various frailty instruments used to predict mortality, functional status, or major adverse cardiovascular and cerebrovascular events (MACCEs) in older adults undergoing cardiac surgical procedures. Data Sources:MEDLINE and EMBASE (without language restrictions), from their inception to 2 May 2016. Study Selection:Cohort studies evaluating the association between frailty and mortality or functional status at 6 months or later in patients aged 60 years or older undergoing major or minimally invasive cardiac surgical procedures. Data Extraction:2 reviewers independently extracted study data and assessed study quality. Data Synthesis:Mobility, disability, and nutrition were frequently assessed domains of frailty in both types of procedures. In patients undergoing major procedures (n = 18 388; 8 studies), 9 frailty instruments were evaluated. There was moderate-quality evidence to assess mobility or disability and very-low- to low-quality evidence for using a multicomponent instrument to predict mortality or MACCEs. No studies examined functional status. In patients undergoing minimally invasive procedures (n = 5177; 17 studies), 13 frailty instruments were evaluated. There was moderate- to high-quality evidence for assessing mobility to predict mortality or functional status. Several multicomponent instruments predicted mortality, functional status, or MACCEs, but the quality of evidence was low to moderate. Multicomponent instruments that measure different frailty domains seemed to outperform single-component ones. Limitation:Heterogeneity of frailty assessment, limited generalizability of multicomponent frailty instruments, few validated frailty instruments, and potential publication bias. Conclusion:Frailty status, assessed by mobility, disability, and nutritional status, may predict mortality at 6 months or later after major cardiac surgical procedures and functional decline after minimally invasive cardiac surgery. Primary Funding Source:National Institute on Aging and National Heart, Lung, and Blood Institute.
Topics: cardiac surgery procedures, frailty, elderly
Editorials | 
Elizabeth L. Hohmann, MD
Kelly and colleagues report a randomized trial of fecal microbiota transplantation versus autologous stool for recurrent Clostridium difficile infection. The editorialist discusses possible explanations for the site differences in cure rates among patients receiving autologous stool.
Topics: feces, politics, fecal transplant, microbiome, transplantation, clostridium difficile infection
Editorials | 
Victoria L. Tang, MD, MAS; and Kenneth Covinsky, MD, MPH
Frailty is a syndrome of aging that increasingly is being recognized as an important predictor of patient outcomes. In their current article, Kim and colleagues present a systematic review on preoperative frailty assessment and long-term outcomes in older adults undergoing cardiac surgical procedures. The editorialists discuss how the findings support assessing older adults considering surgery for frailty. Through identifying frailty, we may be able to improve care for our older surgical patients.
Topics: frailty, decision making
Original Research | 
Amy Trentham-Dietz, PhD; Karla Kerlikowske, MD, MS; Natasha K. Stout, PhD; Diana L. Miglioretti, PhD; Clyde B. Schechter, MD, MA; Mehmet Ali Ergun, MSc; Jeroen J. van den Broek, MS; Oguzhan Alagoz, PhD; Brian L. Sprague, PhD; Nicolien T. van Ravesteyn, PhD; Aimee M. Near, MPH; Ronald E. Gangnon, PhD; John M. Hampton, MS; Young Chandler, DrPH, MS, MPH; Harry J. de Koning, MD, PhD; Jeanne S. Mandelblatt, MD, MPH; Anna N.A. Tosteson, ScD, on behalf of the Breast Cancer Surveillance Consortium and Cancer Intervention and Surveillance Modeling Network
Background:Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits. Objective:To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer. Design:Collaborative simulation modeling using national incidence, breast density, and screening performance data. Setting:United States. Patients:Women aged 50 years or older with various combinations of breast density and relative risk (RR) of 1.0, 1.3, 2.0, or 4.0. Intervention:Annual, biennial, or triennial digital mammography screening from ages 50 to 74 years (vs. no screening) and ages 65 to 74 years (vs. biennial digital mammography from ages 50 to 64 years). Measurements:Lifetime breast cancer deaths, life expectancy and quality-adjusted life-years (QALYs), false-positive mammograms, benign biopsy results, overdiagnosis, cost-effectiveness, and ratio of false-positive results to breast cancer deaths averted. Results:Screening benefits and overdiagnosis increase with breast density and RR. False-positive mammograms and benign results on biopsy decrease with increasing risk. Among women with fatty breasts or scattered fibroglandular density and an RR of 1.0 or 1.3, breast cancer deaths averted were similar for triennial versus biennial screening for both age groups (50 to 74 years, median of 3.4 to 5.1 vs. 4.1 to 6.5 deaths averted; 65 to 74 years, median of 1.5 to 2.1 vs. 1.8 to 2.6 deaths averted). Breast cancer deaths averted increased with annual versus biennial screening for women aged 50 to 74 years at all levels of breast density and an RR of 4.0, and those aged 65 to 74 years with heterogeneously or extremely dense breasts and an RR of 4.0. However, harms were almost 2-fold higher. Triennial screening for the average-risk subgroup and annual screening for the highest-risk subgroup cost less than $100 000 per QALY gained. Limitation:Models did not consider women younger than 50 years, those with an RR less than 1, or other imaging methods. Conclusion:Average-risk women with low breast density undergoing triennial screening and higher-risk women with high breast density receiving annual screening will maintain a similar or better balance of benefits and harms than average-risk women receiving biennial screening. Primary Funding Source:National Cancer Institute.
Topics: breast cancer, breast neoplasm screening, breast density, mammography
Trentham-Dietz and colleagues modeled the benefits and harms of tailoring breast cancer screening intervals by breast density category and cancer risk. The editorialist explains and critiques the findings, welcoming them as a possible way to individualize mammography screening intervals.
Topics: breast neoplasm screening, mammography
Ideas and Opinions | 
Frank A. Lederle, MD; William C. Cushman, MD; Ryan E. Ferguson, ScD, MPH; Mary T. Brophy, MD, MPH; and Louis D. Fiore, MD, MPH
This article presents an overview of a large, multicenter, randomized clinical trial that will compare the effects of hydrochlorothiazide with chlorthalidone on cardiovascular events among Veterans Affairs patients. The trial has several unique features that will allow it to be conducted efficiently and inexpensively within the context of ongoing clinical care received by study participants.
Topics: chlorthalidone, veterans, hydrochlorothiazide (hctz)
Original Research | 
Mark Loeb, MD; Margaret L. Russell, MD, PhD; Vanessa Manning, BSc; Kevin Fonseca, PhD; David J.D. Earn, PhD; Gregory Horsman, MD; Khami Chokani, MD; Mark Vooght, MD; Lorne Babiuk, PhD; Lisa Schwartz, PhD; Binod Neupane, PhD; Pardeep Singh, BSc; Stephen D. Walter, PhD; and Eleanor Pullenayegum, PhD
Includes: Supplemental Content
Background:Whether vaccinating children with intranasal live attenuated influenza vaccine (LAIV) is more effective than inactivated influenza vaccine (IIV) in providing both direct protection in vaccinated persons and herd protection in unvaccinated persons is uncertain. Hutterite colonies, where members live in close-knit, small rural communities in which influenza virus infection regularly occurs, offer an opportunity to address this question. Objective:To determine whether vaccinating children and adolescents with LAIV provides better community protection than IIV. Design:A cluster randomized blinded trial conducted between October 2012 and May 2015 over 3 influenza seasons. Setting:52 Hutterite colonies in Alberta and Saskatchewan, Canada. Participants:1186 Canadian children and adolescents aged 36 months to 15 years who received the study vaccine and 3425 community members who did not. Intervention:Children were randomly assigned according to community in a blinded manner to receive standard dosing of either trivalent LAIV or trivalent IIV. Measurements:The primary outcome was reverse transcriptase polymerase chain reaction–confirmed influenza A or B virus in all participants (vaccinated children and persons who did not receive the study vaccine). Results:Mean vaccine coverage among children in the LAIV group was 76.9% versus 72.3% in the IIV group. Influenza virus infection occurred at a rate of 5.3% (295 of 5560 person-years) in the LAIV group versus 5.2% (304 of 5810 person-years) in the IIV group. The hazard ratio comparing LAIV with IIV for influenza A or B virus was 1.03 (95% CI, 0.85 to 1.24). Limitation:The study was conducted in Hutterite communities, which may limit generalizability. Conclusion:Immunizing children with LAIV does not provide better community protection against influenza than IIV. Primary Funding Source:The Canadian Institutes for Health Research.
Topics: influenza, influenza virus vaccine, vaccination, vaccines, influenza vaccine, trivalent live attenuated, attenuation
Reviews | 
Gowri Raman, MD, MS; Gaelen P. Adam, MLIS; Christopher W. Halladay, BA, ScM; Valerie N. Langberg, ScM; Ijeoma A. Azodo, MD, ChM; and Ethan M. Balk, MD, MPH
Includes: Supplemental Content
Background:Atherosclerotic renal artery stenosis (ARAS) is associated with high blood pressure (BP), decreased kidney function, renal replacement therapy (RRT), and death. Purpose:To compare benefits and harms of percutaneous transluminal renal angioplasty with stent placement (PTRAS) versus medical therapy alone in adults with ARAS. Data Sources:MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from 1993 to 16 March 2016; gray literature; and prior systematic reviews. Study Selection:Randomized, controlled trials (RCTs); nonrandomized, comparative studies (NRCSs); single-group studies; and selected case reports that reported all-cause and cardiovascular mortality, RRT, kidney function, BP, and adverse events. Data Extraction:Six researchers extracted data on design, interventions, outcomes, and study quality into a Web-based database. Data Synthesis:Eighty-three studies met eligibility criteria. In 5 of 7 RCTs, PTRAS and medical therapy led to similar BP control in patients with ARAS, and no RCTs showed statistically significant differences in kidney function, mortality, RRT, cardiovascular events, or pulmonary edema. Eight NRCSs had more variable results, finding mostly no significant differences in mortality, RRT, or cardiovascular events but heterogeneous effects on kidney function and BP. Procedure-related adverse events were rare, and medication-related adverse events were not reported. Two RCTs found no patient characteristics that were associated with outcomes with either PTRAS or medical therapy. Single-group studies found various but inconsistent factors that predict outcomes. Case reports provided examples of clinical improvement after PTRAS in patients with acute decompensation. Limitation:Limited clinical applicability and power in RCTs, and possible publication bias and lack of adjusted analyses in NRCSs. Conclusion:The strength of evidence regarding the relative benefits and harms of PTRAS versus medical therapy alone for patients with ARAS is low. Studies have generally focused on patients with less severe ARAS. Primary Funding Source:Agency for Healthcare Research and Quality.
Topics: atherosclerotic renal artery stenosis, stent, renal artery stenosis, renal function, decompensation, cardiovascular event, adverse event, comparative effectiveness research, medical management, percutaneous transluminal angioplasty of renal artery, mortality, pulmonary edema, blood pressure regulation
The results of recent randomized trials indicate benefit from even lower systolic blood pressure targets than previously recommended for the treatment of hypertension. The author argues that duplicating these benefits in clinical practice will require validated means of identifying the appropriate patients, not just the provision of antihypertensive therapies.
Topics: systolic blood pressure, antihypertensive therapy
This commentary from the new Director of the National Library of Medicine (NLM) discusses the NLM's commitment to accelerating discovery and achieving the promise of precision medicine.
Topics: national library of medicine (u.s.)
Medicine and Public Issues | 
Wendy Macias-Konstantopoulos, MD, MPH
Human trafficking, a form of modern slavery, is an egregious violation of human rights with profound personal and public health implications. It includes forced labor and sexual exploitation of both U.S. and non-U.S. citizens and has been reported in all 50 states. Victims of human trafficking are currently among the most abused and disenfranchised persons in society, and they face a wide range of negative health outcomes resulting from their subjugation and exploitation.Medicine has an important role to play in mitigating the devastating effects of human trafficking on individuals and society. Victims are cared for in emergency departments, primary care offices, urgent care centers, community health clinics, and reproductive health clinics. In addition, they are unknowingly being treated in hospital inpatient units. Injuries and illnesses requiring medical attention thus represent unique windows of opportunity for trafficked persons to receive assistance from trusted health care professionals.With education and training, health care providers can recognize signs and symptoms of trafficking, provide trauma-informed care to this vulnerable population, and respond to exploited persons who are interested and ready to receive assistance. Multidisciplinary response protocols, research, and policy advocacy can enhance the impact of antitrafficking health care efforts to interrupt the cycle of abuse and violence for these victims.
Topics: violence, human trafficking, wounds and injuries, health personnel
Original Research | 
Gregory J. Dore, MD; Frederick Altice, MD; Alain H. Litwin, MD; Olav Dalgard, MD; Edward J. Gane, MD; Oren Shibolet, MD; Anne Luetkemeyer, MD; Ronald Nahass, MD; Cheng-Yuan Peng, MD; Brian Conway, MD; Jason Grebely, PhD; Anita Y.M. Howe, PhD; Isaias N. Gendrano, MPH; Erluo Chen, MPH; Hsueh-Cheng Huang, PhD; Frank J. Dutko, PhD; David C. Nickle, PhD; Bach-Yen Nguyen, MD; Janice Wahl, MD; Eliav Barr, MD; Michael N. Robertson, MD; Heather L. Platt, MD, on behalf of the C-EDGE CO-STAR Study Group
Includes: Supplemental Content
Background:Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective:To evaluate elbasvir–grazoprevir in treating HCV infection in PWID. Design:Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688) Setting:Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients:301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid-agonist therapy (OAT). Intervention:The immediate-treatment group (ITG) received elbasvir–grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir–grazoprevir for 12 weeks. Measurements:The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results:The SVR12 was 91.5% (95% CI, 86.8 to 95.0) in the ITG and 89.5% (95% CI, 81.5 to 94.8) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8 to 96.9) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation:These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion:Patients with HCV infection who were receiving OAT and treated with elbasvir–grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source:Merck & Co., Inc., Kenilworth, New Jersey, USA.
Topics: therapeutics, hepatitis c virus, opioid agonists, reinfection, grazoprevir, elbasvir, hepatitis c, safety, follow-up
Reviews | 
Roger Chou, MD; Tracy Dana, MLS; Ian Blazina, MPH; Monica Daeges, BA; Christina Bougatsos, MPH; and Thomas L. Jeanne, MD, MPH
Background:Dyslipidemia may occur in younger adults (defined as persons aged 21 to 39 years) and is an important risk factor for cardiovascular disease. Screening might identify younger adults with asymptomatic dyslipidemia who may benefit from lipid-lowering therapies. Purpose:To update the 2008 U.S. Preventive Services Task Force review on dyslipidemia screening in younger adults. Data Sources:The Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and MEDLINE through May 2016, and reference lists. Study Selection:Randomized, controlled trials; cohort studies; and case–control studies on screening for or treatment of asymptomatic dyslipidemia in adults aged 21 to 39 years. Data Extraction:The plan was for 1 investigator to abstract data and a second to check their accuracy, and for 2 investigators to independently assess study quality; however, no studies met the inclusion criteria. Data Synthesis:No study evaluated the effects of lipid screening versus no screening, treatment versus no treatment, or delayed versus earlier treatment on clinical outcomes in younger adults. In addition, no study evaluated the diagnostic yield of alternative screening strategies (such as targeted screening of persons with a family history of hyperlipidemia vs. general screening) in younger adults. Limitation:No direct relevant evidence. Conclusion:Direct evidence on the benefits and harms of screening for or treatment of dyslipidemia in younger adults remains unavailable. Estimating the potential effects of screening for dyslipidemia in this population requires extrapolation from studies performed in older adults. Primary Funding Source:Agency for Healthcare Research and Quality.
Topics: dyslipidemias
Original Research | 
Daniel Murphy, MD; Charles E. McCulloch, PhD; Feng Lin; Tanushree Banerjee, PhD; Jennifer L. Bragg-Gresham, PhD; Mark S. Eberhardt, PhD; Hal Morgenstern, PhD; Meda E. Pavkov, MD, PhD; Rajiv Saran, MBBS, MD, MS; Neil R. Powe, MD, MPH, MBA; Chi-yuan Hsu, MD, MSc, for the Centers for Disease Control and Prevention Chronic Kidney Disease Surveillance Team
Background:Trends in the prevalence of chronic kidney disease (CKD) are important for health care policy and planning. Objective:To update trends in CKD prevalence. Design:Repeated cross-sectional study. Setting:NHANES (National Health and Nutrition Examination Survey) for 1988 to 1994 and every 2 years from 1999 to 2012. Participants:Adults aged 20 years or older. Measurements:Chronic kidney disease (stages 3 and 4) was defined as an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2, estimated with the Chronic Kidney Disease Epidemiology Collaboration equation from calibrated serum creatinine measurements. An expanded definition of CKD also included persons with an eGFR of at least 60 mL/min/1.73 m2 and a 1-time urine albumin–creatinine ratio of at least 30 mg/g. Results:The unadjusted prevalence of stage 3 and 4 CKD increased from the late 1990s to the early 2000s. Since 2003 to 2004, however, the overall prevalence has largely stabilized (for example, 6.9% prevalence in 2003 to 2004 and in 2011 to 2012). There was little difference in adjusted prevalence of stage 3 and 4 CKD overall in 2003 to 2004 versus 2011 to 2012 after age, sex, race/ethnicity, and diabetes mellitus status were controlled for (P = 0.26). Lack of increase in CKD prevalence since the early 2000s was observed in most subgroups and with an expanded definition of CKD that included persons with higher eGFRs and albuminuria. Limitation:Serum creatinine and albuminuria were measured only once in each person. Conclusion:In a reversal of prior trends, there has been no appreciable increase in the prevalence of stage 3 and 4 CKD in the U.S. population overall during the most recent decade. Primary Funding Source:American Society of Nephrology Foundation for Kidney Research Student Scholar Grant Program, Centers for Disease Control and Prevention, and National Institutes of Health.
Topics: kidney failure, chronic, trend, diabetes mellitus
Murphy and colleagues analyze trends in the prevalence of chronic kidney disease (CKD) in U.S. adults by using data from NHANES (National Health and Nutrition Examination Survey) from 1999 to 2012 compared with earlier periods. The editorialists note that, unfortunately, the observed improvement in CKD prevalence has not been uniform across all populations. In addition, although the data showing stabilization in CKD prevalence are cause for optimism, the underlying reason for the bending of the CKD prevalence curve is uncertain.
Topics: kidney failure, chronic, positive attitude
Reviews | 
Francine Chingcuanco, MHS; Jodi B. Segal, MD, MPH; Seoyoung C. Kim, MD, ScD, MSCE; and G. Caleb Alexander, MD
Background:Biosimilars are of growing clinical, regulatory, and commercial importance. Purpose:To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors. Data Sources:PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016. Study Selection:Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-α inhibitor with a reference biologic in humans. Data Extraction:Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality. Data Synthesis:Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes. Limitation:Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars. Conclusion:Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors. Primary Funding Source:Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262)
Topics: tumor necrosis factors, biological products, tumor necrosis, biosimilar pharmaceuticals, therapeutic equivalency, adverse event
Original Research | 
Diana Lopez, MD; Miguel Angel Luque-Fernandez, PhD, MPH, MSc; Amy Steele, BA; Gail K. Adler, MD, PhD; Alexander Turchin, MD, MS; and Anand Vaidya, MD, MMSc
Background:Benign adrenal tumors are commonly discovered on abdominal imaging. Most are classified as nonfunctional and are considered to pose no health risk, but some are considered functional because they secrete hormones that increase risk for metabolic and cardiovascular diseases. Objective:To evaluate the hypothesis that nonfunctional adrenal tumors (NFATs) increase risk for cardiometabolic outcomes compared with absence of adrenal tumors. Design:Cohort study. Setting:Integrated hospital system. Participants:Participants with benign NFATs (“exposed”; n = 166) and those with no adrenal tumor (“unexposed”; n = 740), with at least 3 years of follow-up. Measurements:Medical records were reviewed from the time of abdominal imaging for development of incident outcomes (hypertension, composite diabetes [prediabetes or type 2 diabetes], hyperlipidemia, cardiovascular events, and chronic kidney disease) (mean, 7.7 years). Primary analyses evaluated independent associations between exposure status and incident outcomes by using adjusted generalized linear models. Secondary analyses evaluated relationships between NFATs and cortisol physiology. Results:Participants with NFATs had significantly higher risk for incident composite diabetes than those without adrenal tumors (30 of 110 [27.3%] vs. 72 of 615 [11.7%] participants; absolute risk, 15.6% [95% CI, 6.9% to 24.3%]; adjusted risk ratio, 1.87 [CI, 1.17 to 2.98]). No significant associations between NFATs and other outcomes were observed. Higher “normal” postdexamethasone cortisol levels (≤50 nmol/L) were associated with larger NFAT size and higher prevalence of type 2 diabetes. Limitation:Potential bias in the selection of participants and ascertainment of outcomes. Conclusion:Participants with NFATs had a significantly higher risk for diabetes than those without adrenal tumors. These results should prompt a reassessment of whether the classification of benign adrenal tumors as “nonfunctional” adequately reflects the continuum of hormone secretion and metabolic risk they may harbor. Primary Funding Source:National Institutes of Health and Doris Duke Charitable Foundation.
Topics: diabetes mellitus, diabetes mellitus, type 2, adrenal mass, adrenal gland neoplasms, cardiovascular system
Editorials | 
Issam Zineh, PharmD, MPH; and Leah A. Christl, PhD
Chingcuanco and colleagues systematically review the pharmacokinetic, efficacy, adverse event, and immunogenicity profiles of reference tumor necrosis factor-α (TNF-α) inhibitors and biosimilar TNF-α inhibitors approved by regulatory health authorities or in development. With caveats, the authors state that the evidence supports a conclusion that no meaningful differences exist between putative biosimilar TNF-α inhibitors and reference biologics. The editorialists outline important principles that will undoubtedly underpin any regulatory guidance in the evolving area of biosimilars.
Topics: biological products, biosimilar pharmaceuticals, tumor necrosis factors, adverse event
Topics: diabetes mellitus, adrenal glands, diabetes mellitus, type 2, neoplasms
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