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The Anticoagulation Length of Therapy and Risk of New Adverse Events In Venous Thromboembolism (ALTERNATIVE) study was designed to compare the benefits and harms of different treatment options for extended treatment of venous thromboembolism (VTE). In this paper, we describe the study cohort, survey data collection, and preliminary results. We identified 39,605 adult patients (age ≥ 18 years) from two large integrated health care delivery systems who were diagnosed with incident VTE and received initial anticoagulation therapy of 3 months or longer. A subset of the cohort (12,737) was invited to participate in a survey. Surveys were completed in English, Spanish or Mandarin via a mailed questionnaire, an online secure web link, or telephone. The survey domains included demographics, personal medical history, anticoagulant treatment history, anticoagulant treatment satisfaction, health-related quality of life and health literacy. A total of 5,017 patients participated in the survey for an overall response rate of 39.4%. The mean (SD) age of the survey respondents was 63.0 (14.5) years and self-reported race was 76.0% White/European, 11.1% Black/African American, and 3.8% Asian/Pacific Islander and 14.0% reported Hispanic ethnicity. Sixty percent of respondents completed the web survey, while 29.0% completed the mail-in paper survey, and 11.0% completed the survey via telephone. The ALTERNATIVE Study will address knowledge gaps by comparing several treatment alternatives for the extended management of VTE so that this information could be used by patients and clinicians to make more informed, patient-centered treatment choices.

BackgroundEarly reports of increased thrombosis risk with SARS-CoV-2 infection led to changes in venous thromboembolism (VTE) management. Real-world data on the prevalence, efficacy and harms of these changes informs best practices.ObjectiveDefine practice patterns and clinical outcomes related to VTE diagnosis, prevention, and management in hospitalized patients with coronavirus disease-19 (COVID-19) using a multi-hospital US sample.MethodsIn this retrospective cross-sectional study of 1121 patients admitted to 33 hospitals, exposure was dose of anticoagulant prescribed for VTE prophylaxis (standard, intensified, therapeutic), and primary outcome was VTE (pulmonary embolism [PE] and deep vein thrombosis [DVT]); secondary outcomes were PE, DVT, arterial thromboembolism (ATE), and bleeding events. Multivariable logistic regression models accounting for clustering by site and adjusted for risk factors were used to estimate odds ratios (ORs). Inverse probability weighting was used to account for confounding by indication.Results1121 patients (mean age 60 ± 18, 47% female) admitted with COVID-19 between February 2, 2020 and December 31, 2020 to 33 US hospitals were included. Pharmacologic VTE prophylaxis was prescribed in 86%. Forty-seven patients (4.2%) had PE, 51 (4.6%) had DVT, and 23 (2.1%) had ATE. Forty-six patients (4.1%) had major bleeding and 46 (4.1%) had clinically relevant non-major bleeding. Compared to standard prophylaxis, adjusted odds of VTE were 0.67 (95% CI 0.21-2.1) with no prophylaxis, 1.0 (95% CI 0.06-17) with intensified, and 3.0 (95% CI 0.89-10) with therapeutic. Adjusted odds of bleeding with no prophylaxis were 5.6 (95% CI 3.0-11) and 5.3 (95% CI 3.0-10) with therapeutic (no events on intensified dosing).ConclusionsTherapeutic anticoagulation was associated with a 3-fold increased odds of VTE and 5-fold increased odds of bleeding. While higher bleeding rates with high-intensity prophylaxis were likely due to full-dose anticoagulation, we conclude that high thrombosis rates were due to clinical concern for thrombosis before formal diagnosis.

BackgroundAngiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses.Methods and findingsIn this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days).ConclusionsThis observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials.

BACKGROUND:Efforts to characterize healthcare professional students' lesbian, gay, bisexual, and transgender (LGBT) cultural competency are necessary to recommend educational initiatives. Very few studies have evaluated LGBT cultural competency across multiple healthcare disciplines, and no known studies have included students of other healthcare disciplines such as occupational therapy, pharmacy, physical therapy, and physician assistant. METHODS:Healthcare professional students (N = 1701) at three universities across the United States completed a survey consisting of demographics, experiential variables (i.e., LGBT patients and LGBT curricular hours), and the 7-point Likert LGBT-Development of Clinical Skills Scale (LGBT-DOCSS). LGBT-DOCSS scores, annual LGBT patients, and annual LGBT curricular hours were compared across healthcare disciplines. RESULTS:While students reported very high Attitudinal Awareness (M = 6.48, SD = 0.92), they endorsed moderate Basic Knowledge (M = 5.54, SD = 1.16) and low Clinical Preparedness (M = 3.78, SD = 1.28). After controlling for several demographic and experiential variables, there were significant differences among healthcare disciplines on LGBT-DOCSS scores, with social work students reporting the highest on all scores, and dental students reporting the lowest on all scores except Clinical Preparedness. There were also significant differences among healthcare disciplines on annual LGBT patients [mean range: 0.57 (dental) to 7.59 (physician assistant)] and annual LGBT curricular hours [mean range: 0.51 (occupational therapy) to 5.64 (social work)]. Experiential variables were significant predictors for Overall LGBT-DOCSS, Clinical Preparedness, and Basic Knowledge (all p < 0.001); LGBT patients was also a significant predictor for Attitudinal Awareness (p < 0.05). CONCLUSIONS:Taken together, significant differences in LGBT cultural competency exist across healthcare disciplines, which may result from inadequate experiences with LGBT patients and LGBT curricular education. Future efforts should consider increasing LGBT patient contact hours and LGBT formal education hours to enhance healthcare students' LGBT cultural competency.

BackgroundThe duration of an opioid prescribed at hospital discharge does not intrinsically account for opioid needs during a hospitalization. This discrepancy may lead to patients receiving much larger supplies of opioids on discharge than they truly require.ObjectiveAssess a novel discharge opioid supply metric that adjusts for opioid use during hospitalization, compared to the conventional discharge prescription signature.Design, setting, & participantsRetrospective study using electronic health record data from June 2012 to November 2018 of adults who received opioids while hospitalized and after discharge from a single academic medical center.Measures & analysisWe ascertained inpatient opioids received and milligrams of opioids supplied after discharge, then determined days of opioids supplied after discharge by the conventional prescription signature opioid-days ("conventional days") and novel hospital-adjusted opioid-days ("adjusted days") metrics. We calculated descriptive statistics, within-subject difference between measurements, and fold difference between measures. We used multiple linear regression to determine patient-level predictors associated with high difference in days prescribed between measures.ResultsThe adjusted days metric demonstrates a 2.4 day median increase in prescription duration as compared to the conventional days metric (9.4 vs. 7.0 days; PConclusionsThe adjusted days metric, based on inpatient opioid use, demonstrates that patients are often prescribed a supply lasting longer than the prescription signature suggests, though with marked variability for some patients that suggests potential under-prescribing as well. Adjusted days is more patient-centered, reflecting the reality of how patients will take their prescription rather than providers' intended prescription duration.

Systemic sclerosis (SSc) is a chronic autoimmune disorder that can result in extensive tissue damage in the skin and, in advanced cases, internal organs. Vasculopathy, aberrant immune activation, and tissue fibrosis are three hallmarks of the disease that have been identified, with vasculopathy and aberrant immunity being amongst the earliest events. However, a mechanistic link between these processes has not been established. Here, we have identified a novel role of platelet derived growth factor-BB (PDGF-BB)/PDGFRβ activation in combination with dermal injury induced by bleomycin as a driver of early, aberrant expression of interferon stimulatory genes (ISGs) and inflammatory monocyte infiltration. Activation of PDGFRβ in combination with bleomycin-induced dermal injury resulted in increased dermal thickness, vascular density, monocyte/macrophage infiltration, and exacerbation of tissue injury. Many of these features were dependent on IFNAR-signaling, and an increase in the number of interferon-beta (IFN-β) producing monocytes cells was found in the skin lesions. Taken together, these results identify a novel link between PDGFRβ activation, and Type I IFN-driven vascular maintenance and monocyte/macrophage cell recruitment, and provide a potential explanation linking key features of SSc that were previously thought to be unrelated.

Group A Streptococcus (GAS) causes diverse infections ranging from common pharyngitis to rare severe invasive infections. Invasive GAS isolates can have natural mutations in the virulence regulator CovRS, which result in enhanced expression of multiple virulence genes, suppressed the expression of the protease SpeB, and increased virulence. It is believed that CovRS mutations arise during human infections with GAS carrying wild-type CovRS and are not transmissible. CovRS mutants of invasive GAS of the emm1 genotype arise readily during experimental infection in mice. It is possible that invasive GAS arises from pharyngeal GAS through rare genetic mutations that confer the capacity of mutated GAS to acquire covRS mutations during infection. The objective of this study was to determine whether contemporary pharyngeal emm1 GAS isolates have a reduced propensity to acquire CovRS mutations in vivo compared with invasive emm1 GAS and whether emm3, emm12, and emm28 GAS acquire CovRS mutants in mouse infection. The propensity of invasive and pharyngeal emm1 and invasive emm3, emm12, and emm28 SpeBA+ isolates to acquire variants with the SpeBA- phenotype was determined during subcutaneous infection of mice. The majority of both invasive and pharyngeal emm1 SpeBA+ isolates and two of three emm12 isolates, but not emm3 and emm28 isolates, were found to acquire SpeBA- variants during skin infection in mice. All analyzed SpeBA- variants of emm1 and emm12 GAS from the mouse infection acquired covRS mutations and produced more platelet-activating factor acetylhydrolase SsE. Thus, contemporary invasive and pharyngeal emm1 GAS isolates and emm12 GAS have a similar capacity to acquire covRS mutations in vivo. The rarity of severe invasive infections caused by GAS does not appear to be attributable to a reduced ability of pharyngeal isolates to acquire CovRS mutations.

IntroductionTo protect residents from tobacco smoke exposure (TSE), the Boston Housing Authority (BHA) prohibited smoking in BHA-owned apartments beginning in 2012. Our goal was to determine if the smoke-free policy reduced TSE for non-smoking BHA residents.MethodsWe compared TSE before the smoke-free policy (2012) and one year later among BHA residents as well as residents of the neighboring Cambridge Housing Authority (CHA) where no such policy was in place. Participants were a convenience sample of adult non-smoking BHA and CHA residents cohabitating with only non-smokers. Main outcomes were 7-day airborne nicotine in participants' apartments; residents' saliva cotinine; and residents' self-reported TSE.ResultsWe enrolled 287 confirmed non-smokers (192 BHA, 95 CHA). Seventy-nine percent (229) were assessed at follow-up. At baseline, apartment and resident TSE were high in both housing authorities (detectable airborne nicotine: 46% BHA, 48% CHA; detectable saliva cotinine: 49% BHA, 70% CHA). At follow-up there were significant but similar declines in nicotine in both sites (detectable: -33% BHA, -39% CHA, p = 0.40). Detectable cotinine rose among BHA residents while declining among CHA participants (+17% BHA vs. -13% CHA, p = 0.002). Resident self-reported TSE within and outside of the housing environment decreased similarly for both BHA and CHA residents.ConclusionsApartment air nicotine decreased after the introduction of the smoke-free policy, though the decline may not have resulted from the policy. The BHA policy did not result in reduced individual-level TSE. Unmeasured sources of non-residential TSE may have contributed to BHA residents' cotinine levels.

OBJECTIVES:The prevalence of obesity is disproportionately higher among African-Americans and Hispanics as compared to whites. We investigated the role of biogeographic ancestry (BGA) on adiposity and changes in adiposity in the Boston Area Community Health Survey. METHODS:We evaluated associations between BGA, assessed via Ancestry Informative Markers, and adiposity (body mass index (BMI), percent body fat (PBF), and waist-to-hip ratio (WHR)) and changes in adiposity over 7 years for BMI and WHR and 2.5 years for PBF, per 10% greater proportion of BGA using multivariable linear regression. We also examined effect-modification by demographic and socio-behavioral variables. RESULTS:We observed positive associations between West-African ancestry and cross-sectional BMI (percent difference=0.62%; 95% CI: 0.04%, 1.20%), and PBF (β=0.35; 95% CI: 0.11, 0.58). We also observed significant effect-modification of the association between West-African ancestry and BMI by gender (p-interaction:

Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies.The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-α, IL-1β, IL-2, IL-6, IL-8, and IL-10.The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials.At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of -2.6×10⁻² (95%CI: -4.3×10⁻², -8.2×10⁻³, p = 0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was -2.6×10⁻² (95%CI:-4.5×10⁻², -6.1×10⁻³, p = 0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-α, and VEGF.Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length.

BackgroundThe number of retracted scientific publications has risen sharply, but it is unclear whether this reflects an increase in publication of flawed articles or an increase in the rate at which flawed articles are withdrawn.Methods and findingsWe examined the interval between publication and retraction for 2,047 retracted articles indexed in PubMed. Time-to-retraction (from publication of article to publication of retraction) averaged 32.91 months. Among 714 retracted articles published in or before 2002, retraction required 49.82 months; among 1,333 retracted articles published after 2002, retraction required 23.82 months (pConclusionsThe increase in retracted articles appears to reflect changes in the behavior of both authors and institutions. Lower barriers to publication of flawed articles are seen in the increase in number and proportion of retractions by authors with a single retraction. Lower barriers to retraction are apparent in an increase in retraction for "new" offenses such as plagiarism and a decrease in the time-to-retraction of flawed work.

Exotoxins, including the hemolysins known as the alpha (alpha) and beta (beta) toxins, play an important role in the pathogenesis of Staphylococcus aureus infections. A random transposon library was screened for S. aureus mutants exhibiting altered hemolysin expression compared to wild type. Transposon insertions in 72 genes resulting in increased or decreased hemolysin expression were identified. Mutations inactivating a putative cyclic di-GMP synthetase and a serine/threonine phosphatase (Stp1) were found to reduce hemolysin expression, and mutations in genes encoding a two component regulator PhoR, LysR family transcriptional regulator, purine biosynthetic enzymes and a serine/threonine kinase (Stk1) increased expression. Transcription of the hla gene encoding alpha toxin was decreased in a Deltastp1 mutant strain and increased in a Deltastk1 strain. Microarray analysis of a Deltastk1 mutant revealed increased transcription of additional exotoxins. A Deltastp1 strain is severely attenuated for virulence in mice and elicits less inflammation and IL-6 production than the Deltastk1 strain. In vivo phosphopeptide enrichment and mass spectrometric analysis revealed that threonine phosphorylated peptides corresponding to Stk1, DNA binding histone like protein (HU), serine-aspartate rich fibrinogen/bone sialoprotein binding protein (SdrE) and a hypothetical protein (NWMN_1123) were present in the wild type and not in the Deltastk1 mutant. Collectively, these studies suggest that Stk1 mediated phosphorylation of HU, SrdE and NWMN_1123 affects S. aureus gene expression and virulence.

Objective: The objective of this study was to identify the risk factors that influence metastasis and prognosis in patients with nodular melanoma (NM), as well as to develop and validate a prognostic model using artificial intelligence (AI) algorithms., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for 4,727 patients with NM based on the inclusion/exclusion criteria. Their clinicopathological characteristics were retrospectively reviewed, and logistic regression analysis was utilized to identify risk factors for metastasis. This was followed by employing Multilayer Perceptron (MLP), Adaptive Boosting (AB), Bagging (BAG), logistic regression (LR), Gradient Boosting Machine (GBM), and eXtreme Gradient Boosting (XGB) algorithms to develop metastasis models. The performance of the six models was evaluated and compared, leading to the selection and visualization of the optimal model. Through integrating the prognostic factors of Cox regression analysis with the optimal models, the prognostic prediction model was constructed, validated, and assessed., Results: Logistic regression analyses identified that marital status, gender, primary site, surgery, radiation, chemotherapy, system management, and N stage were all independent risk factors for NM metastasis. MLP emerged as the optimal model among the six models (AUC = 0.932, F1 = 0.855, Accuracy = 0.856, Sensitivity = 0.878), and the corresponding network calculator (https://shimunana-nm-distant-m-nm-m-distant-8z8k54.streamlit.app/) was developed. The following were examined as independent prognostic factors: MLP, age, marital status, sequence number, laterality, surgery, radiation, chemotherapy, system management, T stage, and N stage. System management and surgery emerged as protective factors (HR < 1). To predict 1-, 3-, and 5-year overall survival (OS), a nomogram was created. The validation results demonstrated that the model exhibited good discrimination and consistency, as well as high clinical usefulness., Conclusion: The developed prediction model more effectively reflects the prognosis of patients with NM and differentiates between the risk level of patients, serving as a useful supplement to the classical American Joint Committee on Cancer (AJCC) staging system and offering a reference for clinically stratified individualized treatment and prognosis prediction. Furthermore, the model enables clinicians to quantify the risk of metastasis in NM patients, assess patient survival, and administer precise treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Copper (Cu) homeostasis are important processes in the cause of metabolic diseases, but the association between Cu and obesity remains unclear., Methods: Participants were drawn from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression assessed the associations of serum Cu concentrations (tertiles) with obesity and central obesity in individuals without comorbidities. Obesity was defined as a BMI ≥30.0 kg/m2, and central obesity was defined as a waist circumference ≥80 cm for women and ≥95 cm for men., Results: This cross-sectional study included 1,665 adults without comorbidities, representing 24,744,034 people (mean age 35.1 years, 48.5% female). High serum Cu levels (tertile 3: ≥19.19 μmol/L) were associated with higher odds of obesity (adjusted odds ratio [OR]: 4.48, 95% CI[confidence interval]: 2.44-8.32) and central obesity (OR: 2.36, 95% CI: 1.19-4.66) compared to low serum Cu levels (tertile 1: ≤15.64 μmol/L). The dose-response curve showed a nonlinear association between Cu levels and obesity (P-nonlinear = 0.02) and a linear association with central obesity (P-nonlinear = 0.21)., Conclusion: This study suggests that higher serum Cu levels are associated with increased odds of obesity in healthy American adults., Competing Interests: NHANES is a comprehensive cross-sectional study conducted in the United States. The survey employs a sophisticated, stratified, and multistage probability sampling design. The research protocol received approval from the Research Ethics Review Board of the National Center for Health Statistics, and NHANES ensures that written informed consent is obtained from all participants. It’s important to note that our analysis exclusively utilized publicly available data, ensuring the absence of personally identifiable information. All procedures strictly adhered to relevant guidelines and regulations. The interview questionnaires and examination response rates are accessible to the public. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The microvasculature facilitates gas exchange, provides nutrients to cells, and regulates blood flow in response to stimuli. Vascular abnormalities are an indicator of pathology for various conditions, such as compromised vessel integrity in small vessel disease and angiogenesis in tumors. Traditional immunohistochemistry enables the visualization of tissue cross-sections containing exogenously labeled vasculature. Although this approach can be utilized to quantify vascular changes within small fields of view, it is not a practical way to study the vasculature on the scale of whole organs. Three-dimensional (3D) imaging presents a more appropriate method to visualize the vascular architecture in tissue. Here we describe the complete protocol that we use to characterize the vasculature of different organs in mice encompassing the methods to fluorescently label vessels, optically clear tissue, collect 3D vascular images, and quantify these vascular images with a semi-automated approach. To validate the automated segmentation of vascular images, one user manually segmented one hundred random regions of interest across different vascular images. The automated segmentation results had an average sensitivity of 83±11% and an average specificity of 91±6% when compared to manual segmentation. Applying this procedure of image analysis presents a method to reliably quantify and characterize vascular networks in a timely fashion. This procedure is also applicable to other methods of tissue clearing and vascular labels that generate 3D images of microvasculature., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Less than 50% of non-Hispanic Asian adults taking antihypertensive medication have controlled blood pressure., Methods: We compared non-persistence and low adherence to antihypertensive medication between non-Hispanic Asian and other race/ethnicity groups among US adults ≥66 years who initiated antihypertensive medication between 2011 and 2018 using a 5% random sample of Medicare beneficiaries (non-Hispanic Asian, n = 2,260; non-Hispanic White, n = 56,000; non-Hispanic Black, n = 5,792; Hispanic, n = 4,212; and Other, n = 1,423). Non-persistence was defined as not having antihypertensive medication available to take in the last 90 of 365 days following treatment initiation. Low adherence was defined as having antihypertensive medication available to take on <80% of the 365 days following initiation., Results: In 2011-2012, 2013-2014, 2015-2016 and 2017-2018, the proportion of non-Hispanic Asian Medicare beneficiaries with non-persistence was 29.1%, 25.6%, 25.4% and 26.7% (p-trend = 0.381), respectively, and the proportion with low adherence was 58.1%, 54.2%, 53.4% and 51.6%, respectively (p-trend = 0.020). In 2017-2018, compared with non-Hispanic Asian beneficiaries, non-persistence was less common among non-Hispanic White beneficiaries (risk ratio 0.74 [95%CI, 0.64-0.85]), non-Hispanic Black beneficiaries (0.80 [95%CI 0.68-0.94]) and those reporting Other race/ethnicity (0.68 [95%CI, 0.54-0.85]) but not among Hispanic beneficiaries (1.04 [95%CI, 0.88-1.23]). Compared to non-Hispanic Asian beneficiaries, non-Hispanic White beneficiaries and beneficiaries reporting Other race/ethnicity were less likely to have low adherence to antihypertensive medication (relative risk 0.78 [95%CI 0.72-0.84] and 0.84 [95%CI 0.74-0.95], respectively); there was no association for non-Hispanic Black or Hispanic beneficiaries., Conclusions: Non-persistence and low adherence to antihypertensive medication were more common among older non-Hispanic Asian than non-Hispanic White adults., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Choi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Endothelial cell injury is one of the important pathogenic mechanisms in thrombotic diseases, and also neutrophils are involved. MicroRNAs (miRNAs) have been demonstrated to act as essential players in endothelial cell injury, but the potential molecular processes are unknown. In this study, we used cellular tests to ascertain the protective effect of miR-328-3p on human umbilical vein endothelial cells (HUVECs) treated with oxygen-glucose deprivation (OGD)., Methods: In our study, an OGD-induced HUVECs model was established, and we constructed lentiviral vectors to establish stable HUVECs cell lines. miR-328-3p and Toll-like receptor 2 (TLR2) interacted, as demonstrated by the dual luciferase reporter assay. We used the CCK8, LDH release, and EdU assays to evaluate the proliferative capacity of each group of cells. To investigate the expression of TLR2, p-P65 NF-κB, P65 NF-κB, NLRP3, IL-1β, and IL-18, we employed Western blot and ELISA. Following OGD, each group's cell supernatants were gathered and co-cultured with neutrophils. An immunofluorescence assay and Transwell assay have been performed to determine whether miR-328-3p/TLR2 interferes with neutrophil migration and neutrophil extracellular traps (NETs) formation., Results: In OGD-treated HUVECs, the expression of miR-328-3p is downregulated. miR-328-3p directly targets TLR2, inhibits the NF-κB signaling pathway, and reverses the proliferative capacity of OGD-treated HUVECs, while inhibiting neutrophil migration and neutrophil extracellular trap formation., Conclusions: miR-328-3p inhibits the NF-κB signaling pathway in OGD-treated HUVECs while inhibiting neutrophil migration and NETs formation, and ameliorating endothelial cell injury, which provides new ideas for the pathogenesis of thrombotic diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The incidence of cancer in acromegaly patients may be higher than that in the general population, although this has not been fully elucidated yet. This study analyzed the risk of various important types of cancer in acromegaly patients. The study was registered in INPLASY (registration number: INPLASY202340037). The PubMed, Web of Science, and EMBASE databases were searched for studies based on strict inclusion and exclusion criteria, from the time of database inception up to June 30, 2022. All observational studies of acromegaly patients with cancer were included, without language restrictions. We used the Newcastle-Ottawa scale (NOS) checklist to assess the quality of evidence. A meta-analysis revealed the relationship between acromegaly and cancer using the standardized incidence rates (SIRs) and 95% confidence intervals (CIs) retrieved from the included studies. Nineteen studies were included and analyzed. The overall incidence of cancer (SIR = 1.45, 95%CI = 1.20-1.75), as well as that of thyroid (SIR = 6.96, 95%CI = 2.51-19.33), colorectal and anal (SIR = 1.95, 95%CI = 1.32-2.87), brain and central nervous system (SIR = 6.14, 95%CI = 2.73-13.84), gastric (SIR = 3.09, 95%CI = 1.47-6.50), urinary (SIR = 2.66, 95%CI = 1.88-3.76), hematological (SIR = 1.89, 95%CI = 1.17-3.06), pancreatic and small intestine (SIR = 2.59, 95%CI = 1.58-4.24), and connective tissue (SIR = 3.15, 95%CI = 1.18-8.36) cancers, was higher among patients with acromegaly than among the general population. No association between acromegaly and hepatobiliary, respiratory, reproductive, skin, breast, or prostate cancer was observed. This study demonstrated that acromegaly patients have a modestly increased chance of cancer as compared to the general population. Risk factors for cancer need to be further explored to monitor patients with acromegaly at a high risk for cancer more carefully., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Copper is an important mineral and fluctuations in copper prices can affect the stable functioning of some countries' economies. Policy makers, futures traders and individual investors are very concerned about copper prices. In a recent paper, we use an artificial intelligence model long short-term memory (LSTM) to predict copper prices. To improve the efficiency of long short-term memory (LSTM) model, we introduced a simulated annealing (SA) algorithm to find the best combination of hyperparameters. The feature engineering problem of the AI model is then solved by correlation analysis. Three economic indicators, West Texas Intermediate Oil Price, Gold Price and Silver Price, which are highly correlated with copper prices, were selected as inputs to be used in the training and forecasting model. Three different copper price time periods, namely 485, 363 and 242 days, were chosen for the model forecasts. The forecast errors are 0.00195, 0.0019 and 0.00097, respectively. Compared with the existing literature, the prediction results of this paper are more accurate and less error. The research in this paper provides a reliable reference for analyzing future copper price changes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The purpose of this study was to examine the efficacy of ICG-mediated fluorescence molecular imaging (FMI) in debridement of necrotic tissue. 96 wound-infected rats were randomly divided into control group, ICG group, excitation light (EL)group and FMI group for debridement of necrotic tissue (n = 24). (I) Control group: only debridement; (II) ICG group: ICG injection before debridement; (III) EL group: Debridement under EL; (IV) FMI group: Debridement guided by ICG-mediated FMI. On the 3rd, 6th, and 9th days, the wound tissues of the rats in each group were collected for histological examination, and the levels of serum interleukin-4 (IL-4) and interferon-γ (INF-γ) were analyzed. The wound healing rate, wound score and body weight of the rats in each group were followed up until the wound healed. The results showed that the infected wounds of the rats in the FMI group had significant fluorescence development. The level of serum IL-4 in the FMI group was higher than that in the other three groups on the 6th day (p<0.01), while the level of INF-γ was lower than that in the other three groups on the 6th and 9th day (p<0.05). The results of dynamic wound tissue H&E staining indicated that the wound healing in the FMI group was better than the other three groups. The in vivo follow-up results showed that the wound healing rate and wound score of the FMI group were better than the other three groups, and the growth of rats had no difference with the other groups. ICG-mediated FMI can achieve accurate imaging of necrotic tissue for debridement, and so can accelerate wound healing, which has good clinical application prospects., Competing Interests: The authors have no conflicts of interest to declare., (Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To evaluate the practical ability of crews during the navigation of an inward-port single ship, a track evaluation model was developed on a planar forward normal cloud chart under sample information based on the forward normal and the backward normal cloud generator. Since the track sampling cloud may be too divergent, a track belt division method based on the contributions of normal cloud drops was proposed. Combining the track evaluation model with the track belt division method, a comprehensive track evaluation scheme of the local sampling cloud based on sampling information was established. The results of an example of M.V. DAQING 257 unloaded into Dalian Port demonstrated the effectiveness of the model and showed its consistency with expert evaluation results based on subjective information. The proposed uncertainty evaluation model provides a new approach for intelligent evaluation under sample information., Competing Interests: The authors have declared that no competing interests exist.

Introduction: A high prevalence of cryptoglandular and Crohn's perianal fistulas has been reported worldwide, and several surgical options are available for the management of anal fistula, with varying clinical efficacy. However, currently, the available evidence for the effectiveness of these surgical approaches are lacking and of concern in terms of the credibility and strength. The purpose of this study is to evaluate the credibility of the published systematic reviews and meta-analyses that assess the efficacy and safety of the surgical options for cryptoglandular and Crohn's perianal fistulas through an umbrella review., Methods and Analysis: A systematic search in PubMed, Embase and Cochrane library will be performed from inception to December 2020 without any language restriction. We will include systematic reviews and meta-analyses that investigate the efficacy and safety of surgical approaches in the management of cryptoglandular and Crohn's perianal fistulas. Two reviewers will independently screen search results through reading the titles or abstracts. Relevant information will be extracted from each eligible systematic review or meta-analysis. Based on random effects model summary estimates along with their p values, 95% prediction intervals, between-study heterogeneity, small-study effects and excess significance, we will classify the evidence from convincing (class I) to weak (class IV). Findings will be summarized using quantitative synthesis combined with a narrative approach. Cryptoglandular and Crohn's perianal fistulas will be summarized separately. Two authors will independently perform the literature search, data extraction, and quality assessment of each included systematic review and meta-analysis. Any unresolved conflicts or doubts will be resolved by discussion or by consulting a senior author. The risk of bias of the systematic reviews will be assessed using a 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist. The strength of evidence for the included systematic reviews will be classified as "high", "moderate", "low", or "critically low" quality., Ethics and Dissemination: Ethics approval is not required as we will collect data from the published systematic reviews and meta-analyses without using individual patient data. The results of this umbrella review will be published in a peer-reviewed journal and will be presented at an anorectal disease conference., Prospero Registration Number: CRD42020200754., Competing Interests: The authors have declared that no competing interests exist.

Background: Primary acinar cell carcinoma (ACC) is a rare exocrine tumor of the pancreas with unclear clinical characteristics. Our goal was to determine the incidence and update the clinical characteristics and outcomes of ACC., Methods: Through the Surveillance, Epidemiology, and End Results (SEER) database, we identified 252 patients with the latest diagnosis of ACC (2004-2016). The age-adjusted incidence (AAI) was calculated using the SEER*Stat Software version 8.3.6. The Kaplan-Meier method was used to draw survival curves and differences among them were compared by the log-rank test. Cox proportional hazards models were used to evaluate factors that had independent predictive effects on the overall survival., Results: The AAI of pancreatic ACC was on the rise with the mean age at diagnosis of 63.79±14.79 years. Most patients (15.9%) had poorer differentiated tumors. The patients presented with distant stage were 54.4% compared with 53.1% between 1988 and 2003. The 1-, 2-, and 5-years survival rates for pancreatic ACC patients were 53.5%, 34.6%,17.5%, respectively (compared with 78.5%, 67.0%, and 42.8%, between 1988 and 2003). The multivariate COX analysis showed that the patient's age, surgery, chemotherapy, and summary stage, but not marital status were independent prognosis factors for ACC., Conclusions: Pancreatic ACC is a highly malignant tumor with an increasing incidence in recent years. The rate of distant metastasis is increasing and the survival rate is worse than in the past, suggesting that it may require more aggressive treatment and follow-up. Surgery, radiotherapy, and chemotherapy are all effective treatments, but prospective studies are still needed to verify them., Competing Interests: The authors have declared that no competing interests exist.

Theanine (thea) is a unique non-protein amino acid in tea plant (Camellia sinensis) and one of the most important small molecular compounds for tea quality and health effects. The molecular mechanism that maintains thea biosynthesis is not clear but may be reflected in complicated biological networks as other secondary metabolites in plants. We performed an integrative transcriptomic analysis of tea seedlings bud and leave over the time-course of ethylamine (EA) treatment that activated thea pathway. We identified 54 consistent differentially expressed genes (cDEGs, 25 upregulated and 29 downregulated) during thea activation. Gene Ontology (GO) functional enrichment analysis of upregulated genes and downregulated genes showed that they may function as a cascade of biological events during their cooperative contribution to thea biosynthesis. Among the total cDEGs, a diversity of functional genes (e.g., enzymes, transcription factors, transport and binding proteins) were identified, indicating a hierarchy of gene control network underlying thea biosynthesis. A gene network associated with thea biosynthesis was modeled and three interconnected gene functional modules were identified. Among the gene modules, several topologically important genes (e.g., CsBCS-1, CsRP, CsABC2) were experimentally validated using a combined thea content and gene expression analysis. Collectively, we presented here for the first time a comprehensive landscape of the biosynthetic mechanism of thea controlled by a underling gene network, which might provide a theoretical basis for the identification of key genes that contribute to thea biosynthesis., Competing Interests: The authors have declared that no competing interests exist.

Getting a grip on how we may age healthily is a central interest of biogerontological research. To this end, a number of academic teams developed platforms for life- and healthspan assessment in Caenorhabditis elegans. These are very appealing for medium- to high throughput screens, but a broader implementation is lacking due to many systems relying on custom scripts for data analysis that others struggle to adopt. Hence, user-friendly recommendations would help to translate raw data into interpretable results. The aim of this communication is to streamline the analysis of data obtained by the WorMotel, an economically and practically appealing screening platform, in order to facilitate the use of this system by interested researchers. We here detail recommendations for the stepwise conversion of raw image data into activity values and explain criteria for assessment of health in C. elegans based on locomotion. Our analysis protocol can easily be adopted by researchers, and all needed scripts and a tutorial are available in S1 and S2 Files., Competing Interests: The authors have declared that no competing interests exist.

Background: The safety of pirfenidone on pulmonary fibrosis patients with other kinds of interstitial lung diseases (ILDs) in addition to idiopathic pulmonary fibrosis (IPF) is unknown. Furthermore, its effectiveness-related factors on IPF patients are not quite explored., Methods: A retrospective study, on patients prescribed pirfenidone for pulmonary fibrosis, was conducted to assess effectiveness on IPF patients and tolerability of all patients with lung fibrosis. The effectiveness of pirfenidone was tested on 110 IPF subjects receiving treatment for ≥3 months by high-resolution computed tomography (HRCT). Response-linked factors and progression-free survival (PFS) were also analyzed. The data about safety outcomes and drug dose adjustments were collected from all included subjects., Results: A total of 176 subjects were included: 117 were IPF, 19 connective tissue disease-associated interstitial lung disease (CTD-ILD), and 40 unclassifiable ILD. Out of the 110 IPF subjects, 89 subjects were assessed as stable and 21 as progressive, out of which 10 died of acute exacerbation and 11 progressed. The effectiveness was significantly related to their baseline body mass index (BMI). IPF subjects with BMI>25kg/m2 or diffusion capacity of carbon monoxide (DLco)>30% had higher PFS rate. The most common adverse events were skin-related and gastrointestinal-related. Drug discontinuation owing to adverse events occurred similarly in these three groups., Conclusion: Pirfenidone was well tolerated in most of the lung fibrosis patients besides IPF, with a similar pattern of adverse events. Nearly 80% of IPF subjects were assessed as stable. More benefits were seen in IPF patients with higher BMI or mild-to-moderate disease., Competing Interests: The authors have declared that no competing interests exist.

Aim: 'This study aims to establish an open-source algorithm using Python to analyze the accuracy of guided implantation, which simplifies interstudy comparisons., Methods: Given ≥3 landmark pairs, this Tri-Point (TriP) method can register images. With ≥4 landmark pairs, TriP can calculate system errors for image registration. We selected 8 indicators from the literature. Considering development errors in new bone on cone beam computed tomography (CBCT), we added the indicators of apical rectified deviation (ARD) and coronal rectified deviation (CRD), providing accurate references but neglecting depth deviations. Our program can calculate and output these indicators. To evaluate the TriP method's feasibility, an implantation group assisted by a Visual Direction-INdicating Guide (VDING) was analyzed. Accuracy was measured with the traditional and proposed TriP methods. Factors affecting the system error of the method were then analyzed., Results: Comparisons with paired-sample t-tests showed that our TriP method was similar to the traditional method in evaluating implantation accuracy, with no significant difference (P>0.05). The average system error was 0.30±0.10 mm when the TriP method evaluated the VDING template. The results showed that increasing the provided landmarks from 4 to 5 pairs decreased the between-group differences significantly (P<0.05). With ≥6 pairs of landmarks, the system error tended to be stable, and the groups showed no statistically significant differences (P>0.05). Large distances between landmarks are helpful in reducing system error, as demonstrated with a geometric method., Conclusions: This study established an open-source algorithm to analyze the accuracy of guided implantation with system errors reported., Competing Interests: The authors have declared that no competing interests exist.

Identifying the signals of artificial selection can contribute to further shaping economically important traits. Here, a chicken 600k SNP-array was employed to detect the signals of artificial selection using 331 individuals from 9 breeds, including Jingfen (JF), Jinghong (JH), Araucanas (AR), White Leghorn (WL), Pekin-Bantam (PB), Shamo (SH), Gallus-Gallus-Spadiceus (GA), Rheinlander (RH) and Vorwerkhuhn (VO). Per the population genetic structure, 9 breeds were combined into 5 breed-pools, and a 'two-step' strategy was used to reveal the signals of artificial selection. GA, which has little artificial selection, was defined as the reference population, and a total of 204, 155, 305 and 323 potential artificial selection signals were identified in AR&#95;VO, PB, RH&#95;WL and JH&#95;JF, respectively. We also found signals derived from standing and de-novo genetic variations have contributed to adaptive evolution during artificial selection. Further enrichment analysis suggests that the genomic regions of artificial selection signals harbour genes, including THSR, PTHLH and PMCH, responsible for economic traits, such as fertility, growth and immunization. Overall, this study found a series of genes that contribute to the improvement of chicken breeds and revealed the genetic mechanisms of adaptive evolution, which can be used as fundamental information in future chicken functional genomics study.

Epidemiological studies have revealed that noise exposure was associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the exact nature of that association remains to be elucidated. The present study is designed to examine the effects of chronic noise exposure on the development of T2DM in combination with a high-fat-diet (HFD) in mice. Here we show that chronic noise exposure at 85 dB SPL (4 h /day, below the safety limit for occupational noise exposure) exaggerated multiple metabolic abnormalities induced by HFD in C57BL/6J male mice, including worsened glucose intolerance, insulin resistance, fasting hyperglycemia and dyslipidemia. Furthermore, noise exposure exhibited a paradoxical impact on fat accumulation and circulating levels of free fatty acid, indicating a potential stimulating effect of noise on lipolysis. These results provide first in vivo supporting evidence for the causative role of noise exposure in diabetogenesis and pinpoint a noise-associated increase in blood free fatty acid levels as a possible mediator accelerating the effect of noise on the development of insulin resistance and T2DM.

The response of resistant soil organic matter to temperature change is crucial for predicting climate change impacts on C cycling in terrestrial ecosystems. However, the response of the decomposition of different soil organic carbon (SOC) fractions to temperature is still under debate. To investigate whether the labile and resistant SOC components have different temperature sensitivities, soil samples were collected from three forest and two grass land sites, along with a gradient of latitude from 18°40'to 43°17'N and elevation from 600 to 3510 m across China, and were incubated under changing temperature (from 12 to 32 oC) for at least 260 days. Soil respiration rates were positively related to the content of soil organic carbon and soil microbial carbon. The temperature sensitivity of soil respiration, presented as Q10 value, varies from 1.93 ± 0.15 to 2.60 ± 0.21. During the incubation, there were no significant differences between the Q10 values of soil samples from different layers of the same site, nor a clear pattern of Q10 values along with the gradient of latitude. The result of this study does not support current opinion that resistant soil carbon decomposition is more sensitive to temperature change than labile soil carbon.

Biochars produced from the pyrolysis of waste biomass under limited oxygen conditions could serve as adsorbents in environmental remediation processes. Biochar samples derived from rice straw that were pyrolyzed at 300 (R300), 500 (R500) and 700°C (R700) were used as adsorbents to remove tetracycline from an aqueous solution. Both the Langmuir and Freundlich models fitted the adsorption data well (R2 > 0.919). The adsorption capacity increased with pyrolysis temperature. The R500 and R700 samples exhibited relative high removal efficiencies across a range of initial tetracycline concentrations (0.5mg/L-32mg/L) with the maximum (92.8%-96.7%) found for adsorption on R700 at 35°C. The relatively high surface area of the R700 sample and π-π electron-donor acceptor contributed to the high adsorption capacities. A thermodynamic analysis indicated that the tetracycline adsorption process was spontaneous and endothermic. The pH of solution was also found to influence the adsorption processes; the maximum adsorption capacity occurred at a pH of 5.5. These experimental results highlight that biochar derived from rice straw is a promising candidate for low-cost removal of tetracycline from water.

Dipeptidyl peptidase-4 (DPP4) is one of the most potent mammalian serine proteases participated in the pathogenesis of subclinical atherosclerosis. Here we investigated whether the plasma soluble form of DPP4 is associated with the prevalence of coronary artery disease (CAD) with and without diabetes mellitus (DM). A cross-sectional study was conducted of 496 aged 26-81 years with (n = 362) and without (n = 134) CAD. Plasma DPP4 activity, high sensitive C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein levels were measured. The coronary atherosclerotic plaques were evaluated by coronary angiography. The CAD patients with (n = 84) and without (n = 278) DM had significantly higher DPP4 levels (11.8 ± 3.1 vs. 6.9 ± 3.5 ng/mL, P<0.01) than the nonCAD subjects. The acute coronary syndrome patients (n = 299) had elevated DPP4 levels than those with stable angina patients (n = 83). CAD patients even without DM had increased plasma DPP4 activities as compared with nonCAD subjects (10.9 ± 4.9 vs. 6.4 ± 3.1, ng/L, P< 0.01). A linear regression analysis revealed that overall, the DPP4 levels were positively associated with LCL-C and hs-CRP levels as well as syntax scores. A multiple logistic regression analysis demonstrated that plasma DPP4 activity was independent predictor of CAD (odds ratio, 1.56; 95% CI, 1.19-1.73; P<0.01). Our study shows that increased DPP4 activity levels are associated with the presence of CAD and that the plasma DPP4 level serves as a novel biomarker for CAD even without DM., Competing Interests: The authors have no relationships that could be considered a conflict of interest.

Background and Aim: The present study was aimed at assessing the characteristics of children with nosocomial multidrug-resistant Acinetobacter baumannii complex (MDR ABC) in a tertiary hospital of eastern China. MDR ABC poses a serious threat to public health. However, information on nosocomial MDR ABC in children is lacking., Method: This study retrospectively reviewed the cases in a tertiary hospital of eastern China between January 1, 2011, and December 31, 2014 (excluding outpatients)., Results: A total of 377 non-duplicated nosocomial ABC isolates were collected from various samples including 200 (53.1%) MDR ABC isolates. Moreover, 158 of the 200 MDR ABC isolates were collected from intensive care units (ICUs; MDR constituent ratios, 62.5%), while 98 of the 200 MDR ABC isolates were collected from children older than 1 year (MDR constituent ratios, 62.8%). Multivariate logistic analysis revealed that being in the surgical intensive care unit (SICU), prolonged hospital stay, surgical intervention, and mechanical ventilation were independent risk factors for MDR acquisition among children with nosocomial ABC. The interleukin (IL)-6 level of children with nosocomial MDR ABC was significantly lower than that of the children with nosocomial non-MDR ABC., Conclusion: Nosocomial MDR ABC infection is a serious concern in pediatric patients. Being in the SICU, prolonged hospital stay, surgical intervention, and mechanical ventilation increased the risk of nosocomial MDR ABC. IL-6 might be involved in developing nosocomial MDR ABC among children., Competing Interests: The authors have declared that no competing interests exist.

Background: Sarcoidosis is a granulomatous disease, the etiology of which is currently unknown. The role of mycobacteria in the etiology of sarcoidosis has been extensively investigated. In this meta-analysis, we assessed the immunological evidence of the possible role of mycobacteria in the pathogenesis and development of sarcoidosis., Methods: We performed a systematic search of relevant articles from PubMed, Embase and Cochrane Library databases published between January 1990 and October 2015. Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK)., Results: In this meta-analysis, 13 case-control studies (733 participants) were considered eligible according to our criteria. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The positivity incidence of the immune response (either the cell-mediated response or humoral response) in sarcoidosis patients was significantly higher than that in controls, as determined using fixed-effects model. The odds ratio (OR) of the positivity incidence of T-cell response in the patients with sarcoidosis versus the controls with PPD- or unknown PPD status was 5.54 (95% CI 3.56-8.61); the ORs were 16.70 (95% CI 8.19-34.08) and 1.48 (95% CI 0.74-2.96) for the two subgroups with PPD- controls and unknown PPD status respectively. However, the OR of the positivity incidence in patients with sarcoidosis versus PPD+ controls (latent tuberculosis infection; LTBI) was 0.26 (95% 0.10-0.66). Regarding the humoral response, pooled analysis of the positivity incidence revealed an OR (95%CI) of 20.43 (5.53-75.53) for the patients with sarcoidosis versus controls; the ORs were 11.93 (95% CI 2.15-66.27) and 41.97 (95% CI 5.24-336.15) in two subgroups of controls with PPD- and unknown PPD statuses respectively. Data on heterogeneity and evidence of publication bias were examined., Conclusions: This meta-analysis confirmed the existence of an association between mycobacteria (especially M.tuberculosis) and sarcoidosis. The current available evidence indicates that some insoluble mycobacterial antigens that preferentially within the body are involved in the pathogenesis of sarcoidosis rather than the whole mycobacteria and that they elicit a type IV immune response.

Background: Understanding how leukocytes in the cervicovaginal and colorectal mucosae respond to pathogens, and how medical interventions affect these responses, is important for developing better tools to prevent HIV and other sexually transmitted infections. An effective cryopreservation protocol for these cells following their isolation will make studying them more feasible., Methods and Findings: To find an optimal cryopreservation protocol for mucosal mononuclear leukocytes, we compared cryopreservation media and procedures using human vaginal leukocytes and confirmed our results with endocervical and colorectal leukocytes. Specifically, we measured the recovery of viable vaginal T cells and macrophages after cryopreservation with different cryopreservation media and handling procedures. We found several cryopreservation media that led to recoveries above 75%. Limiting the number and volume of washes increased the fraction of cells recovered by 10-15%, possibly due to the small cell numbers in mucosal samples. We confirmed that our cryopreservation protocol also works well for both endocervical and colorectal leukocytes. Cryopreserved leukocytes had slightly increased cytokine responses to antigenic stimulation relative to the same cells tested fresh. Additionally, we tested whether it is better to cryopreserve endocervical cells on the cytobrush or in suspension., Conclusions: Leukocytes from cervicovaginal and colorectal tissues can be cryopreserved with good recovery of functional, viable cells using several different cryopreservation media. The number and volume of washes has an experimentally meaningful effect on the percentage of cells recovered. We provide a detailed, step-by-step protocol with best practices for cryopreservation of mucosal leukocytes.