CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment.

BACKGROUND: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development. METHODS: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebra fish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development. RESULTS: In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebra fish treated with the Cxcr3 inhibitor AMG487 or in homozygous cxcr3.1/3.2/3.3 triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts. CONCLUSIONS: Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment.

Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries.

Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a levels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressed klf2a and increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increased klf2a levels and decreased vSMC association with arteries. We supported the small molecule data with in vivo genetic suppression of piezo1 and 2 in zebrafish, resulting in loss of transgelin+ vSMCs on the dorsal aorta. Further, endothelial cell (EC)-specific Piezo1 knockout in mice was sufficient to decrease vSMC accumulation along the descending dorsal aorta during development, thus phenocopying our zebrafish data, and supporting functional conservation of Piezo1 in mammals. To determine mechanism, we used in vitro modeling assays to demonstrate that differential sensing of pulsatile versus laminar flow forces across endothelial cells changes the expression of mural cell differentiation genes. Together, our findings suggest a crucial role for EC Piezo1 in sensing force within large arteries to mediate mural cell differentiation and stabilization of the arterial vasculature.

Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting.

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aß]40, Aß42, Aß42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.

Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer's disease plasma biomarkers.

INTRODUCTION: The reliability of plasma Alzheimer's disease (AD) biomarkers can be compromised by protease-induced degradation. This limits the feasibility of conducting plasma biomarker studies in environments that lack the capacity for immediate processing and appropriate storage of blood samples. We hypothesized that blood collection tube supplementation with protease inhibitors can improve the stability of plasma biomarkers at room temperatures (RT). This study conducted a comparative analysis of blood biomarker stability in traditional ethylenediaminetetraacetic acid (EDTA) tubes versus BD™ P100 collection tubes, the latter being coated with a protease inhibitor cocktail. The stability of six plasma AD biomarkers was evaluated over time under RT conditions. METHODS: We evaluated three experimental approaches. In Approach 1, pooled plasma samples underwent storage at RT for up to 96 hours. In Approach 2, plasma samples isolated upfront from whole blood collected into EDTA or P100 tubes were stored at RT for 0h or 24h before biomarker measurements. In Approach 3, whole blood samples were collected into paired EDTA or P100 tubes, followed by storage at RT for 0h or 24h before isolating the plasma for analyses. Biomarkers were measured with Single Molecule Array (Simoa) and immunoprecipitation-mass spectrometry (IP-MS) assays. RESULTS: Both the IP-MS and Simoa methods revealed that the use of P100 tubes significantly improved the stability of Aß42 and Aß40 across all approaches. Additionally, the Aß42/Aß40 ratio levels were significantly stabilized only in the IP-MS assay in Approach 3. No significant differences were observed in the levels of plasma p-tau181, GFAP, and NfL for samples collected using either tube type in any of the approaches. CONCLUSION: Supplementation of blood collection tubes with protease inhibitors could reduce the protease-induced degradation of plasma Aß42 and Aß40, and the Aß ratio for IP-MS assay. This has crucial implications for preanalytical procedures, particularly in resource-limited settings.

Intradermal Vaccination with PLGA Nanoparticles via Dissolving Microneedles and Classical Injection Needles.

PURPOSE: A dissolving microneedle array (dMNA) is a vaccine delivery device with several advantages over conventional needles. By incorporating particulate adjuvants in the form of poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) into the dMNA, the immune response against the antigen might be enhanced. This study aimed to prepare PLGA-NP-loaded dMNA and to compare T-cell responses induced by either intradermally injected aqueous-PLGA-NP formulation or PLGA-NP-loaded dMNA in mice. METHODS: PLGA NPs were prepared with microfluidics, and their physicochemical characteristics with regard to encapsulation efficiencies of ovalbumin (OVA) and CpG oligonucleotide (CpG), zeta potentials, polydispersity indexes, and sizes were analysed. PLGA NPs incorporated dMNA was produced with three different dMNA formulations by using the centrifugation method, and the integrity of PLGA NPs in dMNAs was evaluated. The immunogenicity was evaluated in mice by comparing the T-cell responses induced by dMNA and aqueous formulations containing ovalbumin and CpG (OVA/CpG) with and without PLGA NP. RESULTS: Prepared PLGA NPs had a size of around 100 nm. The dMNA formulations affected the particle integrity, and the dMNA with poly(vinyl alcohol) (PVA) showed almost no aggregation of PLGA NPs. The PLGA:PVA weight ratio of 1:9 resulted in 100% of penetration efficiency and the fastest dissolution in ex-vivo human skin (< 30 min). The aqueous formulation with soluble OVA/CpG and the aqueous-PLGA-NP formulation with OVA/CpG induced the highest CD4 + T-cell responses in blood and spleen cells. CONCLUSIONS: PLGA NPs incorporated dMNA was successfully fabricated and the aqueous formulation containing PLGA NPs induce superior CD4+ and CD8+ T-cell responses.

Affordable Care Act Medicaid expansion associated with increased liver transplant waitlist access without worsening mortality.

It is unclear what impact Affordable Care Act (ACA) Medicaid expansion has had on the liver transplantation (LT) waitlist. We aimed to assess associations between ACA Medicaid expansion and LT waitlist outcomes. The United Network for Organ Sharing Standard Transplant Analysis and Research (UNOS STAR) database was queried for patients listed for LT between January 1, 2009, and December 31, 2018. Our primary outcome was waitlist mortality and our secondary outcomes included Medicaid use on the LT waitlist and transplant rate. States were divided into groups based on their expansion status and the study period was divided into 2 time intervals-pre-expansion and post-expansion. Difference-in-difference (DiD) models were created to assess the impacts of expansion on each of the outcomes and for racial/ethnic and sex groups. In total, 56,414 patients from expansion states and 32,447 patients from nonexpansion states were included. Three-year waitlist mortality decreased at a similar rate in both cohorts [DiD estimate: 0.1, (95% CI, -1.1, -1.4), p = 0.838], but Medicaid use increased [DiD estimate: +7.7, (95% CI, 6.7, 8.7), p < 0.001] to a greater degree in expansion states after expansion than nonexpansion states. Between the 2 time intervals, Medicaid use on the LT waitlist increased from 19.4% to 26.1% in expansion states but decreased from 13.4% to 12.1% in nonexpansion states. In patients on Medicaid, there was a slight increase in the 3-year transplant rate associated with Medicaid expansion [DiD estimate +5.0, (95% CI, 1.8, 8.3), p = 0.002], which may in part be explained by differences in patient characteristics. Medicaid expansion was associated with increased Medicaid use on the LT waitlist without worsening overall waitlist mortality or transplant rate, suggesting that lenient and widespread public health insurance may increase access to the LT waitlist without adversely affecting outcomes.

Prognostic Factors in Alcohol-associated Liver Disease Patients Presenting With First Evidence of Ascites.

GOALS: To identify factors associated with transplantation and death in alcohol-associated liver disease (ALD) patients presenting with first evidence of ascites. BACKGROUND: Ascites development is a poor prognostic sign for patients with cirrhosis. Among ALD patients, the baseline factors at time of ascites development that are associated with eventual transplantation or death are currently unknown. STUDY: Adult patients with ascites in the "Evaluating Alcohol Use in Alcohol-related Liver Disease Prospective Cohort Study" (NCT03267069 clinicaltrials.gov) were identified from 2016 to 2020. Demographic, clinical, and laboratory factors at initial ascites presentation were identified as potential predictors of transplant and death as competing risks. RESULTS: A total of 96 patients were identified. Median (interquartile range) follow-up time was 2.00 years (0.87 to 3.85). By last follow-up, 34/96 patients had been transplanted (35.4%) and 11/96 had died (11.4%). Prognostic factors for transplant included age per decade [hazard ratio (HR): 0.52 (95% CI, 0.33 to 0.83)], employed status [HR: 0.35 (95% CI, 0.14 to 0.90)], and sodium [HR: 0.94 (95% CI, 0.90 to 0.99)], whereas prognostic factors for death were body mass index [HR: 1.11 (95% CI, 1.00 to 1.22)], Charlson index [HR: 2.14 [95% CI, 1.13 to 4.08]), Maddrey Discriminant Function >32 (HR: 5.88 (95% CI, 1.18, 29.39)], aspartate aminotransferase [HR: 0.99 (95% CI, 0.98 to 0.997)], and a prior 12-month abstinence period [HR: 5.53 (95% CI, 1.10 to 27.83)], adjusted for age, sex, and ALD subcategory. CONCLUSIONS: Several factors at initial ascites presentation are associated with increased risk of transplantation or death and validation in larger cohorts will allow for improved risk stratification for ALD patients.

Examining Utilization of Formal Supports and Related Impacts on Overall Well-Being Among East Asian American Family Caregivers of Persons With Dementia: A Mixed-Methods Study.

BACKGROUND AND OBJECTIVES: Although East Asian American family caregivers are known to underutilize formal support services, there is a lack of evidence regarding the associations of formal service utilization with caregivers' well-being. This study examined the prevalence of different types of home-and community-based formal service utilization among Korean and Chinese American family caregivers of persons with dementia and how utilization of such services was associated with their well-being. We also explored their overall experience in accessing and utilizing formal dementia support services and programs. RESEARCH DESIGN AND METHODS: We employed a convergent mixed-methods study design. In a convenience sampling method, we recruited 62 family caregivers. Logistic regression and thematic analysis were utilized to analyze data. RESULTS: The results showed in-home services were mostly utilized among family caregivers of these ethnic groups. Out of 9 different support services, those who utilized nutrition programs and case management were more likely to report higher overall well-being. Four themes were developed: (1) awareness of formal support services but uncertainty on how to access them, (2) language barriers imposing additional challenges in accessing formal support services, (3) traveling to access culturally appropriate services, and (4) desire for culturally tailored medical and long-term care services. DISCUSSION AND IMPLICATIONS: Findings from this study suggest the importance of case management services to overcome barriers to accessing and utilizing a wide range of formal support services and provision of culturally appropriate food in formal support services to increase East Asian American family caregivers' utilization of long-term care services.

CXCR3-CXCL11 signaling restricts angiogenesis and promotes pericyte recruitment.

Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces, yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor, CXCR3, and one of its ligands, CXCL11-that delimits EC angiogenic potential and suppresses pericyte recruitment during development through regulation of pdgfb expression in ECs. In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with and expansion of the vasculature in zebrafish treated with the Cxcr3 inhibitor AMG487. We also demonstrate using flow modeling platforms that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared to their control counterparts. Together these data suggest that CXCR3 signaling in ECs drives vascular stabilization events during development.

Efficient fabrication of thermo-stable dissolving microneedle arrays for intradermal delivery of influenza whole inactivated virus vaccine.

Dissolving microneedle arrays (dMNAs) can be used to deliver vaccines via the intradermal route. Fabrication of dMNAs using centrifugation is the most common preparation method of dMNAs, but it results in a substantial loss of antigens. In order to solve the issue of antigen waste, we engineered an automatic dispensing system for dMNA preparation. Here, we report on the fabrication of influenza whole inactivated virus (WIV) vaccine-loaded dMNAs (WIV dMNAs) by using the automatic dispensing system. Prior to the dispensing process, polydimethylsiloxane (PDMS) moulds were treated with oxygen plasma to increase surface hydrophilicity. WIV dMNAs were prepared with 1% (w/v) trehalose and pullulan (50 : 50 weight ratio). During the dispensing process, reduced pressure was applied to the PDMS mould via a vacuum chamber to make microneedle cavities airless. After producing dMNAs, WIV was quantified and 1.9 µg of WIV was loaded per dMNA, of which 1.3 µg was in the microneedle tips. Compared to the centrifugation method, this automatic dispensing system resulted in a 95% reduction of antigen waste. A hemagglutination assay confirmed that WIV dMNA maintained the stability of the antigen for at least four weeks of storage, even at room temperature or at 37 °C. The WIV dMNAs displayed 100% penetration efficiency in human skin, and 83% of the microneedle volume was dissolved in the skin within 10 minutes. In a vaccination study, mice immunised with WIV dMNAs showed similar IgG levels to those that received WIV intramuscularly. In conclusion, using the automatic dispensing system for dMNA production strongly reduced antigen waste and yielded dMNAs with excellent physical, mechanical, and immunological properties.

Course of Subtypes of Late-Life Depression Identified by Bipartite Network Analysis During Psychosocial Interventions.

Importance: Approximately half of older adults with depression remain symptomatic at treatment end. Identifying discrete clinical profiles associated with treatment outcomes may guide development of personalized psychosocial interventions. Objective: To identify clinical subtypes of late-life depression and examine their depression trajectory during psychosocial interventions in older adults with depression. Design, Setting, and Participants: This prognostic study included older adults aged 60 years or older who had major depression and participated in 1 of 4 randomized clinical trials of psychosocial interventions for late-life depression. Participants were recruited from the community and outpatient services of Weill Cornell Medicine and the University of California, San Francisco, between March 2002 and April 2013. Data were analyzed from February 2019 to February 2023. Interventions: Participants received 8 to 14 sessions of (1) personalized intervention for patients with major depression and chronic obstructive pulmonary disease, (2) problem-solving therapy, (3) supportive therapy, or (4) active comparison conditions (treatment as usual or case management). Main Outcomes and Measures: The main outcome was the trajectory of depression severity, assessed using the Hamilton Depression Rating Scale (HAM-D). A data-driven, unsupervised, hierarchical clustering of HAM-D items at baseline was conducted to detect clusters of depressive symptoms. A bipartite network analysis was used to identify clinical subtypes at baseline, accounting for both between- and within-patient variability across domains of psychopathology, social support, cognitive impairment, and disability. The trajectories of depression severity in the identified subtypes were compared using mixed-effects models, and time to remission (HAM-D score ≤10) was compared using survival analysis. Results: The bipartite network analysis, which included 535 older adults with major depression (mean [SD] age, 72.7 [8.7] years; 70.7% female), identified 3 clinical subtypes: (1) individuals with severe depression and a large social network; (2) older, educated individuals experiencing strong social support and social interactions; and (3) individuals with disability. There was a significant difference in depression trajectories (F2,2976.9 = 9.4; P < .001) and remission rate (log-rank χ22 = 18.2; P < .001) across clinical subtypes. Subtype 2 had the steepest depression trajectory and highest likelihood of remission regardless of the intervention, while subtype 1 had the poorest depression trajectory. Conclusions and Relevance: In this prognostic study, bipartite network clustering identified 3 subtypes of late-life depression. Knowledge of patients' clinical characteristics may inform treatment selection. Identification of discrete subtypes of late-life depression may stimulate the development of novel, streamlined interventions targeting the clinical vulnerabilities of each subtype.

Nucleolin Regulates Pulmonary Artery Smooth Muscle Cell Proliferation under Hypoxia by Modulating miRNA Expression.

Hypoxia induces the abnormal proliferation of vascular smooth muscle cells (VSMCs), resulting in the pathogenesis of various vascular diseases. RNA-binding proteins (RBPs) are involved in a wide range of biological processes, including cell proliferation and responses to hypoxia. In this study, we observed that the RBP nucleolin (NCL) was downregulated by histone deacetylation in response to hypoxia. We evaluated its regulatory effects on miRNA expression under hypoxic conditions in pulmonary artery smooth muscle cells (PASMCs). miRNAs associated with NCL were assessed using RNA immunoprecipitation in PASMCs and small RNA sequencing. The expression of a set of miRNAs was increased by NCL but reduced by hypoxia-induced downregulation of NCL. The downregulation of miR-24-3p and miR-409-3p promoted PASMC proliferation under hypoxic conditions. These results clearly demonstrate the significance of NCL-miRNA interactions in the regulation of hypoxia-induced PASMC proliferation and provide insight into the therapeutic value of RBPs for vascular diseases.

Sociodemographic characteristics of living liver donors: Few changes over 20 years.

INTRODUCTION: Although there are well-documented challenges in access to living donor liver transplant (LDLT) among recipients, it is unclear whether living liver donors (LLDs) face similar challenges. METHODS: We analyzed the UNOS Standard Transplant Analysis and Research database, including LLDs ≥ 18 years in the United States from 1/1998 to 12/2018. We compared sociodemographic characteristics (age, gender, race/ethnicity, education level, employment status, BMI, and relationship to recipient) of LLDs across three eras-pre-MELD (1998-2002), MELD (2003-2013), and post-direct acting antivirals (DAA) (2014-2018). We also described sociodemographic characteristics of living donor recipients and waitlisted patients. Chi-squared and one-way analysis of variance (ANOVA) were used to compare categorical and continuous variables, respectively. RESULTS: From 1998 to 2018, 4756 LDLTs and 99 765 DDLTs were performed. Across the three eras, LLD age did not change significantly (P = .3), but donors were generally young (mean age 37 ± 11). While men comprised most LLDs in the pre-MELD era (55.2%), women surpassed them in the post-DAA era (52.9%), P < .001. In total, White donors comprised 81.5% of total LLDs, while Black and Asian donors were a small minority of total donors (3.7% and 2.5%, respectively). Most donors had at least a college education and were employed. Educational attainment and employment did not significantly change over the study period. CONCLUSION: During the last 20 years, LLDs have remained White, employed, highly educated, and young with increasing numbers of women LLDs. The relative lack of change in the characteristics of donors is likely attributable largely to socioeconomic factors, which should be assessed in future investigation.

The association between immunosuppressants use and COVID-19 adverse outcomes: national COVID-19 cohort in South Korea.

BACKGROUND: There is uncertainty of the effect of immunosuppression, including corticosteroids, before COVID-19 infection on COVID-19 outcomes. The aim of this study was to investigate the relationship between prehospitalization immunosuppressants use (exposure) and COVID-19 patient outcomes. METHODS: We conducted a population-based retrospective cohort study using a nationwide healthcare claims database of South Korea as of May 15, 2020. Confirmed COVID-19 infection in hospitalized individuals aged 40 years or older were included for analysis. We defined exposure variable by using inpatient and outpatient prescription records of immunosuppressants from the database. Our primary endpoint was a composite endpoint of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Inverse probability of treatment weighting (IPTW)-adjusted logistic regression analyses were used, to estimate odds ratio (OR) and 95% confidence intervals (CI), comparing immunosuppressants users and non-users. RESULTS: We identified 4,349 patients, for which 1,356 were immunosuppressants users and 2,993 were non-users. Patients who used immunosuppressants were at increased odds of the primary endpoint of all-cause death, ICU admission and mechanical ventilation use (IPTW OR =1.32; 95% CI: 1.06-1.63), driven by higher odds of all-cause mortality (IPTW OR =1.63; 95% CI: 1.21-2.26). Patients who used corticosteroids (n=1,340) were at increased odds of the primary endpoint (IPTW OR =1.33; 95% CI: 1.07-1.64). CONCLUSIONS: Immunosuppressant use was associated with worse outcomes among COVID-19 patients. These findings support the latest guidelines from the CDC that people on immunosuppressants are at high risk of severe COVID-19 and that immunocompromised people may benefit from booster COVID-19 vaccinations.

The prognostic role of anticoagulants in COVID-19 patients: national COVID-19 cohort in South Korea.

BACKGROUND: There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated thromboembolism. The aim of this study was to assess the association between pre-admission anticoagulants use and COVID-19 adverse outcomes. METHODS: We conducted a population-based cohort studying using the Health Insurance Review and Assessment Service (HIRA) claims data released by the South Korean government. Our study population consisted of South Koreans who were aged 40 years or older and hospitalized with COVID-19 between 1 January 2020 through 15 May 2020. We defined anticoagulants users as individuals with inpatient and outpatient prescription records in 120 days before cohort entry. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Individual components of the primary endpoint were secondary endpoints. We compared the risk of endpoints between the anticoagulants users and non-users by logistic regression models, with the standardized mortality ratio weighting (SMRW) adjustment. RESULTS: In our cohort of 4,349 patients, for the primary endpoint of mortality, mechanical ventilation and ICU admission, no difference was noted between anticoagulants users and non-users (SMRW OR 1.11, 95% CI: 0.60-2.05). No differences were noted, among individual components. No effect modification was observed by age, sex, history of atrial fibrillation and thromboembolism, and history of cardiovascular disease. When applying the inverse probability of treatment weighting (IPTW) and SMRW with doubly robust methods in sensitivity analysis, anticoagulants use was associated with increased odds of the primary endpoint. CONCLUSIONS: Pre-admission anticoagulants were not determined to have a protective role against severe COVID-19 outcomes.

The association between statin and COVID-19 adverse outcomes: national COVID-19 cohort in South Korea.

BACKGROUND: There currently exist limited and conflicting clinical data on the use of statins in coronavirus disease 2019 (COVID-19) patients. The aim of this paper was to compare hospitalized patients with COVID-19 who did and did not receive statins. METHODS: We performed a population-based retrospective cohort study using South Korea's nationwide healthcare claim database. We identified consecutive patients hospitalized with COVID-19 and aged 40 years or older. Statin users were individuals with inpatient and outpatient prescription records of statins in the 240 days before cohort entry to capture patients who are chronic statin users and, therefore, receive statin prescriptions as infrequently as every 8 months. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, mechanical ventilation use and cardiovascular outcomes [myocardial infarction (MI), transient cerebral ischemic attacks (TIA) or stroke]. We compared the risk of outcomes between statin users and non-users using logistic regression models after inverse probability of treatment weighting (IPTW) adjustment. RESULTS: Of 234,427 subjects in the database, 4,349 patients were hospitalized with COVID-19 and aged 40+ years. In total, 1,115 patients were statin users (mean age =65.9 years; 60% female), and 3,234 were non-users (mean age =58.3 years; 64% female). Pre-hospitalization statin use was not significantly associated with increased risk of the primary endpoint [IPTW odds ratio (OR) 0.82; 95% confidence interval (CI): 0.60-1.11]. Subgroup analysis showed a protective role of antecedent statin use for individuals with hypertension (IPTW OR 0.40; 95% CI: 0.23-0.69, P for interaction: 0.0087). CONCLUSIONS: Pre-hospitalization statin use is not detrimental and may be beneficial amongst hypertensive COVID-19 patients. Further investigation into statin is needed for more conclusive effects of statins for treatment of COVID-19.

Skewing of the antibody repertoire in cerebrospinal fluid B cells from healthy controls and patients with schizophrenia.

Autoantibodies play a role in the etiology of some neuropsychiatric disorders. To address the possibility that B cells and their antibodies may be involved in the pathophysiology of schizophrenia, we examined B cells in cerebrospinal fluid (CSF) and peripheral blood (PB) of 4 schizophrenic patients (SP) and 4 healthy control (HC) volunteers by analyzing immunoglobulin VH gene usage. All CSF samples contained measurable levels of B cells. We found for both SP and HC, CSF B cells represented a select subset of, and were not the same as, B cells in PB. Moreover, we found statistically significant differences in antibodies generated by CSF B cells in SP compared to CSF B cells in HC. Although binding characteristics of CSF SP-associated B cell antibodies is unknown, the study number is small, and pathophysiology has not been established, these results suggest the value of focusing further study on the distinctly separate population of CSF B cells in SP.

Role of MicroRNAs and Long Non-Coding RNAs in Sarcopenia.

Sarcopenia is an age-related pathological process characterized by loss of muscle mass and function, which consequently affects the quality of life of the elderly. There is growing evidence that non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a key role in skeletal muscle physiology. Alterations in the expression levels of miRNAs and lncRNAs contribute to muscle atrophy and sarcopenia by regulating various signaling pathways. This review summarizes the recent findings regarding non-coding RNAs associated with sarcopenia and provides an overview of sarcopenia pathogenesis promoted by multiple non-coding RNA-mediated signaling pathways. In addition, we discuss the impact of exercise on the expression patterns of non-coding RNAs involved in sarcopenia. Identifying non-coding RNAs associated with sarcopenia and understanding the molecular mechanisms that regulate skeletal muscle dysfunction during aging will provide new insights to develop potential treatment strategies.

Optimal surgeon-volume threshold for neck dissections in the setting of primary thyroid malignancies.

BACKGROUND: Although the surgeon-volume relationship is well documented for thyroidectomy, less is known about central neck and lateral neck dissections. The aim of this study was to evaluate and determine the surgeon-volume threshold for central neck and lateral neck dissections for thyroid cancer. METHODS: A retrospective analysis of patients with thyroid malignancies who received a central or lateral neck dissection in the New York Statewide Planning and Research Cooperative System was performed (2007-2017). Demographic variables included age, sex, race, and a Charlson Comorbidity Score. Thirty-day complications were identified using International Classification of Diseases (ICD) codes for central neck, lateral neck, and other surgical complications. Optimal surgeon-volume threshold was estimated using a change-point logistic regression. Using the identified threshold, surgeons were then classified to low versus high volume surgeons. Logistic regression analysis was conducted to examine the effect of high-volume status on outcomes. RESULTS: In total, 3,808 patients who underwent neck dissections (3,485 central neck dissections and 977 lateral neck dissections) were analyzed. Surgeon-volume threshold to distinguish high volume surgeons for central neck dissections and lateral neck dissections was 7.0 (95% bootstrap confidence interval 1.3-7.5) and 3.3 (1.2-4.8) neck dissections/year, respectively. For central neck dissection, high volume surgeons were associated with a lower rate of vocal cord paralysis (odds ratio 0.45 [0.24-0.82]), hypocalcemia (0.31 [0.14-0.65]), and all-cause complications (0.42 [0.29-0.59]). For lateral neck dissection, high volume surgeons were associated with a lower odds all-cause complications (0.42 [0.23-0.74]) but not lateral neck specific complications (0.18 [0.01-1.07]). CONCLUSION: A threshold of 7.0 central neck dissections and 3.3 lateral neck dissections for thyroid cancer per year improves outcomes. Guidelines for training and centralization of care can be guided by these results to reduce complications.

Colchicine use in patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: Colchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage. METHODS: The literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design (RCT vs observational) and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately. RESULTS: Eight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality-HR of 0.25 (95% CI: 0.09, 0.66) and OR of 0.22 (95% CI: 0.09, 0.57). There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not-OR of 0.26 (95% CI: 0.06, 1.09). CONCLUSION: Colchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.