IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.

Single-Cell Transcriptomic Analysis Links Nonmyelinating Schwann Cells to Proinflammatory Response in the Lung.

The lung is a barrier tissue with constant exposure to the inhaled environment. Therefore, innate immunity against particulates and pathogens is of critical importance to maintain tissue homeostasis. Although the lung harbors both myelinating and nonmyelinating Schwann cells (NMSCs), NMSCs represent the most abundant Schwann cell (SC) population in the lung. However, their contribution to lung physiology remains largely unknown. In this study, we used the human glial fibrillary acidic protein promoter driving tdTomato expression in mice to identify SCs in the peripheral nervous system and determine their location within the lung. Single-cell transcriptomic analysis revealed the existence of two NMSC populations (NMSC1 and NMSC2) that may participate in pathogen recognition. We demonstrated that these pulmonary SCs produce chemokines and cytokines upon LPS stimulation using in vitro conditions. Furthermore, we challenged mouse lungs with LPS and found that NMSC1 exhibits an enriched proinflammatory response among all SC subtypes. Collectively, these findings define the molecular profiles of lung SCs and suggest a potential role for NMSCs in lung inflammation.

Unintended Consequences: Risk of Opportunistic Infections Associated With Long-term Glucocorticoid Therapies in Adults.

Glucocorticoids are widespread anti-inflammatory medications used in medical practice. The immunosuppressive effects of systemic glucocorticoids and increased susceptibility to infections are widely appreciated. However, the dose-dependent model frequently used may not accurately predict the risk of infection in all patients treated with long-term glucocorticoids. In this review, we examine the risks of opportunistic infections (OIs) in patients requiring glucocorticoid therapy by evaluating the influence of the glucocorticoid dose, duration, and potency, combined with biological and host clinical factors and concomitant immunosuppressive therapy. We propose strategies to prevent OIs, which involve screening, antimicrobial prophylaxis, and immunizations. While this review focuses on patients with autoimmune, inflammatory, or neoplastic diseases, the potential risks and preventative strategies are likely applicable to other populations. Clinicians should actively assess the benefit-harm ratios of systemic glucocorticoids and implement preventive efforts to decrease their associated infections complications.

Meta-analysis of Pregnancy Events in Biomedical HIV Prevention Trials in Sub-Saharan Africa: Implications for Gender Transformative Trials.

Historically, pregnant and lactating populations (PLP) have been excluded or disenrolled from biomedical HIV prevention trials, despite being more likely to acquire HIV during pregnancy and the post-partum period. We conducted a meta-analysis of pregnancy events in biomedical HIV prevention trials in sub-Saharan Africa to support trialists moving toward more inclusive clinical and implementation studies. We searched peer-reviewed literature reporting pregnancy events and contraceptive requirements in HIV prevention trials between 2001 and 2022. We hypothesized four variables to explain variation: contraceptive requirements, study start year, study product, and sub-region. We fit a meta-analytic model to estimate individual effect sizes and sampling variances, then conducted sub-group analyses to assess moderating effects. We identified 38 references for inclusion, across which the proportion of pregnancy events was 8% (95% confidence interval [CI]: 6-10%) with high heterogeneity (I2 = 99%). Studies not requiring contraceptives (21%, 95%CI: 7-48%) reported a significantly higher proportion of pregnancy events than studies requiring two methods (5%, 95%CI: 2-10%). Studies launched between 2001 and 2007 (11%, 95%CI: 8-16%), microbicide gel trials (12%, 95%CI: 8-18%), and studies conducted in Western Africa (28%, 95%CI: 13-51%) reported higher proportions of pregnancy events than reference groups. Together, these variables have a moderating effect on pregnancy events (p < 0.0001), explaining 63% of heterogeneity in trials. Results describe how, over time, more stringent contraceptive requirements reduced pregnancy events, which ensured necessary statistical power but limited reproductive choice by participants. With the move toward continuing PLP on experimental products, trialists can utilize estimated pregnancy events reported here to inform strategies that accommodate participants' changing fertility preferences.

Assessing the effect of COVida orphans and vulnerable children support services on viral load coverage and suppression among children and adolescents living with HIV in four provinces in Mozambique.

Orphans and vulnerable children (OVC) programs focusing on improving HIV outcomes for children and adolescents living with HIV (C&ALHIV) may improve viral load (VL) testing coverage, a critical step toward achieving VL suppression. In Mozambique, we conducted a retrospective medical record review comparing VL testing coverage and suppression between C&ALHIV receiving OVC support and two cohorts of non-participants constructed using propensity score matching. We collected data for 25,783 C&ALHIV in Inhambane, Maputo City, Nampula, and Tete between October 2020-September 2021. Unadjusted rates of VL testing were 62.9% among OVC participants compared with 39.2% and 50.4% of non-participants in OVC support and non-OVC support districts, respectively. In multivariate models, OVC participants were 18 and 10 percentage points more likely to have received a VL test than non-participants in OVC districts (p < 0.01) and non-OVC districts (p < 0.01), respectively. OVC participants under 5 years old were significantly more likely to have received a VL test than their same-age counterparts in both comparison groups. Overall, the OVC program did not demonstrate significant effects on VL suppression. This approach could be replicated in other contexts to improve testing coverage. It is crucial that clinical partners and governments continue to share data to enable timely monitoring through OVC programming.

Multi-organ clinical manifestations of Mpox: an umbrella review of systematic reviews.

BACKGROUND: Mpox is a severe viral zoonosis that has emerged as a public health concern due to its potential for human-to-human transmission and severe illness. Understanding its clinical manifestations is crucial for effective management and control. Several systematic reviews have assessed various manifestations of Mpox. This umbrella review synthesizes evidence on Mpox's manifestations across different organ systems. METHOD: We conducted an umbrella review, adhering to Joanna Briggs Institute (JBI) methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on systematic reviews of Mpox manifestations. We performed a literature search up to 25th September 2023, in databases like PubMed, Embase, and Web of Science. We included systematic reviews of observational studies, case reports, case series, or RCTs reporting any manifestations of Mpox in humans, focusing on a global scope. AMSTAR 2 was used to evaluate the quality of systematic reviews, and data has been synthesized in narrative and tabular manners. RESULTS: A total of 25 systematic reviews were included, uncovering diverse manifestations of Mpox, such as cutaneous, cardiovascular, oral, ophthalmic, gastrointestinal, respiratory, and pregnancy-related. Cutaneous manifestations (up to 100%) were the most prevalent, featuring lesions and rashes. Constitutional symptoms of viral illness were reported in ~ 60% to > 85% of the cases. Significant respiratory symptoms were present in ~ 50% of cases overall. Headaches were the leading neurological symptom present in > 30%. Symptoms of gastrointestinal involvement ranged from 39% (oral lesions) with decreasing frequency to low diarrhea at ~ 5%, with proctitis percentages ranging from high teens to mid-twenties. Ophthalmic manifestations (6% but with wide variations among studies). Many primary studies included in the systematic reviews consisted of case reports and case series. A wide range of manifestations across different organ systems was observed. Negative outcomes for pregnancies were reported, but evidence is limited. Adverse cardiovascular and neurological outcomes were identified, though only a few studies provided insights into these findings. CONCLUSION: Mpox exhibits diverse manifestations, impacting multiple organ systems, with substantial variations. The findings highlight the importance of ongoing, nuanced, and region-specific research and management strategies for Mpox. The reliance on case reports and series underscores the need for more high-quality, long-term studies to deepen our understanding and management of this significant public health concern.

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Comprehensive compilation of congener profiles to support health assessment of environmental exposures to polychlorinated biphenyl mixtures.

Exposure to polychlorinated biphenyls (PCBs) remains a potential human health risk due to their persistence in the environment, despite a global ban on their production. Understanding the composition of PCB mixtures is essential for the application of a mixtures-based approach to assessing health risks of PCB exposure. This work represents the most extensive effort to date to compile and make publicly available the PCB congener profiles for mixtures with toxicological data, providing a foundation for understanding toxicological potency of PCB mixtures in the environment. We searched for published congener profiles across 29 commercial and simulated environmental PCB mixtures, including various Aroclors, Phenoclors, Clophens, and Kanechlors, among others. A total of 117 references containing 401 distinct complete or partial tabularized profiles were found. Aroclor 1254 had the most published profiles, with 79 unique datasets characterizing multiple mixture lots. In contrast, no congener-specific composition data were identified for Fenclors, Clophen C, or Pyralenes. Eighty-seven of the most complete and clearly reported profiles underwent a detailed extraction of the congener data, PCB mixture source, and analytical methods. Challenges encountered during data extraction included congener coelutions, incomplete methods reporting, and inconsistencies in PCB nomenclature. These factors complicate data visualization, comparisons across datasets, and use of the data in subsequent analyses. Where possible, we have converted profiles to the same units and congener numbering convention to allow for easier comparison. The extracted data are publicly available online as interactive visuals and as a downloadable Microsoft Excel® workbook. This dataset provides researchers with an overview of the current PCB mixture profile landscape that can serve as a tool to support efforts to minimize the health impacts of environmental PCB exposure, including the exploration of links between mixture composition and toxicity and the identification of the most efficient and effective remediation strategies at contaminated sites.

Effects of swift heavy ions on metal nanoparticles embedded in silica: Using linearly polarized light to monitor the elongation kinetics.

The elongation of metallic nanoparticles (NPs) embedded in a dielectric matrix after irradiation with swift heavy ions is a phenomenon that has been known for several years. However, the precise mechanism behind this deformation process is still not fully understood, primarily due to the dearth of information during intermediate stages of deformation. In this study, we report the continuation of our previous work [Peña-Rodríguez et al., Sci. Rep. 7(1), 922 (2017)], exploiting the strong dependence of the localized surface plasmon resonance on the aspect ratio of elongated metal NPs to study the elongation kinetics in situ. In situ optical absorption spectra were measured using a polarizing beam splitter to separate the longitudinal and transverse plasmon modes of the anisotropic NPs. Then, the detailed geometrical and compositional parameters were determined from a fit of these spectra. The use of linearly polarized light allowed for a more accurate analysis of the elongation kinetics, particularly useful in the first stages, where longitudinal and transverse modes overlap.

Glucocorticoids as a risk factor for infection and adverse outcomes in non-HIV and non-transplant patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM), an opportunistic fungal infection affecting immunocompromised hosts, leads to high mortality. The role of previous exposure to glucocorticoids as a risk factor and as an outcome modulator has been observed, but systematic studies are lacking. OBJECTIVE: The primary aim of this study is to evaluate the impact of glucocorticoid use on the clinical outcomes, specifically mortality, of non-HIV and non-transplant (NHNT) patients diagnosed with CM. METHODS: We queried a global research network to identify adult NHNT patients with CM based on ICD codes or recorded specific Cryptococcus CSF lab results with or without glucocorticoid exposure the year before diagnosis. We performed a propensity score-matched analysis to reduce the risk of confounding and analysed outcomes by glucocorticoid exposure. We used a Cox proportional hazards model for survival analysis. RESULTS: We identified 764 patients with a history of glucocorticoid exposure and 1267 patients without who developed CM within 1 year. After propensity score matching of covariates, we obtained 627 patients in each cohort. The mortality risk in 1 year was greater in patients exposed to prior glucocorticoids (OR: 1.3, CI: 1.2-2.0, p = 0.002). We found an excess of 45 deaths among CM patients with previous glucocorticoid use (7.4% increased absolute risk of dying within 1 year of diagnosis) compared to CM controls without glucocorticoid exposure. Hospitalisation, intensive care unit admission, emergency department visits, stroke and cognitive dysfunction also showed significant, unfavourable outcomes in patients with glucocorticoid-exposed CM compared to glucocorticoid-unexposed CM patients. CONCLUSIONS: Previous glucocorticoid administration in NHNT patients seems to associate with 1-year mortality after CM adjusted for possible confounders related to demographics, comorbidities and additional immunosuppressive medications. Serial CrAg screening might be appropriate for higher-risk patients on glucocorticoids after further cost-benefit analyses.

Barriers and facilitators in self-care and management of chronic kidney disease in dialysis patients: A systematic review of qualitative studies.

AIM: To identify and synthesise qualitative studies on barriers and facilitators perceived by dialysis patients in relation to self-care and disease management. DESIGN: Systematic review of qualitative studies. DATA SOURCES: Qualitative study articles were extracted from PUBMED, MEDLINE, COCHRANE, WEB OF SCIENCE (WOS), CINAHL PsycINFO and EMBASE and electronic journals of the Spanish Society of Nephrology and Spanish Society of Nephrological Nursing until May 2022. Studies on barriers and/or facilitators affecting self-care and disease management expressed by people undergoing haemodialysis or peritoneal dialysis were included. REVIEW METHODS: The SPICE (Setting, Perspective, Intervention, Comparison and Evaluation) strategy was used to develop issues and subissues through the thematic synthesis of the qualitative findings. GRADE-CERQual was used to evaluate the articles. RESULTS: From 172 articles, 15 qualitative articles about barriers and facilitators perceived by patients concerning self-care and disease management were finally included. Identified eight facilitators and four barriers. CONCLUSION: Patients perceived a significant number of barriers and facilitators. It is possible to identify which aspects facilitate self-management of their disease and to understand that the processes are individualised. This is why therapeutic strategies should be designed to foster the participation and empowerment of the person in the management of the disease. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Identifying the barriers and facilitators concerning the management of chronic kidney disease furnishes us with knowledge for individualised clinical practice and improved care processes. IMPACT: This review is the first to synthesise barriers and facilitators in haemodialysis patients about the management of their disease and treatment. The results enable the proposal of improvements in the training of healthcare personnel, clinical practice guidelines and action protocols to improve the daily life and management of the disease by patients. No patient or public contribution due to this is a systematic review.

Fused hip conversion to total hip arthroplasty with the direct anterior approach: surgical technique on a regular surgical table under fluoroscopic guidance.

PURPOSE: Conversion of a fused hip to a total hip arthroplasty (THA) is technically challenging due to the loss of anatomical references. Here, a reproducible technique using the direct anterior approach (DAA) with a regular surgical table under fluoroscopic guidance is described, which has several advantages over traditional such as lateral or posterior approaches. METHODS: There were reported 11 cases of ankylosis hip that were converted to THA using the same surgical technique protocol. Clinical and radiographic outcomes were recorded at 3.2 years of follow-up. A detailed preoperative evaluation was performed, including a pelvis radiological evaluation and magnetic resonance image (MRI) to assess the integrity of the periarticular soft tissue and flexor muscles. RESULTS: The DAA has considerable advantages, such as allowing more precise targeting during surgery, avoiding the risk of pseudoarthrosis due to the absence of a trochanteric osteotomy, preserving the abductors, and allowing an easier-to-use of intraoperative fluoroscopy due to the supine position. Besides, the use of a standard table reduces surgical time and allows assessment of limb length, hip stability, and impingement in all planes in an intraoperative dynamic range, which decreases postoperative complications. CONCLUSION: Conversion from hip fusion to THA is a rare and complex procedure. The use of DAA with a standard table and fluoroscopy helps to avoid high complications since it allows a dynamic intra-operative examination of the range of motion to rule out impingements, reduces the risk of dislocation, and allows leg lengthening verification.

Cemented vs cementless stems for revision arthroplasties due to Vancouver B2 periprosthetic hip fracture.

PURPOSE: According to Vancouver classification, B2 type fractures are most often treated with removal of the loose stem and implantation of a long stem that bypasses the fracture site. However, there is a controversy about the stem fixation that should be used: cemented or cementless. Hence, this study aims to compare cemented and cementless stems in prosthetic revision due to Vancouver B2 (VB2) periprosthetic hip fracture. METHODS: A retrospective study was done including all the patients treated with stem exchange due to VB2 periprosthetic hip fracture in a tertiary hospital between 2015 and 2022. Patients were divided into two groups according to the stem fixation used: cemented or cementless. Functional outcomes, hospital stay, surgical time, complication rate, and mortality were compared between the two groups of patients. RESULTS: Of the 30 included patients, 13 (43.4%) were treated with cementless stems and 17 (56.7%) with cemented stems. There were no statistically significant differences in age, gender, anesthesia risk scale (ASA) or functional capacity prior to the intervention. Patients treated with cementless stems had a higher complication and reintervention rate than those treated with cemented stems: 62 and 45% versus 34 and 6% (p = 0.035; p = 0.010), respectively. Furthermore, in the group of cementless stems a higher proportion of non-union was found (53.8% vs. 17.6%; p = 0.037). Also, the hospital stay (33 vs. 24 days; p = 0.037) and the time to full weight-bearing (21 days vs. 9 days; p < 0.001) were longer in the cementless stem group. CONCLUSION: Cemented fixation in stem revision due to Vancouver B2 periprosthetic hip fracture could be an optimal option with faster recovery which could decrease the rate of complications and reintervention, without compromising the fracture healing and patient mortality. Thus, this option can be considered when an anatomical reduction can be obtained, especially in elderly patients with multiple comorbidities in which a less aggressive surgical option should be considered.

Comparative analysis of the quality of the cement mantle in hip hemiarthroplasty after femoral neck fracture between three different surgical approaches: a single-center retrospective observational study.

PURPOSE: Achieving the initial stability of implants is necessary for hip hemiarthroplasty (HHA), especially in elderly patients, and this can be achieved with a cement mantle of quality. The direct anterior approach (DAA) for HHA lately has shown positive results. However, evidence is lacking of HHA in elderly patients with osteoporosis after femoral neck fracture (FNF). This study compares differences in cement mantle quality after HHA, its complications, radiological outcomes and functional status in elderly patients with FNF intervened through different approaches. METHODS: A non-interventional, retrospective case-control study was conducted. 150 cases were selected based on the surgical approach (DAA, DLA and PLA) in a 1:1:1 proportion between 2018 and 2019. Under 75 years old suspicion or confirmation of a pathological fracture were excluded. Antibiotic-loaded cement was utilized. Cement preparation involved vacuum centrifugation and standard instructions for preparation canal and filling, and prosthesis placement were followed. RESULTS: No statistically significant differences in cement mantle quality, radiological outcomes, and the majority of the postoperative complications and functional status considering the surgical approach (p > 0.05). However, the DAA was associated significantly with shorter hospital stays (8.3 days vs 11.3 and 13 days for DLA and PLA) a decrease in postoperative blood transfusion (22% vs 34% and 53%), and lower rate of loss of walking (8% vs 20% and 28.6%). CONCLUSION: The DAA for HHA in patients with FNF provides a high-quality cement mantle, similar to other approaches. Also, the DAA shows advantages like shorter hospital stays and lower transfusion rates in elderly patients.

Treatment pathways, switches, and inappropriate treatment during invasive pulmonary aspergillosis: real-world experiences from a global research network study.

Despite advancements in diagnosing and treating invasive pulmonary aspergillosis (IPA), there is limited knowledge of real-world treatment pathways and medication switches. We queried the TrinetX global research network database and identified 5,410 patients diagnosed with IPA. The most common initial treatments were voriconazole (49%), fluconazole (11%), and posaconazole (7%). Most patients remained on voriconazole (80%) or isavuconazole (78%) throughout the treatment duration. Switches were more frequent for those initially treated with fluconazole, echinocandins, or posaconazole.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Structure-Activity Relationship of Lower Chlorinated Biphenyls and Their Human-Relevant Metabolites for Astrocyte Toxicity.

Exposure to polychlorinated biphenyls (PCBs) is associated with developmental neurotoxicity and neurodegenerative disorders; however, the underlying mechanisms of pathogenesis are unknown. Existing literature has focused mainly on using neurons as a model system to study mechanisms of PCB-mediated neurotoxicity, overlooking the role of glial cells, such as astrocytes. As normal brain function is largely astrocyte-dependent, we hypothesize that astrocytes play an important role in PCB-mediated injury to neurons. We assessed the toxicity of two commercial PCB mixtures, Aroclor 1016 and Aroclor 1254, and a non-Aroclor PCB mixture found in residential air called the Cabinet mixture, all of which contain lower chlorinated PCBs (LC-PCBs) found in indoor and outdoor air. We further assessed the toxicity of five abundant airborne LC-PCBs and their corresponding human-relevant metabolites in vitro models of astrocytes, namely, the C6 cell line and primary astrocytes isolated from Sprague-Dawley rats and C57BL/6 mice. PCB52 and its human-relevant hydroxylated and sulfated metabolites were found to be the most toxic compounds. No significant sex-dependent cell viability differences were observed in rat primary astrocytes. Based on the equilibrium partitioning model, it was predicted that the partitioning of LC-PCBs and their corresponding metabolites in biotic and abiotic compartments of the cell culture system is structure-dependent and that the observed toxicity is consistent with this prediction. This study, for the first time, shows that astrocytes are sensitive targets of LC-PCBs and their human-relevant metabolites and that further research to identify mechanistic targets of PCB exposure in glial cells is necessary.

Invasive pulmonary aspergillosis real-world outcomes: Clinical features and risk factors associated with increased mortality.

Invasive pulmonary aspergillosis (IPA) is a severe fungal infection that primarily affects immunocompromised patients and is associated with high mortality. Contemporary clinical characteristics of IPA and "real-world" estimates and predictors of associated mortality are inadequate. TriNetX, a global research network, was queried to identify adult patients with IPA diagnoses based on the ICD-10 code B44.0. We performed a propensity score-matched analysis comparing clinical characteristics among patients who survived versus non-survivors at 1 year. We identified 4371 patients with IPA. We found neoplasms, solid organ transplant recipients, hematologic malignancies, and aplastic anemia as the most predominant risk factors. The overall 1-year mortality was 32% for IPA. 1-year mortality was highest for patients with COVID-19 in the ICU, followed by those with acute myeloid leukemia and aplastic anemia (54%, 50%, and 39%, respectively). After propensity score matching, severe sepsis, pleural effusion, and candidiasis were mortality contributors within a year after diagnosis. Liver injury, systemic glucocorticoid exposure over the previous 6 months, lower lymphocyte and CD4 counts, elevated ferritin, LDH, thrombocytopenia, anemia, or elevated glycosylated hemoglobin (HbA1c) were independent predictors of mortality at 1 year. Voriconazole was the most common treatment (67%). The annual incidence of IPA was 0.001%, increasing to 0.02% among critically ill patients in the ICU. IPA continues to have a very high mortality. We encourage prospective studies to validate and refine the identified clinical markers linked to increased mortality.

Invasive pulmonary aspergillosis (IPA) is common among immunocompromised patients. Analyzing a global research network, we found 32% of patients with IPA died a year after diagnosis. We identified the primary underlying conditions, contributors, and predictors of mortality.

An Argonaute phosphorylation cycle promotes microRNA-mediated silencing.

MicroRNAs (miRNAs) perform critical functions in normal physiology and disease by associating with Argonaute proteins and downregulating partially complementary messenger RNAs (mRNAs). Here we use clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) genome-wide loss-of-function screening coupled with a fluorescent reporter of miRNA activity in human cells to identify new regulators of the miRNA pathway. By using iterative rounds of screening, we reveal a novel mechanism whereby target engagement by Argonaute 2 (AGO2) triggers its hierarchical, multi-site phosphorylation by CSNK1A1 on a set of highly conserved residues (S824-S834), followed by rapid dephosphorylation by the ANKRD52-PPP6C phosphatase complex. Although genetic and biochemical studies demonstrate that AGO2 phosphorylation on these residues inhibits target mRNA binding, inactivation of this phosphorylation cycle globally impairs miRNA-mediated silencing. Analysis of the transcriptome-wide binding profile of non-phosphorylatable AGO2 reveals a pronounced expansion of the target repertoire bound at steady-state, effectively reducing the active pool of AGO2 on a per-target basis. These findings support a model in which an AGO2 phosphorylation cycle stimulated by target engagement regulates miRNA:target interactions to maintain the global efficiency of miRNA-mediated silencing.

Diabetes Mellitus Type 2 as a Risk Factor and Outcome Modifier for Cryptococcosis in HIV Negative, Non-transplant Patients, a Propensity Score Match Analysis.

Cryptococcosis is an opportunistic fungal infection of worldwide distribution with significant associated morbidity and mortality. HIV, organ transplantation, malignancy, cirrhosis, sarcoidosis, and immunosuppressive medications are established risk factors for cryptococcosis. Type 2 diabetes mellitus (DM2) has been hypothesized as a risk factor and an outcome modifier for cryptococcosis. We aimed to compare outcomes among HIV-negative, non-transplant (NHNT) patients with and without DM2. We queried a global research network to identify NHNT patients (n = 3280). We performed a propensity score-matched (PSM) analysis comparing clinical outcomes among cryptococcosis patients by DM status. We also characterize adults with cryptococcosis and DM2 as the only risk factor. After PSM, NHNT patients with DM2 were more likely to develop cognitive dysfunction [9% vs. 6%, OR 1.6; 95% CI (1.1-2.3); P = 0.01] but had similar mortality, hospitalization, ICU, and stroke risk after acquiring cryptococcosis when compared to NHNT patients without DM2. Pulmonary cryptococcosis was the most common site of infection. Among 44 cryptococcosis patients with DM2 as the only identifiable risk factor for disease, the annual incidence of cryptococcosis was 0.001%, with a prevalence of 0.002%. DM2 is associated with increased cognitive dysfunction risk in NHNT patients with cryptococcosis. It is rare for DM2 to be the only identified risk factor for developing cryptococcosis. Kidney disease, hyperglycemia, and immune dysfunction can increase the risk of cryptococcosis in patients with DM2.