Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. OBJECTIVE To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. DESIGN, SETTING, AND PARTICIPANTS In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. MAIN OUTCOMES AND MEASURES Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. RESULTS The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. CONCLUSIONS AND RELEVANCE Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in contr...

Authors developed an instrument to isolate and quantify bias produced by the availability and representativeness heuristics, and illustrated the utility of their instrument by demonstrating decreased heuristic bias within medical contexts at higher training levels.

Objectives-Possessing the ε4 allele of apolipoprotein E (APOE-ε4) genotype is associated with cognitive impairment in non-demented older adults. We hypothesized that we might find a subtype of depression related to impaired cognitive performance associated with the APOE-ε4 allele. Design-A survey conducted between 2001-2003 with APOE genotyping.Setting-Primary care offices in the Baltimore, Maryland area.Participants-The study sample consisted of 305 adults aged 65 or older with complete information on APOE genotyping and covariates.Measurements-We used the latent class model to classify respondents according to symptom criteria of the American Psychiatric Association's Diagnostic and Statistical Manual as assessed in the Composite International Diagnostic Interview and the following four measures of cognitive function: the Mini-Mental State Exam, Hopkins Verbal Learning Test, Controlled Oral Word Association Test, and the Brief Test of Attention. We examined the relationship between class membership and APOE genotype.Results-The latent class model yielded three classes: a non-depressed class, a class with depressive symptoms and average cognitive functioning, and a class with depressive symptoms (particularly thoughts of death and suicide) and impaired cognitive functioning. Possessing at least one APOE-ε4 allele was not predictive of class membership.Conclusion-A subgroup of elderly patients with depressive symptoms, cognitive impairment, and a high likelihood of experiencing thoughts of death or suicide may exist that may not be related to APOE-ε4. Subgroups of older patients with depressive symptoms may be important to identify because of the association with thoughts of death or suicide and cognitive impairment (249 words). Keywordsaged; depressive symptoms; cognition; genetic testing; apolipoprotein E; primary careCorresponding Author and Reprints: Hillary R. Bogner, MD, MSCE, Assistant Professor, Department of Family Medicine and Community Health, University of Pennsylvania, 3400 Spruce Street, 2 Gates Building, Philadelphia, PA 19104, Phone: 215-615-0851, Fax: 215-662-3591, hillary.bogner@uphs.upenn.edu. NIH Public Access Author ManuscriptAm J Geriatr Psychiatry. Author manuscript; available in PMC 2010 April 1. Objectives A significant percentage of older depressed adults also have cognitive impairment [1]. Studies based on diagnostic criteria for major and minor depression may miss important associations between depression symptoms and cognitive impairment among older adults. Subtypes of depression in which symptoms are present intermittently or in which sadness and anhedonia are denied may be as important as major depression in older adults because of the association with cognitive impairment. For example, Blazer and colleagues, employing grade-ofmembership analysis to analyze the Durham-Piedmont ECA data, found a symptom profile tending to occur in older persons in which cognitive impairment was prominent and accompanied by sleep and appetite disturbance, hopelessness, and thoughts of de...

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