Citations

Abstract Background Despite advances in clinical microbiology, the diagnosis of invasive fungal infections remains challenging. Giant magnetoresistance (GMR) is a novel technology that enables the detection of trace amounts of cell-free DNA (cfDNA). We evaluated a high-multiplex molecular diagnostic assay coupled with GMR-enabled lab-on-a-chip technology that can detect 18 different fungal species. Methods Analytical performance was evaluated in spiked plasma samples. After amplification, cfDNA was digested. Residual single-stranded DNA was flowed over a GMR sensor that was surface-coated with probes specific to different fungal species. After hybridization, magnetic beads bound to the probe complexes produced a GMR signal that was detected by the sensors. Clinical performance was determined using residual serum samples collected before the initiation of antifungal treatment from 20 patients with infection. Results The limit of detection of the assay ranged from 5 to 50 copies per polymerase chain reaction (PCR) reaction. Nonspecific signals were not observed in the spiked samples. Fungal cfDNA was detected in 80% of patients with invasive candidiasis (3/4 with candidemia, 5/6 with invasive candidiasis without candidemia), all 3 cases of invasive pulmonary aspergillosis, and all 3 cases of disseminated histoplasmosis. cfDNA was not detected in 2 patients with cryptococcosis (both had negative blood cultures) and 2 patients with Pneumocystis pneumonia. Conclusions We developed a novel GMR-enabled multiplex PCR assay detecting fungal pathogens that have been prioritized for public health action. Clinical sensitivity was highest in cases of presumed angioinvasion and dissemination. This technology has the potential for use in the clinical microbiology laboratory setting.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

ABSTRACT Introduction The COVID‐19 pandemic accelerated the shift from in‐person to virtual recruitment, prompting residency and fellowship programs to adopt innovative strategies, such as leveraging social media platforms to attract applicants and enhance visibility. Our aim was to identify and describe the presence of U.S. geriatric medicine fellowship programs on X. Methods We identified all U.S. geriatric medicine fellowship programs using FREIDA, and then located their X accounts through a stepwise process. Data were collected on account creation, number of followers, posts, and activity level, with an analysis of the last 100 posts from the most active accounts. Descriptive statistics were used to analyze the data. Results Among the 147 geriatric medicine fellowship programs identified, 38 (25.9%) had an X account. The majority of accounts were created after the start of the pandemic, reflecting likely the adaptation to virtual recruitment processes. Only a few accounts generated the majority of posts and followers. The accounts primarily posted or reposted educational content, research highlights, and promotional material. Conclusion The use of X by geriatric medicine programs is still significantly underutilized, with only one‐fourth of them having an account. Half of the accounts were created after the COVID‐19 pandemic began. Programs should focus on building a robust social media presence to increase their visibility, especially as virtual interviews have become a permanent part of recruitment.

Abstract Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in 2 cohorts, 1 for patients with CAD and the other for those with wAIHA. In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks. Safety end points included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy end points included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and functional assessment of chronic illness therapy (FACIT)-fatigue scale. Thirteen of 13 (100%) and 10 of 11 (91%) patients with CAD and wAIHA, respectively, experienced at least 1 TEAE. Ten patients had at least 1 serious AE; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (−1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective for patients with CAD and wAIHA. This trial was registered at www.ClinicalTrials.gov as #NCT03226678.

AbstractBackgroundThere are no established clinical breakpoints for antifungal agents against Cryptococcus species; however, epidemiological cut‐off values can help distinguish wild‐type (WT) isolates without any acquired resistance from non‐WT strains, which may harbour resistance mechanisms.Patients/MethodsWe describe the trends of antifungal MICs and percentages of WT C. neoformans species complex (CNSC) isolates processed in our reference laboratory from November 2011 to June 2021. There were only nine isolates in 2011, thus, we included them in the year 2012 for data analysis. Clinical data is also described when available.ResultsWe identified 632 CNSC, the majority collected from blood (n = 301), cerebrospinal fluid (n = 230), and respiratory (n = 71) sources. The overall percentage of WT isolates for amphotericin B (AMB), 5‐flucytosine, and fluconazole was 77%, 98%, and 91%, respectively. We noticed a statistically significant change in the percentage of AMB WT isolates over the years, with 98% of isolates being WT in 2012 compared to 79% in 2021 (p < .01). A similar change was not observed for other antifungal agents. Clinical data was available for 36 patients, primarily non‐HIV immunocompromised patients with disseminated cryptococcosis. There were no statistically significant differences in the clinical characteristics and outcomes between patients with WT (58.3%) versus non‐WT (41.7%) isolates, but we noticed higher mortality in patients infected with an AMB non‐WT CNSC isolate.ConclusionsWe observed an increase in the percentage of AMB non‐WT CNSC isolates in the past decade. The clinical implications of this finding warrant further evaluation in larger studies.

Abstract Background Histoplasmosis is an endemic mycosis associated with a wide range of clinical presentations. Cardiovascular histoplasmosis (CVH) was rarely seen at our center before 2007 but has increased in frequency over the last 15 years. Herein, we describe the clinical characteristics of our recent CVH cases. Methods We identified all adults diagnosed with CVH at Mayo Clinic in Rochester, MN, between May 2007 and February 2023. Results Ten cases of CVH were identified, all of whom resided in the Midwest (Table). The majority were male, with a median age of 72 years. Five patients had prosthetic valves, two endovascular grafts, one a prosthetic valve and aortic graft, and one was a heart-kidney transplant recipient. Patients most frequently presented with prolonged night sweats, fever, and dyspnea. Cytopenias, pulmonary nodules, and splenomegaly were common laboratory and imaging findings. The diagnosis was suspected based on a positive Histoplasma antibody (100%) and/or antigen (80%) testing and confirmed by positive culture (blood 60%, explanted valve/graft 20%) and/or histopathology (60%). Identified clinical syndromes included: prosthetic valve endocarditis (PVE; 50%), native valve endocarditis (10%), mycotic aortic aneurysm (10%), aortic graft infection (10%), PVE and aortic graft infection (10%), and myocarditis (10%). Most patients received combined medical and surgical treatment (50%). Three patients (30%) received medical treatment only, including one patient with myocarditis. Two patients (20%) presented progressive clinical decline and were not considered antifungal treatment or surgical candidates. The overall mortality within one year of diagnosis was 50%. Patients with endocarditis and/or graft infection who received only medical treatment had higher mortality than those who received combined medical and surgical treatment (100% vs 20%, respectively).Table.Clinical characteristics of patients presenting with cardiovascular histoplasmosis (N=10) *Patient frequently had more than one comorbidity, symptom, laboratory or imaging finding, positive histoplasmosis testing, or affected valve. **Two patients did not receive treatment given their critical status, and were transitioned to comfort care. Conclusion CVH is being seen more frequently at our institution. One-year mortality of CVH was high, but combined medical and surgical management conferred better outcomes than medical treatment alone. We suggest a high index of suspicion of CVH in patients residing in Histoplasma endemic regions with a history of prior cardiac or vascular surgery presenting with prolonged fevers and/or new cardiomyopathy. Disclosures All Authors: No reported disclosures

Abstract Background Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes. Methods We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers. Results Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9–42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002). Conclusions The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop.