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This pilot randomized control trial (RCT) tested “Do More, Feel Better” (DMFB), a lay-delivered Behavioral Activation intervention for depressed senior center clients. The study examined: 1. the feasibility of training older lay volunteers to fidelity; and 2. the acceptability, safety, and impact of the intervention. Twenty-one lay volunteers at four senior centers were trained in DMFB. Fifty-six depressed clients were randomized to receive 9 sessions of DMFB or Behavioral Activation delivered by social workers (MSW BA). Research assessments of overall client activity level (BADS) and depression severity (HAM-D) were conducted at baseline and weeks 3, 6, and 9. Eighty-one percent of lay volunteers who underwent training were formally certified in DMFB. Depressed clients receiving each intervention reported high levels of satisfaction and showed large and clinically significant changes in 9-week activity level (d ≥ 1.35) and depression severity (d ≥ 3.34). Differences between treatment groups were very small for both activity level (dMSW = 0.16; 95% CI, -0.70 to 1.02) and depression (dMSW = 0.14; 95% CI, -0.63 to 0.91). Increases in activity level were associated with decreases in depression (β = -0.42; 95% CI, -0.55 to -0.30). Both interventions appeared to work as intended by increasing activity level and reducing depression severity. “Do More, Feel Better” shows the potential of evidence-based behavioral interventions delivered by supervised lay volunteers, and can help address the insufficient workforce available to meet the mental health needs of community-dwelling older adults.

Gay, bisexual, and other men who have sex with men (MSM) and transgender women are disproportionately affected by human papillomavirus (HPV). HPV vaccination is routinely recommended for U.S. adolescents at age 11-12years, with catch-up vaccination through age 26years. We assessed HPV vaccination coverage and associated factors among young MSM and transgender women. The Vaccine Impact in Men study enrolled MSM aged 18-26years from clinics in Seattle, Chicago, and Los Angeles, during February 2016-September 2018. Participants self-reported socio-demographic information and HPV vaccination status. Among 1416 participants, 673 (47.5%) reported ≥1 HPV vaccine dose. Among vaccinated participants, median age at first dose was 19years and median age at first sex was 17years; 493 (73.3%) reported that their age at first dose was older than their age at first sex. There were significant differences in HPV vaccination coverage by city (range 33%-62%), age, race/ethnicity, and gender identity. Coverage was highest in Seattle, where younger age was the only factor associated with vaccination. Differences in coverage by city may be due to variation in vaccination practices or enrollment at study sites. Increasing both routine and catch-up vaccination will improve coverage among MSM and transgender women.

Background In the United States, human papillomavirus (HPV) vaccination has been recommended since 2011 for boys aged 11–12 years, with catch-up vaccination recommended through age 26 years for previously unvaccinated men who have sex with men (MSM). Methods During 2016–2018, a cross-sectional study enrolled MSM and transgender women aged 18–26 years in Seattle, Washington. Participants submitted self-collected penile swab specimens for HPV genotyping. HPV vaccination history was self-reported. We compared HPV prevalence among vaccinated participants with that in participants with no or unknown vaccination history, using log-binomial regression to estimate adjusted prevalence ratios and confidence intervals. Results Among 687 participants, 348 (50.7%) self-reported ever receiving ≥1 HPV vaccine dose; the median age at first HPV vaccination was 21 years, and the median age at first sex, 17 years. Overall, the prevalence of penile quadrivalent HPV vaccine (4vHPV)–type HPV was similar in vaccinated participants (12.1%) and participants with no or unknown vaccination (15.6%) (adjusted prevalence ratio, 0.69 [95% confidence interval, .47–1.01]). However, the prevalence was significantly lower in participants vaccinated at age ≤18 years than in those with no of unknown vaccination (0.15 [.04–.62]), corresponding to a vaccine effectiveness of 85% against 4vHPV-type HPV. Conclusions Results suggest that HPV vaccination is effective in preventing penile HPV infections in young MSM when administered at age ≤18 years.

Purpose Exercise therapy (ET) is shown to improve toxicity and surrogates of survival for patients receiving chemotherapy. Current National Comprehensive Cancer Network (NCCN) guidelines lack recommendations for concurrent radiation therapy (RT) and ET. The main objective was to determine the impact of concurrent ET + RT with respect to (1) acceptability, feasibility, safety; and (2) to demonstrate how incorporating ET in cancer treatment can enhance patient-reported outcomes (PROs) and physical function—defined as strength or exercise capacity. Methods and Materials A PICOS/PRISMA selection protocol was used to search PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Review for prospective randomized controlled trials evaluating concurrent ET + RT, including >10 patients and with 1 or more study arms. Acceptability, feasibility, and safety rates were calculated. PROs were assessed with study-specific metrics. Physical function was defined as improvements in strength or range of motion. Statistically significant improvement was defined by P Results Twenty-six of 693 screened studies including 1563 patients (831 receiving exercise, 732 controls) with localized breast cancer (67.1% of patients), prostate cancer (27.4%), head and neck cancers (2.8%), and spinal metastases (2.8%) were assessed. Objective 1: Among 3385 patients approached for ET, 1864 (55.1%) accepted the treatment; of those, 1563 patients (83.9%) completed the trials. Objective 2: Statistical improvements were noted in these PROs: quality of life (14 of 15 studies), fatigue (12 of 16 studies), mood/depression (9 of 13), and anxiety (6 of 7). Physical function improved statically in 16 of 16 studies. Conclusions Combination ET + RT is safe and well-tolerated with improvements in PROs and physical function. Additional studies are needed in patients with metastatic cancers to assess survival and to compare effectiveness of different exercise regimens.

Mailing HPV self-sampling kits to overdue individuals increases cervical cancer screening adherence; offering self-sampling to previously adherent individuals has not been evaluated in the U.S. Given heterogeneity of the U.S. health system and population, data are needed to optimize how HPV self-sampling is offered to individuals who are overdue, due after successful past screening, or have an unknown screening history.STEP is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system, designed to compare different outreach approaches for offering HPV self-sampling in populations defined by prior screening behavior (previously-adherent, overdue, or unknown screening history). Over 14 months, eligible individuals were identified through electronic medical record (EMR) data and randomized to Usual Care (UC), Education (UC + educational materials about cervical cancer screening), Direct-Mail (UC + Education + a mailed self-sampling kit) or Opt-In (UC + Education + option to request a kit), depending on screening history. The primary objective is to compare screening completion by outreach approach and screening history. Secondary objectives include evaluating incremental cost-effectiveness of outreach approaches, and identifying patient preference for, and satisfaction with, HPV self-screening, and barriers to abnormal results follow-up (measured through interviews and focus groups).The trial was designed to generate data that U.S. health systems can use to inform primary HPV screening implementation strategies that incorporate HPV self-sampling options to improve screening access, adherence, and patient satisfaction. The objective of this report is to describe the rationale and design of this pragmatic trial.

HPV vaccine uptake is low among East African-American (EAA) adolescents. We developed a comic book and evaluated the impact on HPV/HPV-vaccine knowledge, beliefs and vaccine intentions. The intervention was delivered to HPV-unvaccinated EAA adolescents attending educational dinners with their mothers. Adolescents aged 14-17 were sequentially assigned alternately to a pre- or post-test. Results were compared with chi-squared tests and generalized estimating equation models adjusted for age, gender, and mother's language. Among 136 (pre-test = 64, post-test = 72) participants (90% Somali), pre/post differences were observed for proportions of correct responses to questions on HPV (44.0% vs. 82.9%, RR:1.87[95%CI 1.54-2.27]), HPV-vaccine knowledge (42.8% vs. 75.4%, RR:1.74[95%CI 1.46-2.07]), comfort discussing HPV/HPV vaccine with parents (57.8% vs. 90.3% somewhat/very comfortable, RR:1.55[95%CI 1.24-1.94]), and willingness (37.5% vs. 83.3% probably/definitely willing, RR:2.16[95%CI 1.55-3.01]) and intention (34.4% vs. 86.1% somewhat/very likely, RR:2.38[95%CI:1.69-3.37]) to get vaccinated. The intervention improved participants' HPV/HPV-vaccine knowledge, beliefs and vaccine intentions. Similar interventions could be adapted for other racial/ethnic minorities.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Background Increased intestinal barrier permeability and subsequent gut microbial translocation are significant contributors to inflammatory non-AIDS comorbidities in people living with HIV (PLWH). Evidence in animal models have shown that markers of intestinal permeability and microbial translocation vary over the course of the day and are affected by food intake and circadian rhythms. However, daily variations of these markers are not characterized yet in PLWH. Herein, we assessed the variation of these markers over 24 h in PLWH receiving antiretroviral therapy (ART) in a well-controlled environment. Methods As in Canada, PLWH are predominantly men and the majority of them are now over 50 years old, we selected 11 men over 50 receiving ART with undetectable viremia for more than 3 years in this pilot study. Blood samples were collected every 4 h over 24 h before snacks/meals from 8:00 in the morning to 8:00 the next day. All participants consumed similar meals at set times, and had a comparable amount of sleep, physical exercise and light exposure. Plasma levels of bacterial lipopolysaccharide (LPS) and fungal (1→3)-β-D-Glucan (BDG) translocation markers, along with markers of intestinal damage fatty acid binding protein (I-FABP) and regenerating islet-derived protein-3α (REG3α) were assessed by ELISA or the fungitell assay. Results Participants had a median age of 57 years old (range 50 to 63). Plasma levels of BDG and REG3α did not vary significantly over the course of the study. In contrast, a significant increase of LPS was detected between 12:00 and 16:00 (Z-score: − 1.15 ± 0.18 vs 0.16 ± 0.15, p = 0.02), and between 12:00 and 24:00 (− 1.15 ± 0.18 vs 0.89 ± 0.26, p Conclusions Conversely to the fungal translocation marker BDG and the gut damage marker REG3α, time of blood collection matters for the proper evaluation for LPS and I-FABP as markers for the risk of inflammatory non-AIDS co-morbidities. These insights are instrumental for orienting clinical investigations in PLWH.

The gut microbiota is emerging as a prominent player in maintaining health through several metabolic and immune pathways. Dysregulation of gut microbiota composition, also known as dysbiosis, is involved in the clinical outcome of diabetes, inflammatory bowel diseases, cancer, aging and HIV infection. Gut dysbiosis and inflammation persist in people living with HIV (PLWH) despite receiving antiretroviral therapy, further contributing to non-AIDS comorbidities. Metformin, a widely used antidiabetic agent, has been found to benefit microbiota composition, promote gut barrier integrity and reduce inflammation in human and animal models of diabetes. Inspired by the effect of metformin on diabetes-related gut dysbiosis, we herein critically review the relevance of metformin to control inflammation in PLWH. Metformin may improve gut microbiota composition, in turn reducing inflammation and risk of non-AIDS comorbidities. This review will pave the way towards innovative strategies to counteract dysregulated microbiota and improve the lives of PLWH.

BackgroundRegenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.MethodsPlasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)–uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers.ResultsCross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH.ConclusionsPlasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-β superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.

IntroductionDespite the success of antiretroviral therapy (ART) in transforming HIV disease into a chronic infection, people living with HIV (PLWH) remain at risk for various non-AIDS inflammatory comorbidities. Risk of non-AIDS comorbidities is associated with gut dysbiosis, epithelial gut damage and subsequent microbial translocation, and increased activation of both circulating CD4+ and CD8+ T-cells. Therefore, in addition to ART, novel gut microbiota-modulating therapies could aid in reducing inflammation and immune activation, gut damage, and microbial translocation. Among various gut-modulation strategies under investigation, the Amazonian fruit Camu Camu (CC) presents itself as a prebiotic candidate based on its anti-inflammatory and antioxidant properties in animal models and tobacco smokers.Method and analysisA total of 22 PLWH on ART for more than 2 years, with a viral load 200 and a CD4+/CD8 +ratio Ethics and disseminationThe Canadian Institutes of Health Research (CIHR)/Canadian HIV Trials Network (CTN) pilot trial protocol CTNPT032 was approved by the Natural and Non-prescription Health Products Directorate of Health Canada and the research ethics board of the McGill university Health Centre committee (number 2020-5903). Results will be made available as free access through publications in peer-reviewed journals and through the CIHR/CTN website.Trial registration numberNCT04058392.

Early establishment of HIV reservoir represents the main impediment to an HIV cure. Mainly composed of infected memory CD4 T-cells and macrophages, HIV reservoirs are found in several organs including lymph nodes, gut, and testes. In men, and as seen in brain and eyes, testes represent a distinctive organ characterized by an immune privilege, allowing the tolerance of spermatozoa which only develop after puberty, long after the establishment of systemic immunity. The immune privilege of testes relies on a strict testis-blood barrier, and a local immunosuppressive environment. Testes has been described as reservoir for several viruses including Ebola, Zika, and HIV. Indeed, HIV reservoirs were detected in tested viremic and virally suppressed donor taking antiretroviral therapy (ART). Herein, we discuss the distinctive environment found in human testes and describe a validated method allowing the characterization and quantification of HIV-infected CD4 T-cells in human testes. Using mechanical and enzymatic treatment, cells can be extracted from human testis samples. Characterization of those cells can be performed by flow cytometry and HIV reservoir quantification performed by nested qPCR after flow cytometry sorting.

BackgroundThe development of more efficient drug delivery devices for ciclesonide inhalation products requires an ultrasensitive bioanalytical method to measure systematic exposure of ciclesonide (CIC) and its active metabolite desisobutyryl-ciclesonide (des-CIC) in humans.MethodSerum sample was extracted with 1-chlorobutane. A reversed-phase liquid chromatography coupled with atmospheric pressure photoionization–tandem mass spectrometry (LC-APPI-MS/MS) method was used for quantification of 1–500 pg/mL for both analytes in a 0.500-mL serum. The analysis time was 4.7 min/injection. CIC-d11 and des-CIC-d11 were used as the internal standards.ResultsCalibration curves showed good linearity (r2 > 0.99) for both analytes. This novel method was precise and accurate with interassay precision and accuracy of all within 9.6% CV and ± 4.0% bias for regular QC samples. Extraction recovery was approximately 85% for both analytes. Serum samples are stable for 3 freeze–thaw cycles, 24 h at bench top, and up to 706 days at both −20 °C and −70 °C. This method was successfully used to support a pharmacokinetic (PK) comparison between the inhalation suspensions and an inhalation aerosol of ciclesonide in healthy participants. The method robustness was also supported by the good incurred sample reanalysis reproducibility.ConclusionAPPI, a highly selective and sensitive ionization source, made possible for quantifying CIC and des-CIC with a lower limit of quantification (LLOQ) of 1 pg/mL in human serum by LC-MS/MS. A 10-fold sensitivity improvement from the most sensitive reported method (LLOQ, 10 pg/mL) is essential to fully characterize the PK profiles of CIC and des-CIC in support of the clinical development of the ciclesonide-related medications for patients.

The introduction of combined antiretroviral therapy (cART) in 1996 has significantly influenced the care of people living with human immunodeficiency virus (HIV) by reducing the risk of opportunist...

To describe critically ill children's coagulation profile with the multisystem inflammatory syndrome (MIS-C) related to coronavirus.Single-center, observational study at a tertiary, pediatric intensive care unit (PICU) in children aged 1 month to 18 years.Sixteen children, with a median age of 5.4 years (interquartile range [IQR] 2.1, 11.75), 56% female, admission Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score of 3.5 (IQR 2, 5), and median PICU length of stay 3 days (IQR 1.5, 4), met criteria of MIS-C. All patients received acetylsalicylic acid (80-100 mg/kg) and none received anticoagulation. Sixty-three percent (10/16) of children had out-of-normal range values on thromboelastography (TEG) (44% [7/16] with hypercoagulability and 19% [3/16] with hypocoagulability). Of those with hypercoagulability, 19% (3/16) had rapid clot formation, and 25% (4/16) had increased clot strength. In 69% (11/16) of children, there was impaired fibrinolysis (0% lysis at 30 minutes) on TEG. Seventy-five percent (12/16) of children had out-of-normal range value on standard coagulation assays (37.5% [6/16] with hypocoagulability and 37.5% [6/16] with hypercoagulability). TEG-G (clot strength as measured by TEG) value (ρ -.553, p = .033) and platelet count (ρ -.840, p .0001) were correlated with admission PELOD-2 score. TEG-G value (ρ -.506, p = .04) and platelet count (ρ -.539, p = .03) were correlated with the duration of intensive care unit stay.Coagulation abnormalities are frequent in children with MIS-C. TEG parameter and platelet count are correlated with the severity of multiorgan dysfunction and the duration of intensive care stay. Multicenter studies are needed to confirm the clinical implications of these coagulation abnormalities.

Spine trauma, vertebral metastases, and osteoporosis (SVO) can result in serious health problems. If the diagnosis of SVO is delayed, the prognosis may be deteriorated. The use of artificial intelligence (AI) is an essential method for minimizing the diagnostic errors associated with SVO. research achievements (RAs) of SVO on AI are required as a result of the greatest number of studies on AI solutions reported. The study aimed to: classify article themes using visualizations, illustrate the characteristics of SVO on AI recently, compare RAs of SVO on AI between entities (e.g., countries, institutes, departments, and authors), and determine whether the mean citations of keywords can be used to predict article citations.A total of 31 articles from SVO on AI (denoted by T31SVOAI) have been found in Web of Science since 2018. The dominant entities were analyzed using the CJAL score and the Y-index. Five visualizations were applied to report: the themes of T31SVOAI and their RAs in comparison for article entities and verification of the hypothesis that the mean citations of keywords can predict article citations, including: network diagrams, chord diagrams, dot plots, a Kano diagram, and radar plots.There were five themes classified (osteoporosis, personalized medicine, fracture, deformity, and cervical spine) by a chord diagram. The dominant entities with the highest CJAL scores were the United States (22.05), the University of Pennsylvania (5.72), Radiology (6.12), and Nithin Kolanu (Australia) (9.88). The majority of articles were published in Bone, J. Bone Miner. Res., and Arch. Osteoporos., with an equal count (=3). There was a significant correlation between the number of article citations and the number of weighted keywords (F = 392.05; P .0001).A breakthrough was achieved by displaying the characteristics of T31SVOAI using the CJAL score, the Y-index, and the chord diagram. Weighted keywords can be used to predict article citations. The five visualizations employed in this study may be used in future bibliographical studies.

Women overdue for cervical cancer screening often have other preventive care gaps. We examined whether mailing unsolicited human papillomavirus (HPV) self-sampling kits to increase cervical cancer screening impacted receipt of other preventive services women were due for: mammography, colorectal cancer (CRC) screening, influenza vaccination, depression screening, and diabetic HbA1c monitoring. From 2014 to 2016, 16,590 underscreened women were randomized to receive a mailed kit or usual care Pap reminders within Kaiser Permanente Washington. We used logistic regression to estimate odds ratios (ORs) of preventive services receipt within 12-months between the intervention vs. control arms, and within the intervention arm (comparing those returning a kit vs. attending Pap vs. nothing), adjusting models for demographic variables. There were no significant between-arm differences in uptake of any of the preventive services: intervention vs. control: mammography OR = 1.01 (95% confidence interval:0.88-1.17), CRC screening OR = 0.98 (0.86-1.13), influenza vaccination OR = 0.99 (0.92-1.06), depression screening OR = 1.07 (0.99-1.16), HbA1c OR = 0.84 (0.62-1.13). Within the intervention arm, preventive services uptake was higher in women who completed cervical cancer screening vs. did not, with stronger effects for women who attended Pap: Pap vs. nothing: mammography OR = 11.81 (8.11-17.19), CRC screening OR = 7.31 (5.57-9.58), influenza vaccination OR = 2.06 (1.82-2.32), depression screening OR = 1.79 (1.57-2.05), HbA1c OR = 3.35 (1.49-7.52); kit vs. nothing: mammography OR = 2.26 (1.56-3.26), CRC screening OR = 5.05 (3.57-7.14), influenza vaccination OR = 1.67 (1.41-1.98), depression screening OR = 1.09 (0.89-1.33), HbA1c OR = 1.23 (0.57-2.65). Mailing HPV self-sampling kits to underscreened women did not negatively impact uptake of other preventive services. However, overall preventive service uptake was the highest among women who attended in-clinic cervical cancer screening.

(1→3)-β-D-Glucan (BDG) represents a potent pathogen-associated molecular pattern (PAMP) in triggering the host response to fungal and some bacterial infections. Monocytes play a key role in recognizing BDG and governing the acute host response to infections. However, the mechanisms regulating monocyte’s acute response to BDG are poorly understood. We sought to investigate the response of monocytes to BDG at the epigenetic, transcriptomic, and molecular levels. Response of human monocytes to 1, 4, and 24 hours of BDG exposure was investigated using RNA-seq, ATAC-seq, H3K27ac and H3K4me1 ChIP-seq. We show that pathways including glutathione metabolism, pentose phosphate pathway, and citric acid cycle were upregulated at the epigenetic and transcriptomic levels in response to BDG exposure. Strikingly, unlike bacterial lipopolysaccharides, BDG induced intracellular glutathione synthesis. BDG exposure also induced NADP synthesis, increased NADPH/NADP ratio, and increased expression of genes involved in the pentose phosphate pathway in a GSH-dependent manner. By inhibiting GSH synthesis with L-buthionine sulfoximine (BSO) before BDG exposure we show that the GSH pathway promotes cell survival and regulates monocyte’s effector functions including NO production, phagocytosis, and cytokine production. In summary, our work demonstrates that BDG induces glutathione synthesis and metabolism in monocytes, which is a major promoter of the acute functional response of monocytes to infections.

Haemophagocytic lymphohistiocytosis (HLH) causing multiorgan failure has been reported as an acute clinical presentation of COVID-19. However, the literature surrounding HLH in the context of a postacute COVID-19 syndrome is limited. This report presents a case of a life-threatening HLH occurring 6 weeks after a pauci-symptomatic COVID-19 infection in a previously healthy adult. A bone marrow aspirate confirmed the HLH and the patient was successfully treated with dexamethasone and etoposide. To our knowledge, this is the first case of HLH occurring as a postacute COVID-19 syndrome following a pauci-symptomatic initial infection.

People with human immunodeficiency virus (HIV) (PWH) have reduced gut barrier integrity (“leaky gut”) that permits diffusion of microbial antigens (microbial translocation) such as lipopolysaccharide (LPS) into the circulation, stimulating inflammation. A potential source of this disturbance, in addition to gut lymphoid tissue CD4+ T-cell depletion, is the interaction between the gut barrier and gut microbes themselves. We evaluated the relationship of gut barrier integrity, as indexed by plasma occludin levels (higher levels corresponding to greater loss of occludin from the gut barrier), to gut microbial diversity. PWH and people without HIV (PWoH) participants were recruited from community sources and provided stool, and 16S rRNA amplicon sequencing was used to characterize the gut microbiome. Microbial diversity was indexed by Faith’s phylogenetic diversity (PD). Participants were 50 PWH and 52 PWoH individuals, mean ± SD age 45.6 ± 14.5 years, 28 (27.5%) women, 50 (49.0%) non-white race/ethnicity. PWH had higher gut microbial diversity (Faith’s PD 14.2 ± 4.06 versus 11.7 ± 3.27, p = 0.0007), but occludin levels were not different (1.84 ± 0.311 versus 1.85 ± 0.274, p = 0.843). Lower gut microbial diversity was associated with higher plasma occludin levels in PWH (r = −0.251, p = 0.0111), but not in PWoH. A multivariable model demonstrated an interaction (p = 0.0459) such that the correlation between Faith’s PD and plasma occludin held only for PWH (r = −0.434, p = 0.0017), but not for PWoH individuals (r = −0.0227, p = 0.873). The pattern was similar for Shannon alpha diversity. Antiretroviral treatment and viral suppression status were not associated with gut microbial diversity (ps &gt, 0.10). Plasma occludin levels were not significantly related to age, sex or ethnicity, nor to current or nadir CD4 or plasma viral load. Higher occludin levels were associated with higher plasma sCD14 and LPS, both markers of microbial translocation. Together, the findings suggest that damage to the gut epithelial barrier is an important mediator of microbial translocation and inflammation in PWH, and that reduced gut microbiome diversity may have an important role.

ImportanceMailing human papillomavirus (HPV) self-sampling kits increases cervical cancer screening participation, but effects may differ across subpopulations. Subpopulation data can inform US health care system implementation.ObjectiveTo identify patient characteristics that modify effectiveness of a mailed kit intervention at increasing screening.Design, Setting, and ParticipantsThis was a secondary analysis of data from the Home-Based Options to Make Cervical Cancer Screening Easy (HOME) randomized clinical trial conducted from 2014 to 2018 at Kaiser Permanente Washington. Data analysis was performed from March 2018 to May 2022. Individuals aged 30 to 64 years with female sex, health plan enrollment longer than 3 years and 5 months, a current primary care clinician, and no Papanicolaou test within the prior 3 years and 5 months were identified through electronic medical records and randomized (1:1) to the control or intervention group.InterventionsThe control group received usual care Papanicolaou screening reminders and outreach. The intervention group received usual care plus an unsolicited mailed HPV self-sampling kit.Main Outcomes and MeasuresScreening uptake was captured within 6 months after randomization. Baseline patient characteristics (age, race, ethnicity, travel time to clinic, income, body mass index, tobacco use, health plan enrollment duration, time since last Papanicolaou test, mammography, comorbidities, and colorectal cancer screening adherence) were extracted from the electronic medical record.ResultsOf 19 734 individuals (mean [SD] age, 50.1 [9.5] years; 14 129 [71.6%] White), 9843 were randomized to the intervention group, and 9891 were randomized to the control group. Screening uptake was 26.3% (2592 of 9843 individuals) in the intervention group vs 17.4% (1719 of 9891 individuals) in the control group (relative risk [RR], 1.51; 95% CI, 1.43-1.60). Although absolute differences in uptake by group varied little by screening history, relative effects were greater with longer vs shorter time since last Papanicolaou test (no prior Papanicolaou test: RRs, 1.85-3.25; ≥10 years: RR, 2.78; 5-10 years: RRs, 1.69-1.86; Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, clinically important improvements in screening uptake were observed for all subgroups. Differences in magnitude of intervention effect and kit use highlighted opportunities to optimize HPV self-sampling for priority groups.Trial RegistrationClinicalTrials.gov Identifier: NCT02005510

A common concern in the literature is the comparison of the similarities and differences between research journals, as well as the types of research they publish. At present, there are no clear methodologies that can be applied to a given article of interest. When authors use an effective and efficient method to locate journals in similar fields, they benefit greatly. By using the forest plot and major medical subject headings (MeSH terms) of Spine (Phila Pa 1976) compared to Spine J, this study: displays relatively similar journals to the target journal online and identifies the effect of the similarity odds ratio of Spine (Phila Pa 1976) compared to Spine J.From the PubMed library, we downloaded 1000 of the most recent top 20 most similar articles related to Spine (Phila Pa 1976) and then plotted the clusters of related journals using social network analysis (SNA). The forest plot was used to compare the differences in MeSH terms for 2 journals (Spine (Phila Pa 1976) and Spine J) based on odds ratios. The heterogeneity of the data was evaluated using the Q statistic and the I-square (I2) index.This study shows that: the journals related to Spine (Phila Pa 1976) can easily be presented on a dashboard via Google Maps; 8 journal clusters were identified using SNA; the 3 most frequently searched MeSH terms are surgery, diagnostic imaging, and methods; and the odds ratios of MeSH terms only show significant differences with the keyword "surgery" between Spine (Phila Pa 1976) and Spine J with homogeneity at I2 = 17.7% (P = .27).The SNA and forest plot provide a detailed overview of the inter-journal relationships and the target journal using MeSH terms. Based on the findings of this research, readers are provided with knowledge and concept diagrams that can be used in future submissions to related journals.

We assessed the sensitivity of self-reported human papillomavirus (HPV) vaccination among young adult men who have sex with men (MSM) with documented HPV vaccination.During 2016-2018, MSM and transgender women aged 18 to 26 years were enrolled in Seattle, WA. A history of HPV vaccination was assessed via self-administered survey, clinic electronic medical records, and the Washington State Immunization Information System. We assessed self-report sensitivity among participants with documented prior HPV vaccination (≥1 dose) in either the electronic medical record or the Washington State Immunization Information System, and used logistic regression to compare sensitivity by age, number of doses, and time since first dose.Of 292 participants with ≥1 documented HPV vaccine dose, 243 self-reported ≥1 dose (sensitivity, 83.2%; 95% confidence interval [CI], 78.4%-87.3%). Compared with participants whose first dose was1 year ago, the likelihood of self-report was lower among those with ≥3 years since first dose (adjusted odds ratio [aOR], 0.2; 95% CI, 0.1-0.5). Furthermore, compared with participants with only 1 documented HPV vaccine dose, the likelihood of self-reporting ≥1 dose was higher among those with 2 (aOR, 2.4; 95% CI, 1.0-5.5) or ≥3 doses (aOR, 6.2; 95% CI, 2.7-14.4). Among 115 participants with ≥3 documented doses, sensitivity for recalling ≥3 doses was 69.6% (95% CI, 60.3%-77.8%).Most young adult MSM with a documented history of HPV vaccination self-reported prior HPV vaccination. Although recall was highest in those with ≥3 doses, 30% of this fully vaccinated subgroup did not correctly recall the number of doses received, highlighting limitations of self-reporting. Furthermore, results indicating reduced recall with ≥3 years since first dose suggest that sensitivity of self-report among young adult MSM may decline over time as adolescent vaccination coverage increases.

Background Human Papillomavirus (HPV) vaccine uptake is low among East African adolescents in the US. Adolescents’ preferences influence HPV vaccine decisions, yet few interventions exist that address East African adolescents’ beliefs about HPV vaccines. We describe a multi-step process on how to create a theory-based comic book by integrating empirical findings, theory and focus group data from East African parents in the US. Methods Our multi-methods process included conducting focus groups with Somali, Ethiopian, and Eritrean mothers (n = 30) to understand mothers and adolescents socio-cultural beliefs and information needs about the HPV vaccine, creating comic book messages integrating the focus group findings, and assessing the acceptability of the finalized comic book among Somali, Ethiopian, and Eritrean adolescents (n = 134). Results We identified categories around socio-cultural beliefs (such ethnic representation and concerns about pork gelatin in vaccines), HPV vaccine information needs, and diffusion of information. We then mapped the categories to theoretical constructs and operationalized them into the comic book. Finally, we describe the overall acceptability of the comic book and specifics on comic book structure, appeal of characters, and message relevance. Conclusions A rigorous multi-step process that integrates theory and focus group data can help create culturally appropriate health messages that can educate and appeal to the community.

In stark contrast to the rapid development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective human immunodeficiency virus (HIV) vaccine is still lacking. Furthermore, despite virologic suppression and CD4 T-cell count normalization with antiretroviral therapy (ART), people living with HIV (PLWH) still exhibit increased morbidity and mortality compared to the general population. Such differences in health outcomes are related to higher risk behaviors, but also to HIV-related immune activation and viral coinfections. Among these coinfections, cytomegalovirus (CMV) latent infection is a well-known inducer of long-term immune dysregulation. Cytomegalovirus contributes to the persistent immune activation in PLWH receiving ART by directly skewing immune response toward itself, and by increasing immune activation through modification of the gut microbiota and microbial translocation. In addition, through induction of immunosenescence, CMV has been associated with a decreased response to infections and vaccines. This review provides a comprehensive overview of the influence of CMV on the immune system, the mechanisms underlying a reduced response to vaccines, and discuss new therapeutic advances targeting CMV that could be used to improve vaccine response in PLWH.

Objective To develop and evaluate an online continuing education (CE) course designed to improve healthcare provider self-efficacy to make strong adolescent HPV vaccine recommendations to East African immigrant families. Methods Focus groups with providers and East African immigrant mothers informed course development. Providers serving East African immigrant families were recruited to view the course and complete pre-/post-test and two-month follow-up surveys. Pre-/post differences were compared with paired t-tests. Results 202 providers completed the course and pre-/post-test; 158 (78%) completed two-month follow-up. Confidence to make strong HPV vaccine recommendations to East African families increased from 68% pre-test to 98% post-test. Confidence to address common parental concerns also increased: safety, 54% pre-test, 92% post-test; fertility, 55% pre-test, 90% post-test; child too young, 68% pre-test, 92% post-test; and pork gelatin in vaccine manufacturing, 38% pre-test, 90% post-test. Two-month follow-up scores remained high (97% for overall confidence, 94%–97% for addressing parental concerns). All pre-/post-test and pre-test/two-month follow-up comparisons were statistically significant (p, Highlights • Online continuing education targeted HPV vaccination in East African communities. • Education addressed culturally-specific vaccine concerns in East African communities. • Education increased provider self-efficacy to recommend HPV vaccine.

Background Cytomegalovirus (CMV) seropositivity and anti-CMV immunoglobulin G (IgG) levels are associated with adverse health outcomes in elderly populations. Among people living with human immunodeficiency virus (PLWH), CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation. Methods A total of 150 PLWH (79 ART-naive and 71 ART-treated) were compared to 26 without human immunodeficiency virus (HIV) infection (uninfected controls). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, nonspecific B-cell activation, anti-CMV and anti–Epstein-Barr virus (EBV) IgG levels, and proinflammatory cytokines were measured. Results CMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and participants without HIV infection. In contrast, total nonspecific IgG, immunoglobulin M, immunoglobulin A, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independent of sociodemographic and behavioral characteristics of the study population. Conclusions CMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV coinfection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH., Cytomegalovirus (CMV) seropositivity and anti-CMV immunoglobulin G levels are associated with increased epithelial gut damage, microbial translocation, and inflammation in antiretroviral therapy (ART)–naive and ART-treated people living with human immunodeficiency virus and uninfected controls.

XMT-1522, an antibody-drug conjugate (ADC) currently in Phase I clinical development, represents the first Dolaflexin®-based, cleavable ADC with a high drug-antibody ratio (DAR). In this work, a novel immunocapture LC–MS/MS method was successfully developed for the simultaneous quantification of both total antibody and cleavable antibody-conjugated drug auristatin F-hydroxypropylamide (AF-HPA) in human plasma. This method utilized microwave-assisted enzymatic digestion for the total antibody and chemical release of the drug from ADC on a 96-well based immunocapture sample preparation platform. The total antibody and the conjugated drug AF-HPA were separated and subsequently quantified concurrently by LC–MS/MS. The linear range of the standard curve for total antibody was from 50 to 5000 ng/mL and for AF-HPA was from 3.3 to 330 ng/mL. The linearities showed R2 ≥ 0.993 for total antibody and R2 ≥ 0.996 for AF-HPA, respectively. The intra- and inter-day precision and accuracy were well within 15%. The validated method, with the characteristics of high efficiency, great selectivity, free of carryover, short LC–MS/MS time (˜3.5 min) and low sample volume (20 μl), was successfully applied for analyzing Phase 1 cancer patient samples.

Interchain cysteine linked antibody-drug conjugates (ADCs) are emerging therapeutic products that antagonize cancers. The toxic payloads are selectively linked to the interchain cysteines and generate heterogeneous mixtures of positional isomers. These positional isomers might contribute differently to the therapeutic efficacy because of the variation in conjugation stability, and thus they need to be well characterized. However, the characterization of the positional isomers of interchain cysteine linked ADCs is very challenging, mainly because of the high similarity between those isomers. In this research, we developed a novel mass spectrometry method for the characterization of positional isomers of interchain cysteine linked ADCs. The subunit analysis and the bottom-up analysis provided abundant information about the drug numbers and drug linking positions on each chain. Because the method can provide accurate data on drug linking numbers and positions on each chain, it will be very useful for researchers in cancer drug development and cancer treatment.

OBJECTIVE HPV vaccine uptake in U.S. East African adolescents is low. We developed and evaluated a culturally-targeted interactive educational intervention for East African immigrant mothers to increase HPV-vaccine-related knowledge, attitudes, and intentions to vaccinate adolescent children. METHODS Eligible mothers had ≥ 1 11-17-year-old child and reported all children's HPV vaccination status as unvaccinated or unknown. The intervention was delivered via 10 dinners in the Seattle metropolitan area (8 with the Somali community, 2 with the Ethiopian community). Educational presentations and pre/post-tests on knowledge, attitudes, and intentions were conducted in the participants' native language by a co-ethnic physician. Pre/post differences in responses were evaluated with McNemar's tests and GEE models. HPV vaccination uptake 6-months post-intervention was evaluated using state immunization registry data. RESULTS Of 115 participating mothers, most (84%) were Somali and

The intestinal epithelial layer serves as a physical and functional barrier between the microbiota in the lumen and immunologically active submucosa. Th17 T-cell function protects the gut epithelium from aggression from microbes and their by-products. Loss of barrier function has been associated with enhanced translocation of microbial products which act as endotoxins, leading to local and systemic immune activation. Whereas the inflammatory role of LPS produced by Gram-negative bacteria has been extensively studied, the role of fungal products such as β-D-glucan remains only partially understood. As HIV infection is characterized by impaired gut Th17 function and increased gut permeability, we critically review mechanisms of immune activation related to fungal translocation in this viral infection. Additionally, we discuss markers of fungal translocation for diagnosis and monitoring of experimental treatment responses. Targeting gut barrier dysfunction and reducing fungal translocation are emerging strategies for the prevention and treatment of HIV-associated inflammation and may prove useful in other inflammatory chronic diseases.

A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.

COVID-19 is a distinctive infection characterized by elevated inter-human transmission and presenting from absence of symptoms to severe cytokine storm that can lead to dismal prognosis. Like for HIV, lymphopenia and drastic reduction of CD4+ T cell counts in COVID-19 patients have been linked with poor clinical outcome. As CD4+ T cells play a critical role in orchestrating responses against viral infections, important lessons can be drawn by comparing T cell response in COVID-19 and in HIV infection and by studying HIV-infected patients who became infected by SARS-CoV-2. We critically reviewed host characteristics and hyper-inflammatory response in these two viral infections to have a better insight on the large difference in clinical outcome in persons being infected by SARS-CoV-2. The better understanding of mechanism of T cell dysfunction will contribute to the development of targeted therapy against severe COVID-19 and will help to rationally design vaccine involving T cell response for the long-term control of viral infection.

Weight gain and obesity are global health concerns contributing to morbidity with increased risks of cardiovascular disease, diabetes, liver steatohepatitis and cancer. Pharmacological therapies or bariatric surgery are often required for those who fail to adhere to diet and lifestyle modifications. Metformin, a widely used antidiabetic agent, seems to have a health benefit beyond its anti-hyperglycemic properties, with few side effects. Emerging evidence shows weight loss to be associated with metformin in both diabetic and non-diabetic individuals. Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss. Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL). This gut-brain cytokine works as a prominent player in reducing food intake and body weight in health and disease, like anorexia nervosa and cancer. Herein, we critically review advances in the understanding of the weight-reducing effects of metformin via the GDF-15 pathway.

Background Associations between vitamin D biomarkers and persistent high-risk human papillomavirus (hrHPV) detection have not been evaluated. Methods 2011–2012 stored sera from 72 women aged 30–50 years with prevalent hrHPV (n = 116 type-specific infections) were tested for 5 vitamin D biomarkers: 25(OH)D and 4 emerging biomarkers, 1,25(OH)2D; 24,25(OH)2D; free vitamin D; and vitamin D binding protein (DBP). The hrHPV detection patterns (persistent vs transient/sporadic) were determined using cervicovaginal swabs collected monthly for 6 months. Associations between vitamin D and short-term type-specific hrHPV persistence were estimated using logistic regression. Our primary exposure was continuous 25(OH)D, with additional biomarkers evaluated as secondary exposures. Primary models were adjusted for age, race, body mass index, education, contraceptives, smoking, season, and calcium/phosphate levels. Sensitivity analyses were restricted from 19 hrHPV types to 14 used in cervical cancer screening. Results In primary analyses, nonsignificant positive associations with hrHPV persistence were observed for measures of 25(OH)D and 24,25(OH)2D. Associations were stronger and significant when restricting to 14 hrHPV types (25(OH)D per 10 ng/mL increase: adjusted odds ratio [aOR], 1.82 [95% confidence interval {CI}, 1.15–2.88] and aOR, 4.19 [95% CI, 1.18–14.88] DBP-adjusted; 25(OH)D ≥30 vs Conclusions Serum vitamin D measured by multiple biomarkers showed positive associations with short-term hrHPV persistence that were significant only when restricting to 14 clinically relevant hrHPV types.

OBJECTIVE: The objective was to study hospitalised COVID-19 patients’ mortality and intensive care unit (ICU) admission with covariates of interest (age, gender, ethnicity, clinical presentation, comorbidities and admission laboratory findings). METHODS: Logistic regression analyses were performed for patients admitted to University Hospital, University Hospitals Coventry and Warwickshire NHS Trust, between 24 January 2020 – 13 April 2020. RESULTS: There were 321 patients hospitalised. Median age was 73 years and 189 (59%) were male. Ethnicity was divided between Caucasian (77%), and black, Asian, and minority ethnic (BAME) groups (23%). Commonest symptoms were dyspnoea (62.9%), fever (59.1%) and cough (56%). Gastrointestinal symptoms amounted to 11.8%. Forty-four patients (13.7%) received ICU care. ICU male to female ratio was 3:1 (p=0.027; odds ratio (OR) 2.3; 95% confidence interval (CI) 1.1–4.9), BAME (p=0.008; OR 2.5; 95% CI 1.3–4.9), age >65 years (p=0.026; OR 0.28; 95% CI 0.09–0.93), heart disease (p=0.009; OR 0.2; 95% CI 0.1–0.6) and elevated C-reactive protein (CRP; p65 years (p=0.011; OR 5; 95% CI 1.6–21.9), neutrophils (p=0.047), neutrophil:lymphocyte ratio (NLR; p=0.028), CRP (p

Supplemental Digital Content is available in the text, Background: Individual researchers’ achievements (IRA) are determined by both personal publications and article citations such as Author Impact Factor, h-index, and x-index. Due to those indicators not truly supporting a normal distribution, the traditional t-test and Analysis of variance are not allowed for RA comparison in groups. The objective of this study is to use the bootstrapping method to verify whether hospital physicians have different h-indexes. Methods: We downloaded 63,266 journal articles with their corresponding citations for 2128 researchers from a Taiwan university website on December 10, 2019. Their IRAs were assessed using the bibliometric h-index. A pyramid plot was used to compare the h-index patterns between institutes. The x-index and the Kano model were found to be complemental to the h-index for identifying the group IRA characteristics and rankings, including colleges and departments in the university study, the School of Medicine, and the Affiliated Hospital. The bootstrapping method was applied with an estimated 95% confidence interval (CI) to distinguish the differences in physicians between the Internal Medicine and Surgery departments. The stronger-than-the-next coefficient (SC) for the highest represents the RA strength. Results: The highest h-indices were found in the College of Engineering, School of Medicine, and the Department of Internal Medicine in groups of colleges (SC = 0.71), all departments (SC = 0.83), the School of Medicine (SC = 0.74), and the Affiliated Hospital (SC = 0.56), respectively. No difference in h-index for hospital physicians was found between departments in Internal Medicine (Mean = 2.14, 95% CI = 1.02,3.26) and Surgery (mean = 2.5, 95%CI = 1.48, 3.52). Conclusions: The x-index and the Kano models can complement the h-index for identifying group IRA characteristics. The bootstrapping method allows estimation of the sampling distribution for almost any statistic using random sampling methods and gains measures of accuracy (as defined by 95% CI). The finding of no difference in h-index for hospital physicians between departments in Internal Medicine and Surgery requires further investigation in the future.

Coronavirus disease 2019 (COVID-19) is a pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most infected people have mild or moderate symptoms and recover without the need for extensive treatment. However, for seriously ill patients, no specific treatments are currently available. Convalescent plasma therapy (CPT), a passive immunotherapy, involves infusing plasma from recovered people into actively infected people, and is thought to be a specific intervention to improve outcome in patients with severe COVID-19. The presumed mechanism involves neutralizing antibodies and antibody dependent cytotoxicity/phagocytosis. Previous CPT trials showed an effect in SARS and pilot studies suggest CPT is an effective and safe strategy for seriously ill COVID-19 patients. CPT is currently being tested in large randomized clinical trials. Herein, we critically review the mechanism, applications and the challenges for CPT in the treatment of severe COVID-19, paving the way toward vaccine and immunotherapy development.

Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption, and thereby elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3 Å-4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives the rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.

One in five U.S. women with health insurance are underscreened for cervical cancer. We sought to identify whether underscreening correlates differed among women with different levels of health care interaction. Among women age 30-64 years who were members of an integrated U.S. health system, we used 2014-2015 electronic health record data to identify underscreened cases (≥3.4 years since last Papanicolaou (Pap) test, n=3,352) and screening-adherent controls (

Background (1-3)-b-D-glucan (BDG) is a fungal cell wall component and, in the absence of invasive fungal infection, a novel biomarker for microbial translocation of endogenous fungal products from the gastrointestinal tract into systemic circulation. However, its value as a marker of fungal translocation is limited by a concern that plant BDG-rich food influences blood BDG levels. Methods We conducted a pilot clinical trial to evaluate the impact of a standardized oral BDG challenge on blood BDG levels in participants with and without elevated microbial translocation. We enrolled 14 participants including 8 with HIV infection, 2 with advanced liver cirrhosis, and 4 healthy controls. After obtaining a baseline blood sample, participants received a standardized milk shake containing high levels of BDG followed by serial blood samples up to 8 hours after intake. Results The standardized oral BDG challenge approach did not change the blood BDG levels over time in all participants. We found consistently elevated blood BDG levels in one participant with advanced liver cirrhosis and a single person with HIV with a low CD4 count of 201 cells/mm3 . Conclusion Our findings indicate that BDG blood levels were not influenced by plant origin BDG-rich nutrition in PWH, people with advanced liver cirrhosis, or healthy controls. Future studies are needed to analyze gut mycobiota populations in individuals with elevated blood BDG levels.

Elite controllers (ECs) are people living with human immunodeficiency virus (HIV) who spontaneously control viral replication without antiretroviral therapy. We observed that elevated anti-cytomegalovirus (CMV) immunoglobulin G (IgG) levels correlated with annual CD4 T-cell count decay in ECs independently of age, sex, and human leukocyte antigen (HLA) type. Elevated anti-CMV titers may favor disease progression in ECs.

Background: Vitamin D has potential immunomodulating benefits in infection. One prior population-based cross-sectional study showed a protective association between serum concentrations of 25(OH)D and high-risk human papillomavirus (hrHPV) detection. Additional biomarkers present at different stages along the vitamin D metabolic pathway may more completely characterize vitamin D status but have not yet been evaluated in relation to hrHPV infection. Methods: Stored sera from women aged 30–50 years (N = 404) enrolled in an HPV natural history study from 2011–2012 were tested for 25(OH)D and 4 novel vitamin D biomarkers: 1,25(OH)2D, 24,24(OH)2D3, free vitamin D, and vitamin D–binding protein. Cross-sectional associations between vitamin D serum concentrations and cervicovaginal hrHPV detection were estimated using logistic regression. Results: 25(OH)D serum concentrations were not associated with hrHPV. After adjusting for age, race, season, education, oral contraceptive use, smoking status, body mass index, and serum concentrations of calcium and phosphate, each 1 ng/mL increase in 24,25(OH)2D3 was nearly statistically significantly associated with higher likelihood of hrHPV detection [aOR = 1.22; 95% confidence interval (CI), 0.97–1.52]. No significant associations were observed for other biomarkers. Conclusions: 25(OH)D serum concentrations were unassociated with prevalent hrHPV. Higher levels of one novel biomarker, 24,25(OH)2D3, were positively associated with hrHPV, an unexpected finding. Impact: Inconsistent with previous findings of a protective association between 25(OH)D and prevalent hrHPV infection, these results suggest serum concentrations of 4 vitamin D biomarkers are unassociated with detection of hrHPV in mid-adult women.

Gut dysbiosis, namely dysregulation of the intestinal microbiota, and increased gut permeability lead to enhanced inflammation and are commonly seen in chronic conditions such as obesity and aging. In people living with HIV (PLWH), several lines of evidence suggest that a depletion of gut CD4 T-cells is associated with gut dysbiosis, microbial translocation and systemic inflammation. Antiretroviral therapy (ART) rapidly controls viral replication, which leads to CD4 T-cell recovery and control of the disease. However, gut dysbiosis, epithelial damage and microbial translocation persist despite ART, increasing risk of developing inflammatory non-AIDS comorbidities such as cardiovascular disease, diabetes mellitus, liver steatosis and cancer. In addition to ART, an emerging research priority is to discover strategies to improve the gut microbial composition and intestinal barrier function. Probiotic interventions have been extensively used with controversial benefits in humans. Encouragingly, within the last decade, the intestinal symbiotic bacterium Akkermansia muciniphila has emerged as the “sentinel of the gut.” A lower abundance of A. muciniphila has been shown in diabetic and obese people as well as in PLWH. Interventions with high levels of polyphenols such as tea or diets rich in fruit, the antibiotic vancomycin and the antidiabetic drug metformin have been shown to increase A. muciniphila abundance, contributing to improved metabolic function in diabetic and obese individuals. We hypothesize that gut microbiota rich in A. muciniphila can reduce microbial translocation and inflammation, preventing occurrences of non-AIDS comorbidities in PLWH. To this aim, we will discuss the protective effect of A. muciniphila and its potential applications, paving the way toward novel therapeutic strategies to improve gut health in PLWH.

Background Little is known about the epidemiology of β and γ human papillomaviruses (HPVs) in oral cavities of healthy women. Methods We performed multiplex polymerase chain reaction analysis for detection of 46 β-HPVs and 51 γ-HPVs in stored oral rinse samples from healthy mid-adult women (age, 30-50 years). A total of 407 women were tested for β-HPVs, and 310 were tested for γ-HPVs. We used log-binomial regression to identify determinants of β-HPV and γ-HPV in separate models. Using paired fingernail data from a subset of 184 women, we also evaluated whether fingernail β-HPV detection was associated with concurrent detection of the same type in the oral cavity. Results Oral HPV prevalence was 20.6% for β-HPV and 10.7% for γ-HPV. In multivariate analysis, oral β-HPV detection was associated with increasing age (adjusted prevalence ratio [aPR] per 5-year difference, 1.37; 95% confidence interval [CI], 1.01-1.86) and a greater lifetime number of oral sex partners (aPR for reporting ≥6 vs 0-5 partners, 2.06; 95% CI, 1.01-4.20). In a separate model, concurrent detection of the same β-HPV type in fingernails was strongly associated with oral β-HPV detection (aPR, 31.44; 95% CI, 19.81-49.49). No significant determinants of γ-HPV detection were identified. Conclusions Our results suggest a sexual transmission route for β-HPVs and support the hypothesis that fingers may serve as a source of transmission or autoinoculation of β-HPVs to the oral cavity.

Return of results is not common in research settings as standards are not yet in place for what to return, how to return, and to whom. As a pioneer of large-scale of return of research results, the Precision Medicine Initiative Cohort now known of All of Us plans to return pharmacogenomic results and variants of clinical significance to its participants starting late 2019. To better understand the local landscape of possibilities regarding return of research results, we assessed the frequency of pathogenic variants and APOL1 renal risk variants in a small diverse cohort of chronic kidney disease patients (CKD) ascertained from a public hospital in Cleveland, Ohio genotyped on the Illumina Infinium MegaEX. Of the 23,720 ClinVar-designated variants directly assayed by the MegaEX, 8,355 (35%) had at least one alternate allele in the 130 participants genotyped. Of these, 18 ClinVar variants deemed pathogenic by multiple submitters with no conflicts in interpretation were distributed across 27 participants. The majority of these pathogenic ClinVar variants (14/18) were associated with autosomal recessive disorders. Of note were four African American carriers of TTR rs76992529 associated with amyloidogenic transthyretin amyloidosis, otherwise known as familial transthyretin amyloidosis (FTA). FTA, an autosomal dominant disorder with variable penetrance, is more common among African-descent populations compared with European-descent populations. Also common in this CKD population were APOL1 renal risk alleles G1 (rs73885319) and G2 (rs71785313) with 60% of the study population carrying at least one renal risk allele. Both pathogenic ClinVar variants and APOL1 renal risk alleles were distributed among participants who wanted actionable genetic results returned, wanted genetic results returned regardless of actionability, and wanted no results returned. Results from this local genetic study highlight challenges in which variants to report, how to interpret them, and the participant’s potential for follow-up, only some of the challenges in return of research results likely facing larger studies such as All of Us.

Cutaneous human papillomaviruses (HPVs) have not been evaluated in fingernails from healthy individuals. To determine prevalence and correlates of β-HPVs in fingernails from healthy mid-adult women, we tested archived samples collected from 2011 to 2012 using a multiplex PCR combined with Luminex technology for 46 β-HPV genotypes. One hundred thirteen (61.1%) of 185 fingernail samples were positive for β-HPV, and the median number of types detected in positive samples was 2 (interquartile range: 1–4). The most common genotypes detected were HPV-23 (β−2) (13.5%), HPV-38 (β−2) (13.0%), HPV-5 (β−1) (9.2%), HPV-107 (β−2) (8.7%), and HPV-120 (β−2) (8.7%). In multivariate analysis, β-HPV detection was associated with age (prevalence ratio [PR] for women 40–51 years versus 30–39 years = 1.30, 95% CI: 1.05–1.62) and race (PR for non-white versus white race = 0.65, 95% CI: 0.45–0.94). The prevalence of β-HPV in fingernail samples from healthy mid-adult women was similar to the prevalence of β-HPV reported at other cutaneous sites in prior studies. We did not identify any significant health or sexual behavior predictors of β-HPV detection in fingernails. Our results support the hypothesis that fingers may serve as a source of transmission or autoinoculation of cutaneous HPVs to other anatomic sites. Keywords: Fingernails, Women, Beta-HPV, Prevalence, Mid-adult, Risk factor