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To assess the clinical implementation of the 2017 Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists, identify content that may result in classification inconsistencies, and evaluate implementation barriers, an Association for Molecular Pathology Working Group conducted variant interpretation challenges and a guideline implementation survey. A total of 134 participants participated in the variant interpretation challenges, consisting of 11 variants in four cancer cases. Results demonstrate 86% (range, 54% to 94%) of the respondents correctly classified clinically significant variants, variants of uncertain significance, and benign/likely benign variants; however, only 59% (range, 39% to 84%) of responses agreed with the working group's consensus intended responses regarding both tiers and categories of clinical significance. In the implementation survey, 71% (157/220) of respondents have implemented the 2017 guidelines for variant classification and reporting either with or without modifications. Collectively, this study demonstrates that, although they may not yet be optimized, the 2017 guideline recommendations are being adopted for standardized somatic variant classification. The working group identified significant areas for future guideline improvement, including the need for a more granular and comprehensive classification system and education resources to meet the growing needs of both laboratory professionals and medical oncologists., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Infection with hepatitis C virus is the leading cause of infectious disease mortality in the United States. BZF961 is a novel small molecule inhibitor of the hepatitis C virus NS3-4A protease. Here we present the results of a randomized, double-blinded, placebo-controlled, multicentered study in treatment-naïve patients with chronic hepatitis C virus genotype-1 infection., Methods: Patients were enrolled sequentially in 2 parts and treated for 3days. BZF961 was administered as monotherapy (500mg BID for 3 days) or in combination with the cytochrome P450 3A4 inhibitor ritonavir to boost its exposure (BZF961 10, 20, or 50mg QD or BID)., Findings: BZF961 was safe and well tolerated in the patients studied with no serious adverse events. There were no appreciable differences in adverse events among patients who received BZF961, BZF961 with ritonavir, or placebo. There was a significant, clinically meaningful reduction in viral load from baseline in patients treated either with BZF961 500mg every 12hours alone or BZF961 50mg every 12hours in combination with ritonavir. Activity against the hepatitis C virus of the lower-dose regimens was apparent but more modest. There were no relevant changes from baseline viral loads in placebo-treated patients., Implications: Coadministration of ritonavir with BZF961 boosted BZF961 exposure (including C min , which is the clinically relevant parameter associated with antiviral activity) in a therapeutic range with less variability compared with BZF961 alone. For strategic reasons, BZF961 is no longer under development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Severe Acinetobacter baumannii infections in immunocompetent patients are uncommon, and the virulence mechanisms of this organism are not fully understood., Methods: Following an outbreak of fatal A. baumannii infections in a cohort of relatively immunocompetent patients (low comorbidity and illness severity scores), isolates were investigated with comparative genomics and in animal models., Results: Two unrelated A. baumannii clades were associated with the outbreak. The clone associated with the majority of patient deaths, clade B, is evolutionarily distinct from the 3 international clonal complexes, belongs to multilocus sequence type (MLST) 10, and is most closely related to strains isolated from the Czech Republic, California, and Germany in 1994, 1997, and 2003, respectively. In 2 different murine models, clade B isolates were more virulent than comparator strains, including the highly virulent reference strain AB5075. The most virulent clade B derivative, MRSN 16897, was isolated from the patient with the lowest combined comorbidity/illness severity score. Clade B isolates possess a unique combination of putative virulence genes involved in iron metabolism, protein secretion, and glycosylation, which was leveraged to develop a rapid and specific clinical assay to detect this clade that cannot be distinguished by MLST., Conclusions: Clade B warrants continued surveillance and investigation., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown etiology characterized by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination. We report a patient with a 4-year history of MSA who developed dementia associated with sporadic Creutzfeldt-Jakob disease (CJD). Our proband was MM homozygous for the M129V polymorphism within the prion protein gene (PRNP), a known risk factor for CJD. We conducted a case-control study to test the hypothesis that homozygosity for the M129V polymorphism of PRNP occurs more frequently in MSA in comparison to Parkinson's disease and healthy volunteers. A total of 63 patients with MSA, 54 age-, race- and gendermatched controls with Parkinson's disease, and 126 matched healthy volunteers were studied. The genotype analysis revealed no significant difference in the codon 129 genotype distribution in MSA as compared to controls. Nonetheless, the frequencies of the MM and VV genotypes were higher in MSA than in Parkinson's disease. Thus, homozygosity, particularly VV homozygosity, at codon 129 of PRNP is associated with MSA compared to a clinically related but pathophysiologically distinct alpha-synucleinopathy. Considering the possibility that the prion protein contributes to the pathogenesis of MSA would require confirmation of these findings in an independent patient population.

Objective: Hypertension (HTN) is a major risk factor for cardiovascular disease (CVD) in the setting of diabetes. There is no consensus on how best to treat hypertension among those with diabetes. Here we describe the characteristics of a cohort of hypertensive adults with diabetes who are part of a large prospective blood pressure study. This study will help clarify the treatment of HTN in the setting of diabetes., Research Design and Methods: The Antihypertensive and Lipid-Lowering high-risk hypertensive participants, ages > or = 55 years, designed to determine whether the incidence of fatal and nonfatal coronary heart disease (CHD) and combined cardiovascular events (fatal and nonfatal CHD, revascularization surgery, angina pectoris, congestive heart failure, and stroke) differs between diuretic (chlorthalidone) treatment and three alternative antihypertensive therapies: a calcium channel blocker (amlodipine), an ACE inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). The planned follow-up is an average of 6 years, to be completed March 2002., Results: There are 15,297 diabetic individuals in the ALLHAT study (36.0% of the entire cohort). Of these individuals, 50.2% are male, 39.4% are African-American, and 17.7% are Hispanic. Demographic and laboratory characteristics of the cohort are similar to those of other studies of the U.S. elderly population with HTN. The sample size has 42 and 93% confidence, treatments for the two study outcomes., Conclusions: The diabetic cohort in ALLHAT wil be able to provide valuable information about the treatment of hypertension in older diabetic patients at risk for incident CVD.

Integrated library systems have not yet been created, although they have been emphasized for nearly two decades. Now and in the future, the task is even more complex because the principal issue is access to information itself, wherever it is located and in whatever form it may exist. The goal becomes more feasible because of changes in library practices achieved with technological innovation. Although individual elements of a campus-wide information system may already exist, the details for implementation are yet to be articulated.

MLA committee membership by category (medical school, society and hospital) for the past three years is examined revealing a heavy reliance upon medical school librarians for committee members. A ten-year examination of committee membership and turnover in individual committee membership rosters points out those committees whose rate of turnover is greatest. Opportunities for service by new MLA members is examined as is committee tenure as experienced during the last decade. Turnover, tenure, and frequency of leadership is examined for the ten-year period. Pointing out that only 360 individuals have served MLA in committee positions listed in the Bulletin, the Ad Hoc Committee to Review the Goals and Structure of the Medical Library Association is urged to more actively seek the opinions of the membership and to consider the service patterns of the past in recommending a course for the future.