Gender differences in symptomatology, socio-demographic information and quality of life in Spanish population with long COVID condition: a cross-sectional study.

Introduction: Long COVID patients experience a decrease in their quality of life due to the symptomatology produced by the disease. It is also important to understand how long COVID affects both men and women. The objective of this study is to examine the impact of long COVID symptomatology on the quality of life of Spanish adults from a gender perspective. Methods: An observational and cross-sectional study was carried out. Participants were able to complete an online questionnaire using an online platform. A sample of 206 people participated in the study. Results: The 80.6% of the sample were women with a mean age of 46.51 (±8.28) and the 19.4% were men with a mean age of 48.03 (±9.50). The medium score in the PAC19-QoL test was 141.47 (±24.96) and segmented by gender, 141.65 (±23.95) for women and 140.82 (±28.66) for men. The most common symptoms in women were muscle and joint pain (94.6%), fatigue (94.0%), discomfort (92.2%), difficulty concentrating (91.0%), and memory loss (88.6%). For men the symptoms included muscle and joint pain (97.5%) and fatigue (97.5%) both occupying first position, discomfort (92.0%), difficulty concentrating (90.0%), mood disturbances (90.0%), and memory loss (87.5%). The chi-square test showed statistical significance (p < 0.005) for socio-demographic information, quality of life scores, and long COVID symptoms by intensities. Conclusion: This study shows that there are gender differences in the way that long COVID is experienced.

Epidemiological trends and clinical outcomes of cryptococcosis in a medically insured population in the United States: a claims-based analysis from 2017 to 2019.

Background: Emerging risk factors highlight the need for an updated understanding of cryptococcosis in the United States. Objective: Describe the epidemiological trends and clinical outcomes of cryptococcosis in three patient groups: people with HIV (PWH), non-HIV-infected and non-transplant (NHNT) patients, and patients with a history of solid organ transplantation. Methods: We utilized data from the Merative Medicaid Database to identify individuals aged 18 and above with cryptococcosis based on the International Classification of Diseases, Tenth Revision diagnosis codes from January 2017 to December 2019. Patients were stratified into PWH, NHNT patients, and transplant recipients according to Infectious Diseases Society of America guidelines. Baseline characteristics, types of cryptococcosis, hospitalization details, and in-hospital mortality rates were compared across groups. Results: Among 703 patients, 59.7% were PWH, 35.6% were NHNT, and 4.7% were transplant recipients. PWH were more likely to be younger, male, identify as Black, and have fewer comorbidities than patients in the NHNT and transplant groups. Notably, 24% of NHNT patients lacked comorbidities. Central nervous system, pulmonary, and disseminated cryptococcosis were most common overall (60%, 14%, and 11%, respectively). The incidence of cryptococcosis fluctuated throughout the study period. PWH accounted for over 50% of cases from June 2017 to June 2019, but this proportion decreased to 47% from July to December 2019. Among the 52% of patients requiring hospitalization, 61% were PWH and 35% were NHNT patients. PWH had longer hospital stays. In-hospital mortality at 90 days was significantly higher in NHNT patients (22%) compared to PWH (7%) and transplant recipients (0%). One-year mortality remained lowest among PWH (8%) compared to NHNT patients (22%) and transplant recipients (13%). Conclusion: In this study, most cases of cryptococcosis were PWH. Interestingly, while the incidence remained relatively stable in PWH, it slightly increased in those without HIV by the end of the study period. Mortality was highest in NHNT patients.

Epidemiological trends of cryptococcosis in the US The epidemiology and outcomes of cryptococcosis across the United States have not been recently examined. This study analyzed an insured population from 2017 to 2019 and revealed a relatively stable incidence of cryptococcosis among people with HIV, while concurrently demonstrating a slightly increased incidence among individuals without HIV. Notably, mortality rates were highest among non-HIV-infected and non-transplant patients.

Aspergillus fumigatus Epidural Abscess and Postsurgical Wound Infection in an Immunocompetent Host.

In this case, we present an immunocompetent patient who had a wound infection secondary to Aspergillus fumigatus after undergoing a neurosurgical procedure that was complicated by an epidural abscess. The patient was treated with voriconazole and responded favorably. We highlight the need for awareness of the possibility of an Aspergillus infection in people without any obvious immunocompromise and advocate for the inclusion of this opportunistic fungus in the workup of postneurosurgical infections and dura-based collections. A brief review of relevant literature is also included.

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.

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.

Baseline Characteristics of Fabry Disease "Amenable" Migalastat Patients in Argentinian Cohort.

Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.

Zinner's Syndrome and Retroperitoneal Fibrosis: An Unknown Association.

We report the case of a 24-year-old male presenting with obstructive renal failure, characterised by imaging evidence of a cystic lesion contingent upon the seminal vesicle and concurrent renal agenesis. Initial management involved urinary diversion, followed by outpatient monitoring and subsequent recurrence. Subsequent diagnostic assessments led to the identification of Zinner's syndrome, accompanied by retroperitoneal fibrosis. We present the clinical course, diagnostic methodology and the efficacious implementation of medical-surgical therapeutic interventions, yielding favourable outcomes. LEARNING POINTS: The value of the Internal Medicine team in the assessment of low prevalence diseases.The importance of multidisciplinary teams.Integration of the internists in the surgical teams.

Chronic Inflammatory Demyelinating Polyneuropathy as the Initial Presentation of Systemic Lupus Erythematosus Successfully Treated With Cyclophosphamide.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that can manifest with a wide range of clinical features, including peripheral nervous system involvement. Among the neurological complications associated with SLE, chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare but significant entity. This case report explores the complex relationship between CIDP and SLE, emphasizing the challenges in diagnosis and the complexities of treatment strategies. We present the case of a patient diagnosed with CIDP as the initial manifestation of SLE, who exhibited a remarkable response to a unique treatment approach. This case underscores the potential overlap of these two conditions, the need for individualized diagnostic, and the importance of considering lupus activity when making therapeutic decisions. While conventional treatment approaches for CIDP are established, the management of CIDP in the context of SLE requires a thorough approach. This report presents a case where early intervention with steroids and cyclophosphamide yielded favorable outcomes, providing insights into alternative treatment options. As this subset of patients remains underrepresented in clinical trials, further research is needed to establish clear guidelines for the management of CIDP in SLE, optimizing patient care while minimizing risks associated with immunomodulatory therapies.

Historical evolution of cancer genomics research in Latin America: a comprehensive visual and bibliometric analysis until 2023.

Background: Cancer genomics, as an interdisciplinary research area within the Global Cancer Research agenda, genomics and precision medicine, its important in research and clinical practice in Latin America. To date, there has been no study investigating evolution of this area in this region. The aim of this study was to evaluate for first time, the historical evolution of cancer genomics research in Latin America. Methods: Bibliometric cross-sectional study of documents on cancer genomics published by Latin American authors until 2023 in Scopus was performed. Statistical and visual analysis was performed with R programming language. Results: A total of 1534 documents were obtained. The first document of cancer genomics research was published in 1997, marking the inception of a 26-year evaluation period that extended until 2023. Among the documents, 74.3% (n = 1140) constituted original articles, followed by 22.7% (n = 349) classified as reviews. International collaboration was observed in 6.5% (n = 100) of the articles. Within the compilation of the ten most prolific authors in this region, 90% of them are from Brazil. This observed pattern extends to affiliations as well, wherein the Universidade de São Paulo emerges as the most active institution (n = 255 documents). This arrangement firmly establishes Brazil's prominence as the preeminent country in the region concerning cancer genomics research, showcasing robust collaboration networks both regionally and intercontinentally. An important transition in the studied hot topics over the last 20 years was identified, from the exploration of the human genome and the characterization of genomic and proteomic cancer profiles (1997-2010) to an in-depth investigation of cancer stem cells and personalized medicine (2011-2023). Among the array of cancer types under study, predominant attention has been directed towards breast, lung, prostate, and leukemia. Conclusion: Over the course of the past 26 years, a favorable and notable evolution has characterized cancer genomics research within Latin America, with Brazil leading the way, which possess a robust network of regional and intercontinental collaboration. Furthermore, the lines of research and hot topics have change in harmony with the region's objectives, strategies, and requisites.

Substance use disorder-associated infections' treatment with dalbavancin enabling outpatient transition (SUDDEN OUT) - an investigator-initiated single-arm unblinded prospective cohort study.

Background: Severe gram-positive infections are frequent in people who inject drugs, and successful completion of treatment presents unique challenges in this population. Objectives: We aimed to evaluate the feasibility of a long-acting antibiotic, dalbavancin, as an alternative to standard-of-care antibiotics for severe infections due to vancomycin-susceptible pathogens requiring ⩾2 weeks of therapy. Design: We designed an investigator-initiated single-arm unblinded prospective cohort study to evaluate the safety and efficacy of an early switch to dalbavancin in two doses administered 1 week apart. Methods: We screened patients admitted with bloodstream infection, osteomyelitis, septic arthritis, infective endocarditis or deep abscesses, and comorbid substance use disorder (SUD) for eligibility. Consenting patients were switched to dalbavancin within 7 days from their index culture. They were monitored in the hospital for efficacy and safety of the treatment until the second dose of dalbavancin 7 days later and then discharged if stable. Study participants were evaluated with a decision support engine for a hypothetical appropriate level of care regarding their SUD after discharge. Their follow-up was planned for 12 months from the index culture, either in-person or via telehealth/telephone. Results: The enrollment was terminated early due to significant loss-to-follow-up. In all, 11 patients were enrolled, 4 completed 12 months of follow-up, 2 completed 8 months of follow-up, and 1 was seen once after discharge. The remaining five patients were lost to follow-up immediately after discharge. All 11 patients continued to improve after switching to dalbavancin between the first and second doses. There were two per-protocol failures of treatment. Dalbavancin was well tolerated, though some adverse events were reported. Conclusion: Dalbavancin may be a safe and effective alternative for an early switch in treating severe gram-positive infections. Trial registration: The trial was registered as NCT04847921 with clinicaltrials.gov.

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.

Resident Hymenopteran Parasitoids with Potential Drosophilid Associations in Andean North Patagonia: Implications for the Biological Control of the Spotted Wing Drosophila.

The spotted wing drosophila, Drosophila suzukii Matsumura, is native to Southeast Asia and has become a serious pest of soft-skinned fruits worldwide. Several control methods are being tested worldwide as part of an integrated pest management approach. Biological control is a promising alternative tactic that can be used to manage D. suzukii populations, especially in unmanaged areas. This study aimed at exploring the diversity of resident hymenopteran parasitoids of drosophilids in northwestern Patagonia, where D. suzukii is considered an important pest. The survey also aimed to investigate possible associations between parasitoids and D. suzukii in several crops and non-crop fruits, and to determine D. suzukii fruits infestation levels. Fourteen sites with mainly berry crops were sampled biweekly using cider vinegar traps and collecting fresh fruits from a variety of crop and non-crop fruit plants. We identified five species of hymenopteran parasitoids, obtained from the baited traps, that have the potential to associate with D. suzukii: Leptopilina heterotoma Thomson, Ganaspis brasiliensis Ihering, Hexacola hexatoma Hartig (Figitidae), Pachycrepoideus vindemmiae Rondani (Pteromalidae), and Spalangia endius Walker (Spalangiidae). Leptopilina heterotoma is reported for the first time in Argentina. High numbers of D. suzukii adults were recovered from baited traps and field-collected fruits. However, no parasitoid emerged from D. suzukii pupae recovered from fruits, nor were any dead parasitoids recorded inside D. suzukii pupae. Overall infestation levels of D. suzukii on field-collected fruits did not differ significantly between species/varieties. The results are discussed with emphasis on the possible functionality and perspectives of using these species as biological control agents.

Lagrangian modelling of oil concentrations at sea: A sensitivity analysis to the grid resolution and number of Lagrangian elements.

This paper presents a novel method to select the optimal combination of grid resolution and number of Lagrangian elements (LEs) required in numerical modelling of oil concentrations at sea. A sensitivity analysis in terms of grid resolution and the number of LEs, was carried out to understand the uncertainty that these user-dependent parameters introduce in the numerical results. A dataset of 211,200 simulations performed under 400 metocean patterns, 6 initial volumes, 11 grid resolutions, and different numbers of LEs (100 to 500,000), was used to analyze the sensitivity of the model along different Thresholds of Concern. Results show the importance of a correct selection of the number of LEs and the grid resolution in Lagrangian modelling of surface oil concentrations. The method proposed will allow selecting the optimal combination of these parameters to find an optimal balance between the accuracy and the computational cost of the simulation.

Positive Toxoplasma IgG Serology Is Associated with Increased Overall Mortality - A Propensity Score-Matched Analysis.

Toxoplasma gondii is a prevalent parasitic disease with significant morbidity and mortality in immunocompromised populations. We lack long-term outcomes for latent infections. We aimed to elucidate the relationship between latent T. gondii infection and mortality risk. We queried TriNetX, a international multicenter network, to validate mortality risk differences among patients with positive or negative toxoplasma IgG through propensity score matching (PSM). We excluded patients with toxoplasmosis disease by International Classification of Diseases codes or polymerase chain reaction testing. We found 28,138 patients with available toxoplasma IgG serology. Seropositive patients were older and had a male preponderance. More seropositive patients identified as Hispanic, Latino, or Black persons. Patients who were positive for T. gondii IgG serology were slightly more likely to have underlying heart failure, a transplanted organ or tissue, malignant neoplasms of lymphoid or hematopoietic tissues, and diseases of the nervous system than seronegative controls. After PSM of patients with positive (N = 6,475) and negative (N = 6,475) toxoplasma IgG serologies, toxoplasmosis-positive patients were more likely to have long-term drug use but less likely to suffer from behavioral disorders. The overall PSM 1- and 5-year mortality was higher among patients with a positive toxoplasma IgG serology. The risk of schizophrenia was increased at 5 years. We found a prevalence of toxoplasma IgG positivity of 0.03% during the last 3 years. Latent T. gondii associates with a higher overall mortality risk. The study of social determinants of health and follow-up studies are necessary to corroborate the findings and find possible causal mechanisms.

Fast HPLC-based affinity method to determine capsid titer and full/empty ratio of adeno-associated viral vectors.

Recombinant adeno-associated viruses (rAAVs) are promising gene delivery vectors in the emerging field of in vivo gene therapies. To ensure their consistent quality during manufacturing and process development, multiple analytical techniques have been proposed for the characterization and quantification of rAAV capsids. Despite their indisputable capabilities for performing this task, current analytical methods are rather time-consuming, material intensive, complicated, and costly, restricting their suitability for process development in which time and sample throughput are severe constraints. To eliminate this bottleneck, we introduce here an affinity-based high-performance liquid chromatography method that allows the determination of the capsid titer and the full/empty ratio of rAAVs within less than 5 min. By packing the commercially available AAVX affinity resin into small analytical columns, the rAAV fraction of diverse serotypes can be isolated from process-related impurities and analyzed by UV and fluorescence detection. As demonstrated by both method qualification data and side-by-side comparison with AAV enzyme-linked immunosorbent assay results for rAAV8 samples as well as by experiments using additional rAAV2, rAAV8, and rAAV9 constructs, our approach showed good performance, indicating its potential as a fast, simple and efficient tool for supporting the development of rAAV gene therapies.

From Multi- to Single-Hollow Trimetallic Nanocrystals by Ultrafast Heating.

Metal nanocrystals (NCs) display unique physicochemical features that are highly dependent on nanoparticle dimensions, anisotropy, structure, and composition. The development of synthesis methodologies that allow us to tune such parameters finely emerges as crucial for the application of metal NCs in catalysis, optical materials, or biomedicine. Here, we describe a synthetic methodology to fabricate hollow multimetallic heterostructures using a combination of seed-mediated growth routes and femtosecond-pulsed laser irradiation. The envisaged methodology relies on the coreduction of Ag and Pd ions on gold nanorods (Au NRs) to form Au@PdAg core-shell nanostructures containing small cavities at the Au-PdAg interface. The excitation of Au@PdAg NRs with low fluence femtosecond pulses was employed to induce the coalescence and growth of large cavities, forming multihollow anisotropic Au@PdAg nanostructures. Moreover, single-hollow alloy AuPdAg could be achieved in high yield by increasing the irradiation energy. Advanced electron microscopy techniques, energy-dispersive X-ray spectroscopy (EDX) tomography, X-ray absorption near-edge structure (XANES) spectroscopy, and finite differences in the time domain (FDTD) simulations allowed us to characterize the morphology, structure, and elemental distribution of the irradiated NCs in detail. The ability of the reported synthesis route to fabricate multimetallic NCs with unprecedented hollow nanostructures offers attractive prospects for the fabrication of tailored high-entropy alloy nanoparticles.

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.

A multi-arm, parallel, preclinical study investigating the potential benefits of acetazolamide, candesartan, and triciribine in combination with fluconazole for the treatment of cryptococcal meningoencephalitis.

Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.

Anakinra authorized to treat severe coronavirus disease 2019; Sepsis breakthrough or time to reflect?

Introduction: The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) announced conditions for using recombinant human interleukin-1 receptor antagonist (rhIL-1ra) to treat hospitalized patients with Coronavirus disease 2019 (COVID-19) and risk for progression. These decisions followed publication of the suPAR-guided Anakinra treatment for Validation of the risk and early Management OF seveRE respiratory failure by COVID-19 (SAVE- MORE) phase 3 clinical trial that yielded positive results. Methods: We conducted a literature review and theoretical analysis of IL-1 blockade as a therapy to treat COVID-19. Using a stepwise analysis, we assessed clinical applicability of the SAVE-MORE results and evaluated conceptual support for interleukin-1 suppression as a suitable approach to COVID-19 treatment. This therapeutic approach was then examined as an example of inflammation-suppressing measures used to treat sepsis. Results: Anakinra use as a COVID-19 therapy seems to rely on a view of pathogenesis that incorrectly reflects human disease. Since COVID-19 is an example of sepsis, COVID-19 benefit due to anti-inflammatory therapy contradicts an extensive history of unsuccessful clinical study. Repurposing rhIL-1ra to treat COVID-19 appears to exemplify a cycle followed by inflammation-suppressing sepsis treatments. A landscape of treatment failures is interrupted by a successful clinical trial. However, subsequent confirmatory study fails to replicate the positive data. Discussion: We suggest further experimentation is not a promising pathway to discover game-changing sepsis therapies. A different kind of approach may be necessary.