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

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

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access.This article is highlighted in the In This Issue feature, p. 1426

COVID-19 Severity and Cardiovascular Outcomes in SARS-CoV-2-Infected Patients With Cancer and Cardiovascular Disease

BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)

Relapsing EBV Encephalitis in a Renal Transplant Recipient

In solid organ transplant recipients, Epstein-Barr virus (EBV) can cause active central nervous system (CNS) infection or malignant transformation of latently infected cells in the CNS, known as post-transplant lymphoproliferative disease (PTLD). Reduction of T-cell immunosuppression is the cornerstone of management. The role of antivirals with in-vitro activity against herpesviruses in EBV-related CNS syndromes is controversial, as they have no effect on latent virus. We report an unusual case of relapsing EBV encephalitis in a donor-positive, EBV-negative renal transplant recipient, with response to valganciclovir. Our report supports the utility of antiviral treatment for EBV encephalitis, as adjunct to reducing immunosuppression, and highlights the need for a systematic approach and long-term, multi-disciplinary follow-up of such patients

Receiver operator characteristics and diagnostic value of progesterone and CA-125 in the prediction of ectopic and abortive intrauterine gestations

Objective: The study was designed to investigate the predictive value of progesterone and CA-125 in the diagnosis of ectopic pregnancy (EP) and inevitable miscarriage. Methods: Forty women with EP, 20 with intrauterine (IU) abortive gestation and 20 regular pregnant women (controls) were studied. IU abortive and EP were confirmed and treated by surgery. Serum progesterone and CA-125 levels were measured at the time of presentation and 24 h after surgery. Results: Women with EP had significantly lower progesterone concentrations, compared to both women with IU abortive pregnancy and controls. Women with IU abortion had significantly higher CA-125 levels, compared to the other two groups. When using a progesterone concentration of less than 10.75 ng/ml as a cut-point for the diagnosis of EP, sensitivity, specificity, positive and negative predictive values were 85%. When using CA-125 concentration of more than 41.9 U/ml as a threshold for the diagnosis of IU abortive pregnancy, sensitivity was 80%, specificity 87%, the positive predictive value was 66% and the negative predictive value 93%. Conclusion: The measurement of progesterone and CA-125 levels is useful in discriminating ectopic and intrauterine abortive from normal gestations. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Serum luteinizing hormone levels are markedly increased and significantly correlated with Delta(4-)-androstenedione levels in lean women with polycystic ovary syndrome

Lean women with polycystic ovary syndrome have markedly increased serum luteinizing hormone levels, which are significantly correlated with Delta(4)-androstenedione levels but not directly linked to insulin resistance

Creatine phosphokinase in ectopic pregnancy revisited: Significant diagnostic value of its MB and MM isoenzyme fractions

Objective: Although evidence on elevated creatine phosphokinase (CPK) as a tool for the diagnosis of ectopic pregnancy (EP).is rather conflictive, no previous study on CPK isoenzyme levels and their relative ratio was found in the literature. Study design: Forty women with EP, 20 with intrauterine (IU) abortive gestation, and 20 regular pregnant women (controls) were studied. Serum total CPK, CPK-MB, and CPK-MM levels were measured at the time of presentation and 24 hours after surgery. Relative operating characteristic (ROC) curves were plotted. Results: Women with EP had significantly higher CPK concentrations and a significantly decreased CPK-MB relative ratio (CPK-MB%), compared with both women with IU abortive pregnancy and controls. The ROC curves demonstrated a significant discriminatory ability of both increased total CPK and decreased CPK-MB% ratio for the diagnosis of EP. Conclusion: Determination of CPK isoenzyme fractions can significantly enhance the diagnostic value of total maternal CPK in the prediction of ectopic pregnancy. (c) 2006 Mosby, Inc. All rights reserved