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This study investigated the association between COVID-19 infection and host metabolic signatures as prognostic markers for disease severity and mortality. We enrolled 82 patients with RT-PCR confirmed COVID-19 infection who were classified as mild, moderate, or severe/critical based upon their WHO clinical severity score and compared their results with 31 healthy volunteers. Data on demographics, comorbidities and clinical/laboratory characteristics were obtained from medical records. Peripheral blood samples were collected at the time of clinical evaluation or admission and tested by quantitative mass spectrometry to characterize metabolic profiles using selected metabolites. The findings in COVID-19 (+) patients reveal changes in the concentrations of glutamate, valeryl-carnitine, and the ratios of Kynurenine/Tryptophan (Kyn/Trp) to Citrulline/Ornithine (Cit/Orn). The observed changes may serve as predictors of disease severity with a (Kyn/Trp)/(Cit/Orn) Receiver Operator Curve (ROC) AUC = 0.95. Additional metabolite measures further characterized those likely to develop severe complications of their disease, suggesting that underlying immune signatures (Kyn/Trp), glutaminolysis (Glutamate), urea cycle abnormalities (Cit/Orn) and alterations in organic acid metabolism (C5) can be applied to identify individuals at the highest risk of morbidity and mortality from COVID-19 infection. We conclude that host metabolic factors, measured by plasma based biochemical signatures, could prove to be important determinants of Covid-19 severity with implications for prognosis, risk stratification and clinical management.

Option B+, an approach that involves provision of antiretroviral therapy (ART) to all HIV-infected pregnant women for life, is the preferred strategy for prevention of mother to child transmission of HIV. Lifelong retention in care is essential to its success. We conducted a discrete choice experiment in Ethiopia and Mozambique to identify health system characteristics preferred by HIV-infected women to promote continuity of care. Women living with HIV and receiving care at hospitals in Oromia Region, Ethiopia and Zambézia Province, Mozambique were shown nine choice cards and asked to select one of two hypothetical health facilities, each with six varying characteristics related to the delivery of HIV services for long term treatment. Mixed logit models were used to estimate the influence of six health service attributes on choice of clinics. 2,033 women participated in the study (response rate 97.8% in Ethiopia and 94.7% in Mozambique). Among the various attributes of structure and content of lifelong ART services, the most important attributes identified in both countries were respectful provider attitude and ability to obtain non-HIV health services during HIV-related visits. Availability of counseling support services was also a driver of choice. Facility type, i.e., hospital versus health center, was substantially less important. Efforts to enhance retention in HIV care and treatment for pregnant women should focus on promoting respectful care by providers and integrating access to non-HIV health services in the same visit, as well as continuing to strengthen counseling.

In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period. In the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Background While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers. Methods We designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity. Results Among tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05–2.06), exposure to COVID-19 outside of work (2.29, 1.14–4.29), working in food or environmental services (4.85, 1.51–14.85), and working in COVID-19 units (ICU: 2.28, 1.29–3.96; ward: 1.59, 1.01–2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10–7.10). Conclusion SARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.

Background Cone contrast threshold testing (CCT) provides quantitative measurements of color and contrast function to reveal changes in vision quality that are not standard endpoints in clinical trials. We utilize CCT to measure visual function in patients with multiple sclerosis (MS), age-related macular degeneration (AMD), epiretinal membrane (ERM), and retinal vein occlusion (RVO). Methods Retrospective data was gathered from 237 patients of the Gavin Herbert Eye Institute. Subjects included 17 patients with MS, 45 patients with AMD, 41 patients with ERM, 11 patients with RVO, and 123 healthy controls. Patients underwent the primary measurement outcome, CCT testing, as well as Sloan visual acuity test and spectral domain optical coherence tomography during normal care. Results Color and contrast deficits were present in MS patients regardless of history of optic neuritis. AMD with intermediate or worse disease demonstrated reduced CCT scores. All 3 stages of ERM demonstrated cone contrast deficits. Despite restoration of visual acuity, RVO-affected eyes demonstrated poorer CCT performance than unaffected fellow eyes. Conclusions CCT demonstrates color and contrast deficits for multiple retinal diseases with differing pathophysiology. Further prospective studies of CCT in other disease states and with larger samples sizes is warranted.

Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 SARS-CoV-2 antigens. In a prospective longitudinal cohort of 240 healthcare workers, composite SARS-CoV-2 IgG antibody levels did not wane significantly over a 6-month study period. In the subset of the study population previously exposed to SARS-CoV-2 based on seropositivity for nucleocapsid antibodies, higher composite anti-spike IgG levels were measured before the vaccine but no significant difference from unexposed individuals was observed at 6 months. Age, vaccine type, or worker role did not significantly impact composite IgG levels, although non-significant trends towards lower antibody levels in older participants and higher antibody levels with Moderna vaccine were observed at 6 months. A small subset of our cohort were classified as having waning antibody titers at 6 months, and these individuals were less likely to work in patient care roles and more likely to have prior exposure to SARS-CoV-2.

Agitation symptoms are common and burdensome in patients with Alzheimer's dementia. In these vulnerable patients, it is important to sustain treatment effects over the longer term while maintaining a favorable safety profile. This post hoc analysis aimed to evaluate clinically meaningful efficacy, and safety, of brexpiprazole throughout 24 weeks of treatment. Data were included from a Phase 3, 12-week, randomized, placebo-controlled trial of brexpiprazole 2 or 3 mg/day in patients with agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov: NCT03548584 [Trial 213]) and a 12-week extension trial (NCT03594123 [Trial 182]). Trial 182 enrolled patients who completed treatment with brexpiprazole or placebo in Trial 213; thereafter, patients received brexpiprazole 2 or 3 mg/day. In this post hoc analysis, the proportion of patients who achieved a sustained clinically meaningful response (20-point reduction in Cohen-Mansfield Agitation Inventory Total score maintained to trial end) was evaluated over 12 weeks (brexpiprazole versus placebo) and 24 weeks ('prior brexpiprazole' [received brexpiprazole in both trials] versus 'prior placebo' [received placebo in Trial 213 and brexpiprazole in Trial 182]). Safety was assessed in the prior brexpiprazole (24-week brexpiprazole) subgroup only, reflecting the longest evaluable brexpiprazole treatment duration. The incidence of treatment-emergent adverse events (TEAEs), and median TEAE duration, were assessed. Analyses of time to first occurrence of any TEAE were conducted using descriptive statistics and Kaplan-Meier methodology. A sustained clinically meaningful response was achieved by 49.3% (brexpiprazole; n=225) versus 32.8% (placebo; n=116) at Week 12, and 75.5% (prior brexpiprazole; n=159) versus 68.4% (prior placebo; n=95) at Week 24. In the prior brexpiprazole subgroup (n =163), 48.5% reported TEAEs over 24 weeks. Median (interquartile range) TEAE duration was 3 (1-8) days and time-to-first event was 7.4 (3-12) weeks. Kaplan-Meier curves indicated that, among patients who had not already experienced a TEAE in the randomized trial, TEAEs were rare throughout the extension trial. Brexpiprazole 2 or 3 mg/day was associated with sustained clinically meaningful efficacy over 24 weeks in patients with agitation associated with dementia due to Alzheimer's disease. Longer-term treatment with brexpiprazole over the 24-week period was not associated with additional safety signals.

Patients with Alzheimer's dementia can experience a wide range of agitation symptoms. In a caregiver survey that assessed the Cohen-Mansfield Agitation Inventory (CMAI), agitation symptoms considered \"most bothersome\", and which influenced caregiver decisions to transfer to long-term care, included aggressive behaviors (e.g., cursing or verbal aggression, hitting), verbally agitated behaviors (e.g., constant unwarranted requests for attention/help, repetitive sentences/questions), and physically non-aggressive behaviors (e.g., pacing/aimless wandering). Brexpiprazole (an atypical antipsychotic with noradrenergic, serotonergic, and dopaminergic activity) is the only FDA-approved treatment for agitation associated with dementia due to Alzheimer's disease. This post hoc analysis explored effects of brexpiprazole on individual agitation symptoms over 24 weeks, focusing on the most bothersome symptoms. Data were included for patients who received brexpiprazole 2 or 3 mg/day in a Phase 3, 12-week, randomized, placebo-controlled trial in patients with agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov: NCT03548584 [Trial 213]) and a 12-week single-arm extension trial (NCT03594123 [Trial 182]). Agitation symptom frequency was evaluated using the CMAI, which comprises 29 symptoms (items) each scored from 1 (never occurs) to 7 (occurs a few times an hour). In subgroups of patients who experienced a particular symptom at least weekly at baseline (CMAI item score ≥3), mean change in that item score from baseline to Week 12, and from Week 12 to Week 24, was calculated. Overall, 159 patients were included across subgroups. From baseline to Week 12, all symptoms in the aggressive, verbally agitated, and physically non-aggressive domains, including those most bothersome to caregivers and/or associated with transfer to long-term care, reduced in frequency. From Week 12 to Week 24, symptoms considered most bothersome and/or associated with transfer to long-term care showed further numerical improvement; other symptoms also improved, or stabilized. Treatment with brexpiprazole 2 or 3 mg/day over 24 weeks was associated with continued and sustained benefits on agitation symptoms that are considered most bothersome to caregivers, and that influence caregiver decisions to transfer patients to long-term care.

Patients with dementia due to Alzheimer's disease may experience multiple different agitation symptoms - including excessive motor activity, verbal aggression, and physical aggression - at varying frequencies. The efficacy of brexpiprazole 2 or 3 mg/day on 29 individual agitation behaviors (Cohen-Mansfield Agitation Inventory [CMAI] items) was previously evaluated. Building upon that work, this post hoc analysis aimed to determine the efficacy of brexpiprazole on the same individual agitation behaviors, but specifically focusing on those patients who were frequently experiencing the behaviors at baseline. Data were included from two 12-week, randomized, double-blind, placebo-controlled, parallel-arm trials of fixed-dose brexpiprazole in patients with agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Efficacy was assessed using the CMAI, which measures the frequency of occurrence of 29 agitation behaviors (each scored 1 [never] to 7 [a few times an hour]). In this analysis, least squares mean change from baseline to Week 12 in each CMAI item score was determined in subsamples of patients for whom the corresponding behavior occurred at least once per week (item score ≥3) at baseline. Data for brexpiprazole 2 or 3 mg/day (FDA-approved dose) and for placebo were pooled. Data were analyzed for 610 patients (brexpiprazole, n = 363; placebo, n = 247). At baseline, the mean (standard deviation) number of different agitation behaviors occurring at least weekly was 12.8 (4.3) per patient. The agitation behaviors most commonly occurring at least weekly were general restlessness (n = 572), pacing/aimless wandering (n = 513), and cursing or verbal aggression (n = 496). For some behaviors (e.g., intentional falling, n = 27), conclusions were limited by small subsample sizes. Across the CMAI items, least squares mean score changes from baseline to Week 12 ranged from -1.80 to -0.04 for brexpiprazole, and -1.34 to +0.84 for placebo, with a greater numerical reduction for brexpiprazole versus placebo on 24/29 items (Figure). Patients with agitation associated with dementia due to Alzheimer's disease exhibited many different frequently occurring agitation behaviors. Fixed-dose brexpiprazole 2 or 3 mg/day was associated with a numerically greater reduction in the frequency of most of these frequently occurring agitation behaviors versus placebo.

Objectives: Antipsychotic use among patients with Alzheimer’s dementia can pose safety concerns, including accidents/injuries, cardiovascular events, extrapyramidal symptoms, and somnolence/sedation. In the US, brexpiprazole is approved for the treatment of agitation associated with dementia due to Alzheimer’s disease. This post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) in three randomized clinical trials of brexpiprazole. Methods: Data were included from three Phase 3, 12-week, randomized, double-blind, placebo-controlled trials of brexpiprazole in patients with agitation associated with Alzheimer’s dementia (ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584). Data for all patients who received ≥1 dose of trial medication were pooled by randomized dose group: brexpiprazole 0.5 or 1 mg/day (fixed-dose), brexpiprazole 2 or 3 mg/day (fixed- dose) (FDA- approved recommended-to-maximum dose), brexpiprazole 0.5 – 2 mg/day (flexible-dose), and placebo. Time-to-event analyses were performed to first occurrence of any TEAE, any serious TEAE, discontinuation due to AE, and TEAEs of interest, separately, and presented using descriptive statistics and Kaplan–Meier Methodsology. The duration of all TEAEs in each category was also determined. Results: The pooled sample comprised 1,043 patients. Median time to first TEAE was 24 days with brexpiprazole .5 or 1 mg/day (fixed-dose), 32 days with brexpiprazole 2 or 3 mg/day (fixed-dose), 28 days with brexpiprazole 0.5–2 mg/day (flexible-dose), and 28 days with placebo. Median duration of all TEAEs was 7 days, 6 days, 8 days, and 4 days (respectively). Median time to (and incidence of) discontinuation due to AEs was 45 days (8.9%) with brexpiprazole 0.5 or 1 mg/day, 46.5 days (4.9%) with brexpiprazole 2 or 3 mg/day, 30 days (6.8%) with brexpiprazole 0.5 –2 mg/day, and 30 days (3.4%) with placebo. The incidence of serious TEAEs and TEAEs of interest is presented in the Table. Conclusions: In patients with agitation in Alzheimer’s dementia, time to first occurrence of any TEAE was similar between brexpiprazole 2 or 3 mg/day (FDA-approved recommended-to- maximum dose) and placebo, and time to discontinuation due to AEs was longer with brexpiprazole 2 or 3 mg/day than placebo. Overall, no unexpected safety concerns were revealed by this analysis.