Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation.

BACKGROUND: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. OBJECTIVE: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs. DESIGN: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir treatment for acute COVID-19. MEASUREMENTS: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. RESULTS: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points]). LIMITATIONS: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. CONCLUSION: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM.

Approaches to neuroscience data integration.

As the number of neuroscience databases increases, the need for neuroscience data integration grows. This paper reviews and compares several approaches, including the Neuroscience Database Gateway (NDG), Neuroscience Information Framework (NIF) and Entrez Neuron, which enable neuroscience database annotation and integration. These approaches cover a range of activities spanning from registry, discovery and integration of a wide variety of neuroscience data sources. They also provide different user interfaces for browsing, querying and displaying query results. In Entrez Neuron, for example, four different facets or tree views (neuron, neuronal property, gene and drug) are used to hierarchically organize concepts that can be used for querying a collection of ontologies. The facets are also used to define the structure of the query results.

Entrez Neuron RDFa: a pragmatic semantic web application for data integration in neuroscience research.

The amount of biomedical data available in Semantic Web formats has been rapidly growing in recent years. While these formats are machine-friendly, user-friendly web interfaces allowing easy querying of these data are typically lacking. We present "Entrez Neuron", a pilot neuron-centric interface that allows for keyword-based queries against a coherent repository of OWL ontologies. These ontologies describe neuronal structures, physiology, mathematical models and microscopy images. The returned query results are organized hierarchically according to brain architecture. Where possible, the application makes use of entities from the Open Biomedical Ontologies (OBO) and the 'HCLS knowledgebase' developed by the W3C Interest Group for Health Care and Life Science. It makes use of the emerging RDFa standard to embed ontology fragments and semantic annotations within its HTML-based user interface. The application and underlying ontologies demonstrate how Semantic Web technologies can be used for information integration within a curated information repository and between curated information repositories. It also demonstrates how information integration can be accomplished on the client side, through simple copying and pasting of portions of documents that contain RDFa markup.

Sharing Cancer Care Information Across VA Health Care Systems.

A telementoring program based on the Specialty Care Access Network Extension for Community Healthcare Outcomes model shared information about cancer care across VA health Care systems.

The formalin test: a tonic pain model in the primate.

The formalin test has been used in monkeys for assessing pain. After formalin injection in the palmar surface of the hand just proximal to the base of the fingers, the monkey's responses are rated for 1 h according to objective behavioral criteria. The present 'tonic' pain model has a fair degree of objectivity, validity, reproducibility and quantifiability. The analgesic effects of morphine and pethidine have been evaluated.

Integrating query of relational and textual data in clinical databases: a case study.

OBJECTIVES: The authors designed and implemented a clinical data mart composed of an integrated information retrieval (IR) and relational database management system (RDBMS). DESIGN: Using commodity software, which supports interactive, attribute-centric text and relational searches, the mart houses 2.8 million documents that span a five-year period and supports basic IR features such as Boolean searches, stemming, and proximity and fuzzy searching. MEASUREMENTS: Results are relevance-ranked using either "total documents per patient" or "report type weighting." RESULTS: Non-curated medical text has a significant degree of malformation with respect to spelling and punctuation, which creates difficulties for text indexing and searching. Presently, the IR facilities of RDBMS packages lack the features necessary to handle such malformed text adequately. CONCLUSION: A robust IR+RDBMS system can be developed, but it requires integrating RDBMSs with third-party IR software. RDBMS vendors need to make their IR offerings more accessible to non-programmers.

Abnormal Excitability of Oblique Dendrites Implicated in Early Alzheimer's: A Computational Study.

The integrative properties of cortical pyramidal dendrites are essential to the neural basis of cognitive function, but the impact of amyloid beta protein (abeta) on these properties in early Alzheimer's is poorly understood. In animal models, electrophysiological studies of proximal dendrites have shown that abeta induces hyperexcitability by blocking A-type K+ currents (I(A)), disrupting signal integration. The present study uses a computational approach to analyze the hyperexcitability induced in distal dendrites beyond the experimental recording sites. The results show that back-propagating action potentials in the dendrites induce hyperexcitability and excessive calcium concentrations not only in the main apical trunk of pyramidal cell dendrites, but also in their oblique dendrites. Evidence is provided that these thin branches are particularly sensitive to local reductions in I(A). The results suggest the hypothesis that the oblique branches may be most vulnerable to disruptions of I(A) by early exposure to abeta, and point the way to further experimental analysis of these actions as factors in the neural basis of the early decline of cognitive function in Alzheimer's.

Can high-attenuation renal cysts be differentiated from renal cell carcinoma at unenhanced CT?

PURPOSE: To retrospectively determine if renal cell carcinoma can be differentiated from high-attenuation renal cysts at unenhanced computed tomography (CT) based on Hounsfield unit measurements and heterogeneity. MATERIALS AND METHODS: The Human Investigation Committee at our institution approved this study with waiver of informed consent. This study was compliant with the HIPAA. Fifty-four pathologically proved renal cell carcinomas in 54 patients (36 men and 18 women; average age, 53 years; range, 23-90 years) and 56 high-attenuation renal cysts in 51 patients (30 men and 21 women; average age, 63 years; range, 28-86 years) were retrospectively evaluated at unenhanced CT. Two independent readers reviewed randomized unenhanced CT images and obtained Hounsfield unit readings of each mass. A subjective determination of lesion heterogeneity was also performed by using a four-point scale (1: homogeneous, 2: mildly heterogeneous, 3: moderately heterogeneous, 4: markedly heterogeneous). Statistical analysis was performed by using Bland-Altman regression tree, classification and regression tree, and Shapiro-Wilk normality test. RESULTS: The average attenuation of cysts for reader 1 was 53.4 HU (range, 23-113 HU) and for reader 2 was 53.8 HU (range, 21-108 HU). The average attenuation of neoplasms for reader 1 was 34.7 HU (range, 21-60 HU) and for reader 2 was 38.4 HU (range, 22-60 HU). For cyst heterogeneity, a score of 1 was given in 55 of 56 (98%) cysts for reader 1 and in 53 of 56 (95%) cysts for reader 2. For neoplasm heterogeneity, a score of 1 was given in 35 of 54 (65%) neoplasms for reader 1 and in 36 of 54 (67%) for reader 2. Given the distribution of cyst and tumor attenuation values and lesion heterogeneity, a homogeneous mass measuring 70 HU or greater at unenhanced CT has a greater than 99.9% chance of representing a high-attenuation renal cyst. CONCLUSION: The findings from this study may help differentiate high-attenuation renal cysts from renal cell carcinomas at unenhanced CT and may suggest the next appropriate imaging study for definitive characterization.

Longitudinal evaluation of apparent diffusion coefficient in children with neurofibromatosis type 1.

OBJECTIVES: Foci of T2-prolongation in both supra- and infratentorial brain in neurofibromatosis type-1 (NF1) patients have been called hamartoma-like NF1 lesions (HLL); however, their behavior is not consistent with this definition. Diffusion-weighted imaging has been used to study structure and cellularity of intracranial lesions. We applied this technique to characterize HLL as they change with time in pediatric patients. METHODS: We retrospectively studied 12 children (ages 2-20 years) with proven NF1. Forty lesions were studied longitudinally on multiple exams for a total of 166 measurements. Apparent diffusion coefficients (ADCs) were also obtained from a comparison group comprising 14 normal children (ages 2-16 years). RESULTS: The ADC for the lesions was generally greater than normal brain. Both supra- and infratentorial lesions had increasing ADC with patient age. This is contrasted to our comparison group of normal subjects who showed decreasing ADC with age. Linear regression analysis of infratentorial lesions yielded a slope of 2.70 x 10(-6) mm2 x s(-1) x year(-1) versus a slope of 17.57 x 10(-6) mm2 x s(-1) x year(-1) for supratentorial lesions. CONCLUSIONS: Our observed increase in ADC of lesions in pediatric patients with NF1 suggests increasing water in the extracellular space and/or decreasing cellularity with patient age. This change may be due to increased number or size of myelin vacuoles in NF1 lesions. Supratentorial lesions had a statistically significant increase in the rate of change of ADC compared with infratentorial lesions which may reflect an intrinsic difference in the lesion or similar lesions expressed in different environments.