Feasibility of a Low-Intensity Intervention to Influence Antibiotic Prescribing Rates Use in Outpatient Settings: A Cluster Randomized Controlled Clinical Trial.

Background: Primary care providers (PCPs) may modify their antibiotic prescription practices if aware of their potentially damaging impact.

Methods: We conducted a cluster randomized controlled trial at 12 Veterans Affairs community-based outpatient clinics. PCPs at clinics randomized to the intervention group received quarterly antibiotic use reports with feedback about antibiotics prescribed for acute respiratory infections and adverse event letters alerting about infection or antibiotic-resistant gram-negative bacteria among their patients.

Nonlinear dynamics of inverse tapered granular chains for mechanical amplification in voice frequency range.

Here, the dynamics of inverse tapered granular chains, which are alignments of beads with progressively increasing radii, are investigated. These chains are subjected to harmonic excitation by a moving wall and probed at the tapered end. Intermediate taperings using Ni-Ti (metal) and Teflon (plastic) granules are considered.

Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year.

Syndromic Antibiograms and Nursing Home Clinicians' Antibiotic Choices for Urinary Tract Infections.

Importance: Empirical antibiotic prescribing in nursing homes (NHs) is often suboptimal. The potential for antibiograms to improve empirical antibiotic decision-making in NHs remains poorly understood.

Objective: To determine whether providing NH clinicians with a urinary antibiogram improves empirical antibiotic treatment of urinary tract infections (UTIs).

Xylitol for the prevention of acute otitis media episodes in children aged 1-5 years: a randomised controlled trial.

Objective: To investigate the regular use of xylitol, compared with sorbitol, to prevent acute otitis media (AOM), upper respiratory tract infections (URTIs) and dental caries.

Design: Blinded randomised controlled trial with a 6-month study period.

Setting: Enrolment took place at 11 primary care practices in Ontario, Canada.

Parents' attitudes towards research involving genome sequencing of their healthy children: a qualitative study.

With widespread genomic sequencing research efforts, there is increasing impetus to return results to participants. Parents of healthy children are increasingly asked to participate in genomic research, yet there are limited studies of parental expectations for the return of results amongst healthy children. We explored parental attitudes towards their healthy children's participation in genomic research and expectations for return of results.

Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.

Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy.

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory.

Low rates of antibiotics prescribed during telehealth primary-care visits persisted during the coronavirus disease 2019 (COVID-19) pandemic.

For primary care clinics at a Veterans' Affairs (VA) medical center, the shift from in-person to telehealth visits during the coronavirus disease 2019 (COVID-19) pandemic was associated with low rates of antibiotic prescription. Understanding contextual factors associated with antibiotic prescription practices during telehealth visits may help promote antibiotic stewardship in primary care settings.

Neither Race nor Ethnicity Impact the Mortality of Residents of Veterans Affairs Community Living Center With COVID-19.

Objectives: COVID-19 disproportionately affected nursing home residents and people from racial and ethnic minorities in the United States. Nursing homes in the Veterans Affairs (VA) system, termed Community Living Centers (CLCs), belong to a national managed care system. In the period prior to the availability of vaccines, we examined whether residents from racial and ethnic minorities experienced disparities in COVID-19 related mortality.

Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

Objective: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA.

During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study.

Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

Background: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here.

High Red Cell Distribution Width and Low Absolute Lymphocyte Count Associate With Subsequent Mortality in HCV Infection.

Background: Hepatitis-C virus (HCV) chronic infection can lead to cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, cardiovascular disease (CVD), and mortality. Transient Elastography (TE) is used to non-invasively assess fibrosis. Whether immune monitoring provides additive prognostic value is not established.

Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons.

Background: The mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown.

Methods: We enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16).

T-cell Activation Is Correlated With Monocyte Activation in HCV/HIV Coinfection and Declines During HCV Direct-Acting Antiviral Therapy.

Background: Immune activation markers associate with morbidity and mortality in HIV and hepatitis C virus (HCV) infection. We investigated how T-cell and monocyte activation are related over the course of HCV direct-acting antiviral (DAA) therapy during HCV/HIV coinfection.

Methods: Peripheral blood mononuclear cells from AIDS Clinical Trials Group (ACTG) A5329 participants and a single-site separate cohort treated with DAAs were analyzed for central memory (CM)/effector memory (EM) T-cell subsets, monocyte subsets, and cell activation (CD38 and HLA-DR expression) before, during, and after therapy.

Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-β Levels in Treated HIV+ Immune Non-responders.

Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR.

Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling.

Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.

Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASi, CDK4/6i, and anti-programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models and , and their effects on downstream signaling were examined.

Psychotic, Mood, and Anxiety Disorders and Venous Thromboembolism: A Systematic Review and Meta-Analysis.

Objective: Several studies have shown that psychiatric disorders can be associated with venous thromboembolism (VTE) risk, that is, pulmonary embolism (PE) and/or deep vein thrombosis (DVT). In this study, we provide a systematic review and meta-analyses of the studies addressing this issue.

Methods: All studies addressing the risk of VTE phenomena (whole VTE, PE, DVT, fatal VTE) in individuals with psychotic, mood, and anxiety disorders published between 1998 and 2019 were reviewed and included in the meta-analyses.

A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts.

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative.

Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus-HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation.

Background: Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved.

Methods: We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy.