Metabolic dysfunction drives hepatic progression in metabolic dysfunction-associated steatotic liver disease (MASLD), yet conventional binary metabolic syndrome (MetS) definitions may obscure dose-response risk of fibrosis. We evaluated the association between MetS severity and advanced fibrosis probability in a representative US MASLD cohort. Adults aged 20-74 years with ultrasound-defined MASLD in the Third National Health and Nutrition Examination Survey were analyzed. Exposure was the validated MetS severity Z-score (quartiles, percentile categories, and continuous percentile with restricted cubic splines). Outcome was the Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS)-defined advanced fibrosis probability (intermediate-to-high: NFS ≥ -1.455; high: NFS > 0.676). Complex survey logistic regression estimated adjusted odds ratios (aORs). Among 3036 participants, 29.6% had intermediate fibrosis probability and 5.2% had high advanced fibrosis probability. High fibrosis probability was most prevalent in non-Hispanic Black adults (8.0%) and least in Mexican Americans (2.6%; P value <.001). Approximately 2.5% of the low MetS severity group had a high probability of advanced fibrosis compared with 11.4% in the very high MetS severity group (P value <.001). Each one-quartile decrease in MetS severity was associated with 21% (aOR = 0.79; 95% confidence interval [CI]: 0.68-0.91) and 32% (aOR = 0.68; 95% CI: 0.48-0.96) lower odds of intermediate-to-high and high probability of advanced fibrosis, respectively. In dose-response analyses, advanced fibrosis risk rose modestly through midrange severities and accelerated beyond the 70th severity percentile, reaching aOR of 3.59 (95% CI: 2.74-4.70) at the 90th vs the 50th percentile. MetS severity demonstrates a graded and nonlinear association with advanced fibrosis probability in MASLD. A continuous metabolic-burden measure may enhance upstream triage and risk stratification alongside existing noninvasive pathways.
Wildlife rehabilitation plays a central role in the conservation of threatened primates, yet parasite dynamics during captivity are rarely reported, particularly in relation to release readiness. We investigated gastrointestinal helminth infection patterns in rehabilitating Javan slow lorises (Nycticebus javanicus), a Critically Endangered species heavily impacted by the illegal wildlife trade. Using repeated fecal sampling (147 samples from 19 adults) and Bayesian mixed-effects models, we examined parasite richness, Shannon diversity, infection probability, and egg-shedding intensity in relation to release readiness status, sex, housing condition, and time since anthelmintic treatment. Four nematode taxa identifiable through egg morphology were detected: Strongyloides spp., strongylids, oxyurids, and Trichuris spp. Parasite richness and Shannon diversity showed no credible associations with release readiness or other host and management variables. In contrast, infection probability for Strongyloides spp. and strongylids increased with time since deworming, and Strongyloides egg counts exhibited a similar temporal pattern, consistent with post-treatment reinfection dynamics. Release readiness did not predict detection probability or parasite intensity for any parasite group, despite marked differences in captivity duration and health history between individuals deemed ready for release or not. These findings indicate that gastrointestinal helminth dynamics in rehabilitating slow lorises are driven primarily by treatment-related temporal processes and individual-level heterogeneity rather than coarse host classification. They also highlight the need for longitudinal parasite monitoring and for future work evaluating how infection dynamics, management interventions, and host health relate to rehabilitation and translocation outcomes.
The SYMPATICO trial demonstrated that ibrutinib combined with venetoclax significantly improved progression-free survival in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL). This study evaluated the cost-effectiveness of the combination of ibrutinib-venetoclax for R/R MCL from the healthcare perspectives of China and the United States (US). A partitioned survival model with a 35-year simulation time horizon was developed to compare the cost-effectiveness of ibrutinib-venetoclax versus ibrutinib-placebo. Primary outcomes included total costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of the model was evaluated through one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). Base-case analysis showed that the ICER of ibrutinib-venetoclax versus ibrutinib-placebo was $128,183.93/QALY in China, which was significantly higher than the willingness-to-pay (WTP) threshold of $40,334/QALY. It was still not cost-effective below the $150,000/QALY WTP threshold in the US, with an ICER of $951,082.87/QALY. OWSA demonstrated the robustness of the model. PSA showed that ibrutinib-venetoclax had a 0% probability of being cost-effective under the current WTP thresholds in China and the US. Price reduction analysis indicated that in China, reducing the price of venetoclax to 20% of its original cost could achieve cost-effectiveness with a 60.80% probability. In the US, a combined price reduction of ibrutinib and venetoclax to 22.53% of their original costs is necessary to achieve a 50% probability of cost-effectiveness. Ibrutinib-venetoclax is unlikely to be cost-effective versus ibrutinib-placebo for R/R MCL in both China and the US.
Canonical babbling is a key stage in speech development, and atypical canonical babbling can be an early sign of speech disability. Speech onset delays and language disability are frequent in autism, but studies that focus on the rate or onset of canonical babbling report mixed findings. Quantity-based metrics can obscure qualitative differences in canonical babbling productions, such as, and more specifically, the sequential organization of syllable transitions, which may be more sensitive to early group differences. Using at-home recordings of thirty-six 18-month-olds (autistic: n = 10, non-autistic: n = 26), we analyzed transition probabilities of consonant categories (stops, nasals, fricatives, liquids, and glides) within canonical babblings. In both autistic and non-autistic children, the probability of producing a consonant depends primarily on the immediately preceding one. We did not find any significant difference in the frequency of canonical babbling between autistic and non-autistic children. However, transition structures differed overall (Frobenius distance), and autistic children's sequences were more predictable and less varied (lower Shannon entropy rate), whereas the tendency to repeat the same category (stay probability) did not differ between groups. Finally, several specific consonant transitions were numerically different, but only one (liquid to the end of the utterance) remained reliable after correction and covariate control. Canonical babbling at 18 months of age reflects local, first-order constraints; in autism, global organization appears more constrained, even though autistic children may babble just as much as their non-autistic peers. Our results provide promising evidence that the structure of babbling, rather than its sheer frequency or segmental diversity, distinguishes the two groups and deserves further exploration. https://doi.org/10.23641/asha.32513430.
Here, we investigate whether stochastic resetting, a technique that periodically reverts training to beneficial checkpoints, recently explored in the context of deep learning with noisy labels, can improve the decoding of anomalous diffusion trajectories, a task made challenging by noise and limited trajectory lengths, which often render subtle differences between diffusion processes indistinguishable. First, we find that incorporating stochastic resets of neural network parameters improves the validation loss across different hyperparameters and noise levels, confirming its applicability in trajectory decoding tasks. Second, we find that the relative benefit of resetting increases with trajectory length, and we offer a mechanistic explanation supported by minibatch-gradient ensemble diagnostics that links this observation to the underlying optimization dynamics. Furthermore, we observe that there exists an optimal resetting probability that yields the best performance, highlighting the importance of tuning this hyperparameter. Building on this insight, we introduce time-varying resetting mechanisms that dynamically adjust the resetting probability during training. Our results show that these mechanisms often match or surpass the performance of the best fixed-resetting probabilities and offer a solid basis for designing effective dynamic resetting strategies for regularization.
Accurate estrus detection in grazing crossbred dairy cows (Zebu × Taurine) remains challenging in Brazil, and automated activity monitoring (AAM) systems may be a viable alternative. This study evaluated the effects of management and environmental factors on AAM performance for estrus detection in grazing Girolando cows. Nonpregnant 5/8 Gir × Holstein cows (n = 25) were monitored during both dry and rainy seasons. During the dry season, cows were managed in semiconfinement with corn silage supplementation. In the rainy season, they grazed Panicum maximum cv. Mombaça pastures with or without eucalyptus trees. Each cow wore an AAM collar (CowMed, Brazil), and after individual baseline calibration, cows followed a timed artificial insemination (TAI) protocol. A statistical model included season, location, parity, and detection method (AAM, visual observation [VO], adhesive patches [APs]) as fixed effects. Cow and cow × season interaction were random effects. Multiparous cows had higher estrus detection probabilities (97%) compared to primiparous cows (85%), regardless of method, location, or season. AAM detection probability was higher during the rainy season (98%) than during the dry season (73%). For AP, the detection probability was 80% in the rainy season and 97% in the dry season. VO detection remained stable at 92% in the dry season and 95% in the rainy season. Based on corpus luteum (CL) presence, AAM sensitivity and accuracy were 85% and 75%, respectively, while specificity was 33%. Parity and seasonal management significantly influenced AAM performance. The generally low specificity across detection methods highlights the need for improved algorithms and integrated estrus detection strategies in grazing systems.
This study aimed to develop and validate a clinically applicable predictive model for estimating the probability of intensive care unit (ICU) readmission within 48 hours following ICU discharge in patients with sepsis. The model's predictive performance was evaluated across development and validation cohorts. Clinical data from patients with sepsis-classified according to 48-hour ICU readmission status-were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database using structured query language. Propensity score matching was applied to balance baseline covariates and reduce confounding between comparison groups. Candidate variables were identified through univariate analysis and refined using least absolute shrinkage and selection operator regression. A logistic regression-based predictive model was subsequently constructed and validated using an independent dataset. The predictive model was developed using clinical data from 1,002 patients and validated in an independent external cohort of 100 patients. The final model incorporated 6 predictors, including the 24-hour serum albumin level at ICU admission, 24-hour activated partial thromboplastin time, antibiotic use, mechanical ventilation, heart rate within 24 hours prior to ICU discharge, and the Acute Physiology Score III. The model demonstrated robust predictive performance, with C-index values of 0.82 in the development cohort, 0.81 in the internal validation cohort, and 0.76 in the external validation cohort. The predictive model demonstrated reliable performance in estimating the probability of ICU readmission within 48 hours among patients with sepsis following ICU discharge. The variables incorporated into the model are routinely collected in clinical practice, supporting its feasibility for early risk stratification and targeted interventions aimed at reducing early ICU readmission rates.
Biopsy-based transcriptomics (BBT) supports antibody-mediated rejection (AMR) diagnostics, but Banff 2022 probable AMR and donor-specific antibodies (DSA)-/C4d-microvascular inflammation (MVI) remain unvalidated by BBT. We analyzed 562 kidney allograft biopsies from Prague and Zurich by histology and Molecular Microscope Diagnostic System (MMDx). Biopsies were classified into the following: (i) active AMR-spectrum lesions without transplant glomerulopathy (cg) (active AMR, probable AMR, MVI, DSA-/C4-); (ii) combined active-chronic lesions with cg (chronic-active AMR, probable AMR with cg, MVI, DSA-/C4d- with cg); (iii) chronic AMR, defined by cg without active lesions; and (iv) controls without rejection. Molecular AMR was detected in 24% of probable AMR and 23% of probable AMR with cg biopsies, 43% of MVI, DSA-/C4d-, 51% of active AMR, 56% of MVI, DSA-/C4d- with cg, and 63% of chronic-active AMR, but was rare in chronic AMR (6%). AMR probability classifier (AMRprob) scores were higher in probable AMR than in controls and similar between chronic AMR and controls. AMRprob scores were comparable among active AMR, chronic-active AMR, and MVI, DSA-/C4d- groups, all of which exhibited elevated T cell-mediated rejection (TCMR) prob scores compared with probable AMR and controls.Least absolute shrinkage and selection operator-penalized Cox regression predicting 3-years graft survival trained in the Zurich cohort showed similar performance of molecular (cgprob, ctprob, tprob, acute kidney injury [AKI]score) and histologic model (Banff cg, interstitial inflammation [ci], tubular atrophy [ct], and tubulitis [t]) (concordance 0.84 vs. 0.82), with the external validation in the Prague cohort (0.78 vs. 0.75). BBT primarily reflects MVI rather than DSA and is particularly informative in probable AMR and MVI-positive biopsies.
Amphibian populations are undergoing global declines, with infectious diseases playing a major role in these losses. While chytridiomycosis has been widely studied, other pathogens, such as mesomycetozoean parasites, are increasingly recognized as potential contributors to amphibian health deterioration. In this study, we investigated the seasonal dynamics of Amphibiocystidium sp. infection in the palmate newt (Lissotriton helveticus) during its aquatic breeding period in western France. From January to July 2023, across 12 sampling sessions and 585 captured individuals, we monitored host morphology, body condition, and infection status. We found strong seasonal variation in host traits, with body mass and condition declining over the breeding season, particularly in females. Infection prevalence and cyst intensity peaked at the end of March, and were not observed after the end of May. Smaller individuals were more likely to be infected, and infected females exhibited higher parasite loads than males. Additionally, infection probability increased with body condition in males only. The temporal restriction of infection suggests that environmental factors and host aggregation during breeding may play a key role in transmission.
Detecting pause events in single-molecule trajectories is essential for extracting kinetic information but remains challenging in noisy measurements. Here, we present a pause-detection method based on model selection using the Bayesian Information Criterion. The approach operates directly on raw trajectories, requires no preprocessing, and does not rely on user-defined parameter tuning. We provide a rigorous analysis of detection sensitivity that quantifies the probability of missing events under given experimental conditions, and the method naturally accommodates missing data in trajectories. Benchmarking shows that the approach outperforms commonly used pause-detection and change-point-detection strategies across simulated and experimental datasets. The method provides a robust and general framework for pause and change-point detection in single-molecule trajectories and is broadly applicable to single-molecule measurements obtained with magnetic tweezers, optical tweezers, and single-particle tracking.
The Bornean ferret badger (Melogale everetti) is one of Southeast Asia's most geographically restricted carnivores and is listed as Endangered, yet its ecology, distribution and conservation needs remain poorly understood. We conducted multi-site camera-trap surveys across Sabah's western mountain massif-the species' only confirmed area of occurrence-and integrated these data with multi-scale habitat suitability modelling and landscape connectivity analyses to refine its probable range, habitat associations and movement potential. Surveys yielded 407 independent detections from 60 camera stations, including the first confirmed records from Nuluhon-Trusmadi Forest Reserve, extending the verified distribution eastward beyond the Kinabalu-Crocker axis. Estimated detection probability per sampling occasion was generally low, but occupancy modelling indicated widespread site use, with highest model-based occupancy in Tenompok Forest Reserve and a mixed farmland site, and similarly high values in adjacent Kinabalu Ecolinc and southern Kinabalu Park. Habitat suitability was primarily associated with topographic position index and soil properties, suggesting edaphic and landform associations consistent with fossorial foraging ecology. The Sunda stink badger (Mydaus javanensis), an ecologically similar musteloid, was detected in only two highland areas, both of which lacked or supported very low ferret badger occurrence; this segregation is consistent with (but not definitive evidence for) interspecific competition. Connectivity analyses revealed contiguous Bornean ferret badger movement zones within core habitat patches but no functional corridors between them, highlighting the importance of the Kinabalu Ecolinc for demographic exchange. Model-based estimates of Area of Occupancy (2424 km2) and Extent of Occurrence (4795.6 km2) exceed previous IUCN values but remain consistent with Endangered status. Our findings identify priority upland conservation areas, emerging barriers to connectivity, and provide a robust basis for conservation planning in Sabah's montane landscapes.
Background Stroke is a leading cause of long-term disability worldwide, with a growing number of survivors requiring assistance with daily activities. In resource-constrained settings, this responsibility is frequently assumed by informal caregivers, potentially leading to caregiver burden and adverse mental health outcomes. However, data from underserved regions remain limited. Objective To determine the prevalence of caregiver burden among primary informal caregivers of patients with stroke sequelae and to explore its relationship with sociodemographic factors and depressive symptoms. Methods A cross-sectional study with an exploratory analytical component was conducted at a secondary-level hospital of the Mexican Social Security Institute in southern Mexico between January 2024 and June 2025. Primary informal caregivers of patients with stroke sequelae were included using a non-probability consecutive sampling strategy. Caregiver burden was assessed using the Zarit Burden Interview (ZBI), and depressive symptoms were evaluated using the Zung Self-Rating Depression Scale (SDS). Descriptive statistics were used to summarize the data. Comparisons between caregivers with and without burden were performed using the Chi-square test for categorical variables. Continuous variables were compared using the Mann-Whitney U test. Results A total of 57 caregivers were included (median age 47 years [q25-q75: 42-58]); 47 (82.5%) were female. The prevalence of caregiver burden was 50 (87.7%), while 25 (43.9%) participants exhibited depressive symptoms. Caregivers with burden were older than those without burden (median 47 vs. 41 years; p = 0.027). A significant association was observed between caregiver burden and relationship to the patient (p = 0.012), with children and spouses more frequently affected. Depressive symptoms were present in 25 (50.0%) caregivers with burden and in 0 (0%) of those without burden (p = 0.013). Conclusions Caregiver burden is highly prevalent among informal caregivers of stroke survivors in this resource-limited setting and is closely related to the presence of depressive symptoms. These findings underscore the importance of incorporating caregiver assessment into routine clinical practice and support the need for strategies aimed at improving caregiver support and preparedness, particularly in underserved contexts.
This study aimed to compare debridement strategies for chronic lower-extremity wounds using a systematic review and Bayesian network meta-analysis. This study followed the PRISMA-NMA guidelines. PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang, and VIP were searched from January 1990 to February 2026. Randomized controlled trials involving venous leg ulcers, arterial or ischemic ulcers, mixed arterial-venous ulcers, or diabetic foot ulcers were included. The outcomes included wound healing, complete debridement, pain score, procedure time, and time to healing. Pairwise meta-analysis and Bayesian network meta-analysis were performed. Surface under the cumulative ranking curve (SUCRA) rankings were interpreted according to the clinical direction of each outcome. A total of 25 randomized controlled trials were included. For wound healing, biological debridement (BIO) had the highest ranking probability (SUCRA = 99.5%), followed by enzymatic debridement (ENZ) (83.1%) and mechanical debridement (MECH) (65.9%). For complete debridement, biological debridement ranked first (95.7%), followed by enzymatic debridement (70.9%), autolytic debridement (AUTO) (32.2%), and standard care (SC) (1.2%). For pain score, procedure time, and time to healing, lower values represented better outcomes; rankings for these endpoints were therefore interpreted in that direction. Enzymatic and autolytic debridement ranked more favorably for pain score, biological and ultrasound-assisted debridement (US) for procedure time, and biological and autolytic debridement for time to healing. Several comparisons had wide credible intervals, and certainty of evidence was limited by clinical heterogeneity, sparse networks, and methodological limitations. The comparative profile of debridement strategies varied by the outcome. Biological and enzymatic debridement ranked favorably for wound healing and complete debridement, whereas enzymatic and autolytic debridement were associated with lower pain scores. Ultrasound-assisted debridement may be more efficient in terms of procedure time. These findings should be interpreted cautiously because ranking probabilities do not establish clinically decisive superiority, especially when evidence is sparse or heterogeneous. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261341535.
To develop a simulation model to guide single embryo transfer (SET) versus double embryo transfer (DET) decisions by minimizing twin risk per transfer while maintaining treatment efficiency. This retrospective observational study included individuals undergoing SET or DET with frozen blastocysts in hormone replacement therapy. Three generalized estimating equation-based models were developed: ongoing pregnancy after SET (Model 1) and DET (Model 2), and twin pregnancy after DET (Model 3). Model 1 was constructed using propensity score-matched SETs comparable to DETs. The simulation aimed to identify the optimal transfer sequence for patients with multiple blastocysts using a stepwise optimization that selects SET or DET at each transfer while maximizing pregnancy probability and constraining twin risk below predefined thresholds. 5721 DET and 5719 matched SET cycles were included in the analysis. The ongoing pregnancy rate was 20.1% in matched SET and 25.1% in DET, while the ongoing twin pregnancy rate following DET was 5.5%. Area under the curve was 0.77, 0.73, and 0.82 for Model 1-3, respectively. Simulation demonstrated an optimal sequence combining SET/DET under the individualized twin risk in a variety of scenarios (https://sites.google.com/view/det-simulator/). This model supports individualized embryo transfer planning by balancing treatment efficiency and twin risk.
To investigate the distribution patterns of physical activity levels, perceptions of physical activity and the social support environment among secondary school students; to examine the associations between students' physical activity levels and factors at the individual, peer and parental levels; and to analyse the dynamic relationships between physical activity and the social support environment across different dimensions, such as gender, year group and school. Using convenience sampling-a non-probability sampling method-we surveyed 841 high school students using the Adolescent Physical Activity Questionnaire, the Physical Activity Perception Questionnaire, and the Adolescent Physical Activity Social Support Scale. Statistical analyses were conducted using SPSS Statistics 26.0 to construct models via stepwise and hierarchical regression. (1) As many as 46.0% of high school students reported low levels of physical activity. The mean peer support score for boys (14.46 ± 4.18) was higher than that for girls (12.55 ± 3.89). No significant differences were found in peer support or parental support across grade levels (p > 0.05). (2) There was no significant association between parental support and physical activity among secondary school students (p > 0.05). With regard to gender, there was a significant positive association between peer support and both perceptions of physical activity and levels of physical activity among boys (p < 0.01), whereas among girls, only the positive association with peer support was significant (p < 0.01). (1) High school students receive relatively little support from peers and parents; among them, boys receive more peer support than girls. (2) Peer support and perceptions of physical activity are significantly and positively associated with physical activity among secondary school students; this association exhibits different characteristics across gender groups, but no significant differences were found across year groups.
The threshold for ordering blood cultures and initiating empiric broad-spectrum antibiotic therapy is often low in pediatric cardiac intensive care units (CICUs). However, excessive blood cultures carry risks, including anemia, false-positive results, and contamination related to vascular access. Overuse of broad-spectrum antibiotics can lead to the development of multidrug-resistant bacteria. In this quality improvement initiative focused on diagnostic stewardship, a blood culture algorithm was developed to reduce unnecessary blood culture sampling in patients with low sepsis probability. All patients admitted to the CICU were included in the study. The preimplementation observation period spanned from January 2022 to June 2023, and the postimplementation observation period lasted from July 2023 to December 2025. There were 5,958 CICU admissions during the study period, with no statistically significant difference in the baseline clinical characteristics. The number of blood culture samples declined by 26% in the postimplementation period, from 111.9 to 82.8 per 1,000 patient-days (P < 0.001), and a centerline shift was observed after the 5-month mark in the statistical process control U-chart. No statistically significant change was observed in the central line-associated bloodstream infection rate per 1,000 line-days (1.7 versus 1.3, P = 0.26). A structured algorithm to support clinicians' decision-making for blood culture testing resulted in a statistically significant reduction in the number of blood cultures sent. The delayed centerline shift indicated that lasting change required complete practice adoption rather than mere intervention launch. This intervention was not associated with any safety concerns in clinical outcomes.
Reintroduction of oxaliplatin after first-line treatment might preserve treatment lines and could improve overall survival. We investigate whether oxaliplatin reintroduction (OXR) or paclitaxel-ramucirumab (PR) is preferred in terms of overall survival for patients with gastroesophageal adenocarcinoma who have disease progression on first-line treatment. We performed a target trial emulation with a propensity-scored inverse probability weighting approach to resemble a randomized controlled trial. Observational data was retrieved from the Netherlands Cancer Registry between 2015 and 2018, with a maximum follow-up until 2022. Patients were included if they received a fluoropyrimidine with oxaliplatin in first-line and as subsequent treatment OXR or PR. There was at least 6 months between planned discontinuation of oxaliplatin and disease progression. We included 129 patients in our model and the weighted cohort was well balanced between the two groups. No statistically significant difference in overall survival was observed between treatment groups (HR: 0.76, 95% CI: 0.3-1.5; p = 0.36). Median overall survival was 9.2 months (95% CI: 3.7-25.1) for OXR and 7.9 months (95% CI: 2.8-11.5) for PR (p = 0.38). Exploratory subgroup analysis did not reach statistical significance. Patients in the OXR-group more often received one or more additional treatment lines, including second-line PR, than patients in the PR group, 47.7% versus 23.3%, respectively. OXR following prolonged response to first-line treatment was associated with similar overall survival compared with PR. In the absence of a demonstrated survival benefit for either treatment, these results propose oxaliplatin reintroduction as a potential option in selected patients.
Despite advances in novel therapeutic modalities, such as molecularly targeted agents and immunotherapies, the probability of success in Phase III oncology trials remains low. This study quantitatively characterized success probabilities of Phase III trials in oncology drug development and evaluated the factors associated with trial success. Phase III interventional oncology drug trials registered at ClinicalTrials.gov between 2007 and 2023 with publicly available primary endpoint results were included. Trial success was defined as the achievement of at least one primary endpoint, and tumor-specific success probabilities were calculated. Multivariable logistic regression analyses were conducted to assess the association between trial success and key trial characteristics. We analyzed 824 trials (358 successful and 466 unsuccessful). Overall success probabilities were comparable between solid tumors and hematologic malignancies, although substantial heterogeneity was observed across solid tumors, with particularly low success probabilities for central nervous system tumors and pancreatic cancer. Multivariable analyses showed that biomarker-based patient selection, more recently initiated trials, line of therapy, and the number of primary endpoints were associated with trial success. Trials evaluating molecularly targeted therapies and those with short-term evaluable endpoints showed higher success probabilities, whereas trials evaluating chemotherapy or assessing overall or event-free survival endpoints showed lower success probabilities. Phase III trial success in oncology is associated with tumor-specific characteristics and development-stage factors, including biomarker-based patient selection and trial design. These results provide quantitative evidence to inform decision-making and trial design in oncology drug development.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome caused by excessive immune activation. Secondary HLH may arise from infection, malignancy, or autoimmune disease. Cytomegalovirus (CMV) reactivation and systemic lupus erythematosus (SLE) are recognized triggers, but their coexistence as concurrent causes is extremely uncommon. Early recognition is critical, as delayed treatment significantly worsens outcomes. A 33-year-old woman presented with prolonged fever, oral ulcers, alopecia, arthralgia, and hepatosplenomegaly. Laboratory tests showed pancytopenia, hyperferritinemia (24 500 ng/mL), hypertriglyceridemia, and hypofibrinogenemia. Autoimmune evaluation confirmed new-onset SLE, while polymerase chain reaction verified CMV reactivation. She met six of eight HLH-2004 criteria, and her HScore was 301 (>99% probability), establishing secondary HLH triggered by CMV in the setting of SLE. Treatment included intravenous methylprednisolone followed by tapering oral prednisolone, cyclosporine, mycophenolate mofetil, hydroxychloroquine, and ganciclovir, with supportive antimicrobials and prophylaxis. The patient improved within 2 weeks, with normalization of ferritin and blood counts. Follow-up was weekly for 1 month, then biweekly, and monthly thereafter. This case highlights CMV-associated secondary HLH presenting in the context of newly diagnosed SLE in a young woman. Overlapping infectious and autoimmune features, along with cytopenias, delayed recognition. Her prompt clinical, hematologic, and ferritin response illustrates the benefit of early diagnosis and immunosuppressive plus antiviral treatment. Concurrent CMV-induced HLH and new-onset SLE are rare but should be considered in patients with unexplained fever and cytopenias. Maintaining a high index of suspicion and initiating prompt, targeted treatment are essential to achieve remission and prevent relapse.
Managing species in an uncertain future is a reality for natural resource decision makers. Climate change is expected to exacerbate threats such as habitat loss and disease, and cause phenological mismatches, but there is uncertainty in the magnitude of these effects. Amphibians are among the most threatened taxa on earth, and most species in North America are uniquely tied to water availability for breeding, larval development, thermal refugia, and food availability. Changes in water availability and temperature may result in phenological mismatches with one or more of these processes. Thus, quantifying the dependency of amphibians to water on the landscape is critical to understanding how species may respond, as well as understanding the interplay with other threats, such as disease. We developed a dynamic co-occurrence occupancy model to explore the effects of climate change on the breeding occurrence of boreal toads (Anaxyrus boreas) and the amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) in the southern Rocky Mountains (SRM). We derived novel covariates to test hypotheses related to multi-generational impacts of climate on the dynamics of both boreal toad breeding and Bd. We report estimates of current (2001-2019) and future (2055-2069) occupancy under a range of plausible climate scenarios. The probability of boreal toad breeding occurrence at a site in the SRM declined > 40% from 2001 to 2019, and further declines are likely under future scenarios, particularly as active season length increases. To help integrate this information into management, we developed a web-based decision support tool to summarize predicted future hydrological and occupancy conditions.