We evaluated the in vivo activity of EL219 against central nervous system coccidioidomycosis. Mice were inoculated intracranially with arthroconidia of Coccidioides immitis, and treatment with EL219 (5, 10, or 20 mg/kg QD by intraperitoneal injection) or fluconazole (25 mg/kg orally BID) began 2 days later. Each dose of EL219 and fluconazole significantly improved survival. Brain fungal burden was also reduced compared to vehicle control. Further studies of EL219 against coccidioidomycosis are warranted.

Invasive fungal diseases are difficult to diagnose because of the limited sensitivity of culture. Panfungal PCR amplicon sequencing assays (targeting ribosomal RNA, such as 18S, 28S, ITS) are recommended for fungal identification in histopathology samples showing fungal elements. However, data describing its overall performance and consistency are lacking. This systematic literature review and meta-analysis assessed the performance of panfungal PCR on formalin-fixed paraffin-embedded (FFPE) and non-fixed (fresh or frozen) tissue samples. A systematic literature search was performed to include studies reporting the use of panfungal PCR for fungal identification in FFPE or non-fixed tissue samples. PCR sensitivity and specificity were assessed using the reference standard of histopathology showing fungal elements. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled estimates were obtained using random-effects meta-analysis. Twenty-eight studies were included. In FFPE samples (18 studies, 852 samples), sensitivity and specificity were 75.4% (95% confidence interval [CI], 59.2-86.6) and 93.5% (70.2-98.9), respectively. Sensitivity in non-fixed samples (13 studies, 207 samples) was 86.5% (74.7-93.3), while specificity could not be assessed (insufficient data). Comparative analyses showed a significantly higher sensitivity of panfungal PCR over culture (88.2%; 76-94.7 vs 52.2%; 39-65, P = 0.001). Sub-analyses could not demonstrate the superiority of one PCR target over another due to limited data. Panfungal PCR exhibited adequate sensitivity and good specificity in FFPE samples. Sensitivity was even higher in non-fixed samples and largely superior to culture. Nevertheless, large interstudy variability was observed, warranting interlaboratory studies to define the optimal PCR target and standardized protocols. IMPORTANCE:Invasive fungal diseases are difficult to diagnose because of the low sensitivity of culture. Panfungal PCRs are widely used for fungal identification in tissue specimens but suffer from heterogeneous procedures and performance. This meta-analysis shows an acceptable sensitivity (75.4% and 86.5% in fixed and non-fixed samples, respectively) and good specificity (93.5%) of panfungal PCR, supporting its use, not only on histopathology-positive fixed samples but also in non-fixed samples concomitantly with other diagnostic tools (cultures and fungal-specific PCRs if available). These results provide a strong basis for further standardization of panfungal PCR techniques via interlaboratory assays to assess reproducibility and optimize analytical protocols. CLINICAL TRIALS:This study is registered with PROSPERO as CRD42023461148.

Treatment of symptomatic patients with coccidioidomycosis often involves the use of triazole antifungals. There is concern for reduced susceptibility of Coccidioides to fluconazole, as a high percentage of isolates were previously reported to have elevated fluconazole MICs. We reviewed our recent azole MICs against Coccidioides and examined temporal trends over a 20-year period. Our clinical laboratory database was queried for data against Coccidioides between 2006 and 2025, and trends in GM MICs and the percentage of isolates with elevated MICs to the azoles were assessed. All testing had been performed by broth dilution according to Clinical and Laboratory Standards Institute (CLSI) M38 methods. The results over the 10-year period from 2016 to 2025 were compared to those previously reported by our group from 2001 to 2015. Overall, the results between the two periods showed similar MIC parameters and distributions for fluconazole, itraconazole, posaconazole, and voriconazole, with posaconazole demonstrating the most potent activity, while fluconazole demonstrated reduced susceptibility. Isavuconazole MIC parameters were available during the second period and similar to those of voriconazole. Weak correlations were observed between fluconazole MICs and those of the other azoles. Fluctuations in GM MICs and the percentage of isolates with elevated MICs were observed with fluconazole, itraconazole, and posaconazole, with elevated values observed between 2011 and 2019. Continued surveillance is needed, and outcome data are required to determine if the consistently reduced susceptibility observed with fluconazole or in those infected with strains that have higher MICs results in poorer outcomes in patients with coccidioidomycosis.

This randomized clinical trial investigates if evidence-based rehabilitation strategies improve cognitive symptoms in persons with long COVID. QuestionDo evidence-based rehabilitation strategies improve cognitive symptoms in persons with long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection)?FindingsThis randomized clinical trial included 328 participants randomly assigned to 3 active interventions over 10 weeks at 22 clinical sites. None of the interventions demonstrated benefits on the modified Everyday Cognition Scale 2 in the intention-to-treat population by the end of the intervention period.MeaningThe trial failed to demonstrate differential benefits from online cognitive training, a structured cognitive rehabilitation program, or transcranial direct current stimulation in participants with cognitive long COVID. ImportanceTreatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need.ObjectiveTo test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID.Design, Setting, and ParticipantsThis was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID.InterventionsParticipants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks.Main Outcomes and MeasuresCognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days.ResultsA total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions.Conclusions and RelevanceThis phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID.Trial RegistrationClinicalTrials.gov Identifier: NCT05965739.

Candida glabrata is a major cause of invasive candidiasis and is considered a high-priority fungal pathogen by the World Health Organization. SCY-247 is a second-generation IV/oral triterpenoid antifungal that targets the fungal cell wall by inhibiting glucan synthase. We evaluated the in vitro activity and in vivo efficacy of SCY-247 against echinocandin-resistant C. glabrata. Susceptibility testing was performed against 34 C. glabrata clinical strains, including 29 echinocandin non-susceptible or resistant strains, by the CLSI broth microdilution method. Neutropenic mice were infected intravenously with either an echinocandin-susceptible or resistant strain. Treatment with vehicle control, SCY-247 (16, 32, and 48 mg/kg PO BID), fluconazole (20 mg/kg PO QD), or caspofungin (5 mg/kg IP QD) was initiated 24 hours post-inoculation. Treatment continued for 7 days, and kidney and lung tissues were collected on day 8 for analysis of fungal burden. SCY-247 maintained in vitro activity against 24 of the 29 echinocandin non-susceptible/resistant strains; SCY-247 was also efficacious against echinocandin-susceptible and resistant C. glabrata invasive candidiasis. Dose-dependent reductions in kidney and lung fungal burdens were observed in mice treated with SCY-247. In contrast, neither fluconazole nor caspofungin led to reductions in fungal burden in mice infected with the resistant strain. SCY-247 concentrations measured 12 hours after the last dose increased in a dose-dependent fashion, and those within the kidneys and lungs were markedly higher than the SCY-247 MIC90 value calculated against all strains tested. These data support the potential utility of SCY-247 therapy against invasive infections caused by resistant C. glabrata.

BACKGROUND:Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. OBJECTIVE:To evaluate olorofim effectiveness and adverse events in patients with DCM. DESIGN:Single-group, open-label, phase 2b study. (ClinicalTrials.gov: NCT03583164). SETTING:Ten U.S. sites. PARTICIPANTS:Forty-one patients with DCM and limited or no treatment options. Patients received olorofim alone or in combination with ongoing standard of care during an 84-day main treatment phase. Extended treatment was offered to patients. MEASUREMENTS:Mycoses Study Group-European Organization for Research and Treatment of Cancer (MSG-EORTC) criteria for global response based on subcategories of clinical, radiologic, and mycologic response were adjudicated by an independent data review committee (DRC) at days 42 and 84 (main treatment phase). Because the slow pace of serologic improvement in DCM limits global response to stable at best, this article focuses on patient clinical responses. Treatment-emergent adverse events (TEAEs) were compiled for both treatment phases. RESULTS:Forty-one patients with DCM were enrolled from May 2019 to August 2022. Thirty-nine (95.1%) did not have immunosuppression. Central nervous system disease was present in 30 (73.2%) patients, and 13 (43.3%) had a ventriculoperitoneal shunt with or without an Ommaya reservoir. Clinical success as adjudicated by the DRC occurred in 31 of 41 patients (75.6% [95% CI, 59.7% to 87.6%]) at day 42 and 30 of 41 patients (73.2% [CI, 57.1% to 85.8%]) at day 84. The main TEAE was hepatic biochemistry elevation in 9 of 41 patients (21.9%), which was managed by liver enzyme monitoring and dose reduction or pause in 8 patients (19.5%) and drug discontinuation in 1 patient (2.4%). LIMITATION:This was a single-group, open-label trial, but a randomized controlled trial would be preferable. CONCLUSION:Olorofim showed effectiveness in patients with DCM with limited or no therapeutic options. PRIMARY FUNDING SOURCE:F2G, Ltd.

Background:There is no prospective, US multicenter study of COVID-19-associated pulmonary aspergillosis (CAPA). CAPA definitions do not differentiate invasive aspergillosis (IPA) from colonization. Validity of single mycologic test results is unclear. Methods:We performed a prospective 7-center US study of mechanically ventilated adults with COVID-19 (April 2021-May 2022). Mycoses Study Group (MSGERC) CAPA criteria include host and clinical factors, imaging and test results (histopathology; bronchoalveolar lavage [BAL] culture and/or BAL or serum galactomannan-immunoassay). Proven, putative, and unlikely IPA were defined by clinical criteria. CAPA-unlikely IPA criteria included survival or negative autopsy following no/limited antifungal treatment. IPA likelihood was estimated using sensitivity/specificity of tests from autopsy data. Results:CAPA incidence was 7% (14/212). Independent CAPA risk factors were EORTC/MSGERC host factor and cavitary lesions. Seven percent, 79%, and 14% of CAPA patients had proven, putative, and unlikely IPA, respectively. Respective estimated IPA likelihoods were 84%, 7%-99%, and 1%-8%. Overall, median estimated IPA likelihood was 30%. Patients with CAPA-unlikely IPA had a single positive BAL galactomannan-immunoassay with other negative tests. CAPA mortality (71%) was not impacted by antifungal treatment or significantly different than without CAPA. CAPA incidence was 10% and 16% by European Confederation of Medical Mycology and Public Health Wales definitions, respectively. IPA was unlikely in 75% (6/8) and 57% (13/23) diagnosed by these definitions but not MSGERC. Conclusions:CAPA is associated with high mortality, but IPA's contribution is unclear. Single positive tests are insufficient for diagnosing CAPA-IPA. IPA likelihood is best estimated by combining test results (both positive and negative).

BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.ObjectiveTo determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.Design, Setting, and ParticipantsRECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).MeasurementsIncidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.ResultsThe incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63-2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91-10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62-6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).LimitationsThe ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.ConclusionME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.

Importance Classification of persons with long COVID (LC) or post-COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves. Objective To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities. Design, Setting, and Participants Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024. Exposure SARS-CoV-2 infection. Main Outcomes and Measures Presence of LC and participant-reported symptoms. Results A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures. Conclusions and Relevance The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

Longitudinal trajectories of Long COVID remain ill-defined, yet are critically needed to advance clinical trials, patient care, and public health initiatives for millions of individuals with this condition. Long COVID trajectories were determined prospectively among 3,659 participants (69% female; 99.6% Omicron era) in the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) Adult Cohort. Finite mixture modeling was used to identify distinct longitudinal profiles based on a Long COVID research index measured 3 to 15 months after infection. Eight longitudinal profiles were identified. Overall, 195 (5%) had persistently high Long COVID symptom burden, 443 (12%) had non-resolving, intermittently high symptom burden, and 526 (14%) did not meet criteria for Long COVID at 3 months but had increasing symptoms by 15 months, suggestive of distinct pathophysiologic features. At 3 months, 377 (10%) met the research index threshold for Long COVID. Of these, 175 (46%) had persistent Long COVID, 132 (35%) had moderate symptoms, and 70 (19%) appeared to recover. Identification of these Long COVID symptom trajectories is critically important for targeting enrollment for future studies of pathophysiologic mechanisms, preventive strategies, clinical trials and treatments.

BACKGROUND:Only a small number of antifungal therapies for invasive fungal disease (IFD) are currently available, and many pathogens are resistant to one or more of these therapies. Olorofim, the first orotomide antifungal agent to be developed, is active against fungi that are resistant to registered therapies. It impairs fungal pyrimidine biosynthesis, leading to cell death. We sought initial data on the efficacy and safety of olorofim as a therapy for IFD. METHODS:In this single-arm, open-label, phase 2b study, patients aged 16 years or older with few or no treatment options for proven IFD or probable invasive pulmonary aspergillosis were recruited from 22 centres in 11 countries. The first 58 patients received a weight-based loading dose of oral olorofim 180-300 mg in two to three divided doses on day 1 followed by 120-240 mg daily in two to three divided doses from day 2 onwards. On the basis of pharmacokinetic data from the first 25 patients, dosing was simplified from patient 59 onwards to a loading dose of 150 mg twice on day 1 followed by a fixed maintenance dose of 90 mg twice a day up to day 84 (main treatment phase) with extended therapy as needed. The primary endpoint was global response rate (based on a composite of clinical, radiological, and mycological responses) at day 42, determined as success (complete or partial improvement in all three components) or failure (stable disease or progression on any one component or death from any cause) by a data review committee (DRC). Secondary efficacy endpoints included global response rate at day 84 and all-cause mortality at day 42 and day 84. Global response rate with stable disease classified as success and response rate in the clinical component of the global response at day 42 and day 84 were also assessed. Efficacy was analysed for all patients who were confirmed by the DRC to have an IFD and who received at least one dose of olorofim (the modified intention-to-treat population). Safety was analysed in all patients who received at least one dose of olorofim (the safety population). This trial is registered with ClinicalTrials.gov, NCT03583164, and is completed. FINDINGS:Between June 6, 2018, and Sept 8, 2022, 204 patients were enrolled. Of these, 203 were treated with olorofim and 202 (124 male, 78 female) had DRC-adjudicated IFD. Causative pathogens were Aspergillus spp (n=101, including 22 azole-resistant strains), Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12). Successful global response was confirmed in 58 of 202 patients (28·7%, 95% CI 22·6-35·5) at day 42 and in 55 patients (27·2%, 21·2-33·9) at day 84. Successful global response with stable disease included in the definition of success was seen in 152 patients (75·2%, 68·7-81·0) at day 42 and in 128 patients (63·4%, 56·3-70·0) at day 84. A successful clinical response was seen in 121 patients (59·9%, 52·8-66·7) at day 42 and in 109 patients (54·0%, 46·8-61·0) at day 84. All-cause mortality was documented in 24 patients (11·9%, 7·8-17·2) at day 42 and in 33 patients (16·3%, 11·5-22·2) at day 84. Mean dosing duration was 73 days (SD 25) for the 203 patients in the main treatment phase (median 84 days [range 2-99, IQR 78-87]) and 361 days (SD 220) for the 114 patients who received extended treatment after the main phase (median 309 days [38-988, 180-502]). Medically significant liver enzyme elevations adjudicated to be at least possibly due to olorofim occurred in 20 (10%) of 203 patients and were managed to resolution by dose modification in 14 (7%) patients or by discontinuation of treatment in six (3%). Gastrointestinal intolerance, which occurred in 20 (10%) patients, was predominantly reported as mild or moderate and self-limiting. There were no treatment-related deaths. INTERPRETATION:Olorofim showed efficacy and good tolerability in patients with IFD with few or no treatment options. Further studies will be needed to fully delineate the role of this new antifungal agent. FUNDING:F2G.

Antifungal resistance in Candida glabrata can develop to different classes of drugs, including the azoles and echinocandins. This organism is known to cause infective endocarditis with a particular predilection for prosthetic valves. Herein we present a case of recurrent fungemia with C. glabrata in a middle-aged woman with Tetralogy of Fallot who had a right ventricle to pulmonary artery conduit, and a transcatheter pulmonary valve replacement in the past. Her isolate showed increasing minimum inhibitory concentrations (MIC) to various antifungals with higher MICs to azoles, including resistance to fluconazole, resulting in limited treatment options. She had affliction of her prosthetic pulmonic valve with C. glabrata and was treated with the second-generation echinocandin, rezafungin, for six months. This case illustrates the tolerability profile of long-term treatment with rezafungin.

Importance Olfactory dysfunction is common after SARS-CoV-2 infection and has been associated with cognitive loss in other conditions. Formal testing is needed to characterize the presence, severity, and patterns of olfactory dysfunction. ObjectiveTo characterize long-term olfactory dysfunction after SARS-CoV-2 infection. Design, Setting, and Participants This prospective cohort study included adults enrolled in the Researching COVID to Enhance Recovery (RECOVER)-Adult study. All those with and a random sample of those without self-reported change or loss in smell or taste were offered olfactory testing, performed at 83 sites in 35 US states and territories. Participants included 2956 enrollees with prior infection (1393 with and 1563 without self-reported change or loss) and 569 without prior infection (9 with and 560 without self-reported change or loss in taste) who underwent olfactory testing a mean (SD) of 671.6 (417.8) days after the index date. Data were collected from October 29, 2021, to June 6, 2025.ExposureSARS-CoV-2 infection.Main Outcomes and Measures Olfactory function, as defined by age- and sex-standardized performance on the University of Pennsylvania Smell Identification Test (UPSIT), a well-validated test comprising 40 unique odors. ResultsThe study included 3525 participants with a mean (SD) age of 47.6 (15.2) years; of 3520 with data available, 2548 (72.4%) were female or intersex. Among 1393 infected participants with self-reported change or loss, 1111 (79.8%) had hyposmia on the UPSIT, including 321 (23.0%) with severe microsmia or anosmia. Among 1563 infected participants without self-reported change or loss, 1031 (66.0%) had hyposmia, including 128 (8.2%) with severe microsmia or anosmia. Participants with prior infection and self-reported change or loss scored at the 16th age- and sex-standardized UPSIT percentile, compared with the 23rd and 28th percentiles for those without self-reported change or loss with and without prior known infection, respectively. Younger women had scores corresponding to lower mean age- and sex-standardized percentiles. Among participants who self-reported change or loss in smell, those with abnormal UPSIT scores more often reported cognitive problems (742 of 1111 [66.8%]) than those with normal UPSIT scores (179 of 282 [63.5%]).Conclusions and RelevanceIn this cohort study of RECOVER-Adult participants, self-reported change or loss in smell or taste was an accurate signal of verified hyposmia, but a high rate of hyposmia among those with no reported change or loss was also observed. Formal smell testing may be considered in those with prior SARS-CoV-2 infection to diagnose occult hyposmia and counsel patients about risks.

Coastal forests are highly vulnerable to disturbances from tropical cyclones (TCs), yet the long-term impacts of storm surges on tree growth remain understudied. This study examines the relationship between TC-induced storm surges and annual tree-ring growth in Pinus elliottii at three coastal sites along the northern Gulf of Mexico. Using dendrochronological methods, we analyzed total ring width, earlywood, and latewood growth patterns to assess suppressions in response to past TC activity. Our results indicate that storm surge events consistently cause growth suppression, with recovery periods averaging two to three years. However, suppression patterns vary by site, with trees in more protected locations displaying stronger correlations with TC storm surge events, while those in chronically stressed environments exhibit frequent growth limitations independent of TCs. For example, only 38% of suppression events at the unprotected Gulf State Park correspond with TC storm surge events, and this increases to 67% at the protected Weeks Bay NERR site. Additionally, latewood ring width corresponds with TC storm surge events more than total or earlywood ring width. These findings highlight the complexity of TC impacts on coastal tree growth, emphasizing the importance of site-specific factors such as topographic position and hydrological conditions. Understanding these interactions is critical for improving paleotempestology reconstructions and informing forest management strategies in coastal environments facing increasing TC activity due to climate change.

The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied. To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites. Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days. The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis. Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy = .11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy = .13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group. In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population. ClinicalTrials.gov Identifier: NCT04885530

Abstract Background Disseminated coccidioidomycosis (DCM) requires long courses of antifungal treatment. Olorofim, a novel antifungal in development, selectively blocks pyrimidine biosynthesis by inhibiting fungal dihydroorotate dehydrogenase (DHODH), and we evaluated its impact on clinical and mycologic response in patients with refractory DCM. Methods Adults >18y with limited or no treatment options enrolled in NCT03583164 (Study 32), an open label olorofim Phase 2b study. A Main Phase of 84+6 days was followed by an Extension Phase; we report here outcomes through 1 year. Results 41 DCM patients enrolled at 10 US sites from 05/2019 to 08/2022. Median age was 47y (range 21-72y). 30 (73.2%) had CNS disease, of whom 13 (43%) had ventriculoperitoneal shunt or Ommaya reservoir. Median time from DCM diagnosis to olorofim initiation was 936d (range 47d to 8y). Median (mean) olorofim treatment was 353d (382d). Data Review Committee (DRC)-adjudicated EORTC-MSG was Partial Clinical Response (PCR) in 28 (68.3%) at Day 42 and 27 (65.9%) at Day 84. Complete Clinical Response (CCR) was in 3 (7.3%) at both timepoints. Constitutional findings (fever, malaise) often resolved within 4 weeks. Integrated Overall Response (Clinical + Mycologic + Imaging) was 0% at Day 42 & 84 due to slow resolution of serologic findings of DCM, even in patients with CCR. Patients in the Extension Phase had PCR or CCR ranging 52.6% to 65.8% with lower rates due, in part, to missing data at study visit dates being assessed as failures, in addition to the fluctuating clinical status of DCM patients over time. Hepatic injury, judged at least possibly related to olorofim was 9 (22.0%) in Main Phase, was managed by dose reduction/pause, and led to discontinuation in 1 (2.4%) patient. Non-serious and self-limited GI symptoms were noted in 16 patients (39%) of which 1 (2.4%) was related to olorofim. Three deaths during Extension Phase were not attributed to olorofim. Conclusion Olorofim has a positive benefit-risk profile in DCM patients with no or limited treatment options. Favorable Clinical Responses were seen in 73.2% and often sustained through 1 year of treatment. Hepatic injury was usually manageable with monitoring. Future studies should assess earlier use of olorofim in serious DCM. Disclosures Fariba Donovan, MD/PhD, F2G: Grant/Research Support George R. Thompson, III, MD, Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant Thomas F. Patterson, MD, F2G: Grant/Research Support Martin Hoenigl, MD, Aicuris: Advisor/Consultant|Astra Zeneca: Honoraria|Gilead: Grant/Research Support|Gilead: Honoraria|IMMY: Grant/Research Support|Melinta: Grant/Research Support|Melinta: Honoraria|MSD: Grant/Research Support|Mundipharma: Grant/Research Support|Mundipharma: Honoraria|Pfizer: Grant/Research Support|Pulmocide: Advisor/Consultant|Pulmocide: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Shionogi: Honoraria Joanna M. Schaenman, MD, PhD, FAST, Eurofins Viracor: Honoraria|F2G: Grant/Research Support|MedCure: Advisor/Consultant|Moderna: Clinical trial support to institution|OneLegacy: Advisor/Consultant Shmuel Shoham, MD, F2G: Grant/Research Support Monica K. Sikka, MD, F2G: Grant/Research Support Andrej Spec, MD, MSCI, F2G: Grant/Research Support Mark Bresnik, MD, F2G Ltd: Employee John H. Rex, MD, F2G: Employee

BACKGROUND:This study evaluated the impact of aging on the frequency and prevalent symptoms of Long COVID, also termed post-acute sequelae of SARS-CoV-2, using a previously developed Long COVID research index (LCRI) of 41 self-reported symptoms in which those with 12 or more points were classified as likely to have Long COVID. METHODS:We analyzed community-dwelling participants ≥ 60 years old (2662 with prior infection, 461 controls) compared to participants 18-59 years (7549 infected, 728 controls) in the Researching COVID to Enhance Recovery adult (RECOVER-Adult) cohort ≥ 135 days post-onset. RESULTS:Compared to the Age 18-39 group, the adjusted odds of LCRI ≥ 12 were higher for the Age 40-49 group (odds ratio [OR] = 1.40, 95% confidence intervals [CI] = 1.21-1.61, p < 0.001) and 50-59 group (OR = 1.31, CI = 1.14-1.51, p < 0.001), similar for the Age 60-69 group (OR = 1.09, CI = 0.93-1.27, p = 0.299), and lower for the ≥ 70 group (OR = 0.68, CI = 0.54-0.85, p < 0.001). Participants ≥ 70 years had smaller adjusted differences between infected and uninfected symptom prevalence rates than those aged 18-39 for the following symptoms: hearing loss, fatigue, pain (including joint, back, chest pain and headache), post-exertional malaise, sleep disturbance, hair loss, palpitations, and sexual desire/capacity, making these symptoms less discriminating for Long COVID in older adults than in younger. Symptom clustering, as described in Thaweethai et al. (JAMA 2023) also exhibited age-related shifts: clusters 1 (anosmia and ageusia) and 2 (gastrointestinal, chronic cough and palpitations, without anosmia, ageusia or brain fog) were more likely, and clusters 3 (brain fog, but no loss of smell or taste) and 4 (a mix of symptoms) less likely to be found in older adults (relative risk ratios for clusters 3-4 ranging from 0.10-0.34, p < 0.001 vs. 18-39 year-olds). CONCLUSIONS:Within the limits of this observational study, we conclude that in community-dwelling older adults, aging alters the prevalence and pattern of reported Long COVID.

We evaluated the in vivo activity of nikkomycin Z against central nervous system coccidioidomycosis. Mice were inoculated intracranially with arthroconidia of Coccidoides immitis, and treatment with nikkomycin Z (50, 100, or 300 mg/kg orally TID) or fluconazole (25 mg/kg orally BID) began 2 days later. Each dose of nikkomycin Z and fluconazole significantly improved survival and reduced brain fungal burden compared with vehicle control. Further studies of nikkomycin Z against coccidioidomycosis are warranted. IMPORTANCE:Coccidioides species are endemic fungi that are capable of causing disease in patients with various comorbidities, as well as in otherwise healthy individuals. Treatment options for coccidioidomycosis are suboptimal, as azole antifungals may be limited by drug interactions and adverse effects due to interactions with enzymes found in humans and other mammals. Nikkomycin Z is an investigational agent that works against a target specific to the fungal cell wall (chitin), which is not present in the cells of humans or other mammals. In this study, we show that frequent oral administration of nikkomycin Z is effective in an experimental model of central nervous system coccidioidomycosis. Further studies of nikkomycin Z against coccidioidomycosis may be warranted.

Introduction Since the publication of the ARUBA trial, interventional management of cerebral arteriovenous malformations has become an area of debate. Treatment practices may have changed based on data from this recent trial which suggested that the risk of AVM treatment is greater than medical management in unruptured AVMs. To assess the 'real world' experience with interventional AVM outcomes, we compared outcomes of ARUBA eligible patients from the NVQI-QOD registry database to the ARUBA trial results. Methods In an IRB approved study, the NVQI-QOD AVM registry database was queried for treated patients between 2017 to present with the following inclusion criteria: age > 18 years, baseline mRS> 1, unruptured AVMs. 174/364 patients were ARUBA eligible and were included in the analysis. Patients were divided into embolization alone, microsurgery with or without embolization, and gamma knife radiation therapy with or without embolization. Primary outcomes of ischemic/hemorrhagic stroke or death were analyzed with a mean follow up time of 5.8 months (range 1 to 128 months). Results A total of 14 (8.0%) of patients that underwent any type of intervention suffered stroke or mortality. The risk of stroke or death was 6.8% (5 of 74) for microsurgery, 5.4% (2 of 37) for gamma knife, and 10.9% (7 of 64) for embolization alone. Annual stroke or death rates for all treatments were 7.5% (13 of 174) at one year and 0.57% (1 of 174) at 2 years. Conclusion ARUBA eligible patients from the NVQI-QOD registry demonstrate a significantly lower risk of stroke or death with intervention of 8.0% (N=174) compared to the 30.7% (N=114) ARUBA trial interventional risk, and is nearly equivalent to the ARUBA trial medical management risk of 10.1% (N=109) over 33 months. Disclosures N. Moore: 1; C; SNIS Joe Niekro Research Grant. R. Abdalla: None. T. Patterson: None. Y. Moazeni: None. P. Rasmussen: 2; C; Blockade Medical, Covidien/Medtronic, Stryker Neurovascular, Perflow Medical. 4; C; Perflow Medical. G. Toth: None. M. Bain: 2; C; Stryker Neurovascular. S. Ansari: None. S. Hussain: 2; C; Pulsar Inc.