Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.

The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata. We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy

Uterine Cytokine Production During the Menstrual Cycle and Preimplantation Stages in Mice

Female reproduction is the only system subjected to well defined periodic changes. The final stage of the menstrual cycle in mammals is the maturation of the ovum and the preparation of the female organism to support fetal development fertilization. Once pregnancy occurs, both maternal and fetal sites emit regulatory signals to ensure embryo development and maternal protection against a graft versus host (GvH) reaction initiated by the semi-allogeneic fetus. We and others have previously shown that each day of fetal development in mice is characterized by different cytokine production, detected not only at the proximity of the feto-placental unit (decidua, uterus), but also in maternal lymphoid organs (spleen), as well as in the serum. In the present study, we concentrated on the menstrual cycle and the preimplantation stages of pregnancy and defined the levels of GM-CSF, IL-10, IL-6, and IL-3 in the murine uterus during anoestrus, proestrus, oestrus, and second and third day of gestation. We show by immunofluorescence and ELISA techniques that GM-CSF is maintained at high levels during anoestrus, proestus, oestrus, and the second day of pregnancy while dropping on the third day. IL-3 levels are found elevated during proestrus, second and third day of gestation, IL-6 increases essentially during proestrus, whereas the production of IL-10 was detected during oestrus and the early stages of pregnancy. Immunoperoxidase staining on frozen sections of uteri during the early gestational period localize GM-CSF and IL-3 production in the endometrium, IL-10 in the endometrium on the second day of pregnancy, and endometrium/myometrium on the third day. Low levels of IL-6 could be detected in the endometrium/epithelium on the second day and endometrium/myometrium on the third day of gestation. The role of IL-3, IL-10, and, to a lesser degree, IL-6 is fortified by the embryo itself, since these cytokines were found to be produced by blastocysts as well. These results demonstrate the existence of a specific distribution of lymphokines within the uterine tissue, the role of which is being discussed

Atypical Strokes in a Young African American Male: A Case of Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare but important cause of stroke-like symptoms which can often be missed Thambisetty and Newman 2004. We describe a case of a young male presenting with stroke-like episodes, later diagnosed with MELAS in an attempt to improve the understanding about diagnosing MELAS in the appropriate clinical context

Medical malpractice in organ transplantation: public allegations and key legal outcomes

IntroductionDespite significant advances in surgical techniques and patient outcomes, organ transplantation (OT) remains fraught with legal challenges and ethical dilemmas. This study aims to address the notable gap in literature on malpractice claims specifically related to OT, providing insights into litigation trends, outcomes, and implications for medical practice and patient care.MethodsWe retrospectively queried the Verdictsearch database from 1988 to 2023, and captured malpractice claims involving several organs. Data on demographics, organ types, and litigation outcomes were collected to compare compensation across different categories of malpractice and patient outcomes.ResultsOut of 292 malpractice cases identified, 62 met inclusion criteria, distributed across 19 states with kidney being the most implicated organ (46.8%). Defendants prevailed in 53.2% of cases, while settlements were reached in 29.0%, and plaintiffs won in 16.1% of cases. Surgical errors and complications were the most frequent allegations, followed by medication and treatment errors. The median compensation for deceased plaintiffs was significantly higher ($1,300,000) compared to living plaintiffs at litigation initiation ($128,000).DiscussionOur study sheds light on the challenges and trends in malpractice litigation within the field of OT. By identifying key areas of concern and the influence of patient outcomes on litigation resolution, this study offers valuable insights for healthcare providers, legal practitioners, and policymakers aimed at enhancing patient safety, reducing litigation risks, and fostering a deeper understanding of the ethical and legal complexities in OT

An Avid Imitator

We present a case of disseminated cryptococcal disease, coexisting with and mimicking lymphoma. Determination of serum cryptococcal antigen should be considered for lymphopenic patients with hematologic malignancies, presenting with unexplained fever, and/or lymphadenopathy and/or pulmonary findings. Patients with hematologic malignancies treated with chemotherapy regimens are susceptible to diverse opportunistic infections. Therefore, in this patient population, it is often necessary to obtain a definitive pathologic diagnosis, to diagnose uncommon syndromes and guide management

A prognostic model of all-cause mortality at 30 days in patients with cancer and COVID-19

Background: Patients with cancer are at higher risk of dying of COVID-19. Known risk factors for 30-day all-cause mortality (ACM-30) in patients with cancer are older age, sex, smoking status, performance status, obesity, and co-morbidities. We hypothesized that common clinical and laboratory parameters would be predictive of a higher risk of 30-day ACM, and that a machine learning approach (random forest) could produce high accuracy. Methods: In this multi-institutional COVID-19 and Cancer Consortium (CCC19) registry study, 12,661 patients enrolled between March 17, 2020 and December 31, 2021 were utilized to develop and validate a model of ACM-30. ACM-30 was defined as death from any cause within 30 days of COVID-19 diagnosis. Pre-specified variables were: age, sex, race, smoking status, ECOG performance status (PS), timing of cancer treatment relative to COVID19 diagnosis, severity of COVID19, type of cancer, and other laboratory measurements. Missing variables were imputed using random forest proximity. Random forest was utilized to model ACM-30. The area under the curve (AUC) was computed as a measure of predictive accuracy with out-of-bag prediction. One hundred bootstrapped samples were used to obtain the standard error of the AUC. Results: The median age at COVID-19 diagnosis was 65 years, 53% were female, 18% were Hispanic, and 16.7% were Black. Over half were never smokers and the median body mass index was 28.2. Random forest with under sampling selected 20 factors prognostic of ACM-30. The AUC was 88.9 (95% CI 88.5-89.2). Highly informative parameters included: COVID-19 severity at presentation, cancer status, age, troponin level, ECOG PS and body mass index. Conclusions: This prognostic model based on readily available clinical and laboratory values can be used to estimate individual survival probability within 30-days for COVID-19. In addition, this model can be used to select or classify patients with cancer and COVID-19 into risk groups based on validated cut points, for treatment selection, prophylaxis prioritization, and/or enrollment in clinical trials. Future work includes external validation using other large datasets of patients with COVID-19 and cancer

Remdesivir Use Compared With Supportive Care in Hospitalized Patients With Severe COVID-19: A Single-Center Experience.

BackgroundThe US Food and Drug Administration issued an Emergency Use Authorization for remdesivir use in patients with severe COVID-19.MethodsWe utilized data from 2 quaternary acute care hospitals. The outcomes of interest were the impact of remdesivir on in-hospital death by day 28 and time to recovery, clinical improvement, and discharge. We utilized Cox proportional hazards models and stratified log-rank tests.ResultsTwo hundred twenty-four patients were included in the study. The median age was 59 years; 67.0% were male; 17/125 patients (13.6%) who received supportive care and 7/99 patients (7.1%) who received remdesivir died. The unadjusted risk for 28-day in-hospital death was lower for patients who received remdesivir compared with patients who received supportive care (hazard ratio [HR], 0.42; 95% CI, 0.16-1.08). Although this trend remained the same after adjusting for age, sex, race, and oxygen requirements on admission (adjusted HR [aHR], 0.49; 95% CI, 0.19-1.28), as well as chronic comorbidities and use of corticosteroids (aHR, 0.44; 95% CI, 0.16-1.23), it did not reach statistical significance. The use of remdesivir was not associated with an increased risk of acute kidney injury (AKI) or liver test abnormalities. Although not statistically significant, the rate ratios for time to recovery, clinical improvement, and discharge were higher in women and black or African American patients.ConclusionsPatients on remdesivir had lower, albeit not significant, all-cause in-hospital mortality, and the use of remdesivir did not increase the risk for AKI. Promising signals from this study need to be confirmed by future placebo-controlled randomized clinical trials

Dalbavancin Sequential Therapy for Gram-Positive Bloodstream Infection: A Multicenter Observational Study

Introduction Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI. Methods One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021. Results Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q1–Q3) of 10 (6–19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%. Conclusions Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards