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Aluminum nitride (AlN) is an ultrawide-bandgap semiconductor whose large intrinsic band gap limits low-energy interband optical absorption. This work compares Ce substitution at the Al site, C substitution at the N site, and Ce-C co-substitution in wurtzite AlN to clarify how Ce 4f/5d states and C 2p states modify the local structure, band-edge electronic states, and optical response. Among five neutral CeAl-CN configurations considered in a 2 × 2 × 2 supercell, the nearest-neighbor Ce-C pair has the lowest total energy, with the other configurations lying 6.6-17.7 meV higher. The selected Ce-C pair also has a negative binding energy of -3.26 eV relative to the corresponding isolated single-substitution reference supercells. Structural relaxation shows lattice expansion after substitution, with the largest volume increase of 7.93% obtained for AlN:Ce-C. The calculated band gap of intrinsic AlN is 4.19 eV, whereas the effective electronic gaps of AlN:C, AlN:Ce, and AlN:Ce-C are 3.59, 2.18, and 2.04 eV, respectively. Since AlN:Ce-C is only 0.14 eV smaller in effective gap than AlN:Ce, the role of Ce-C co-substitution is interpreted mainly through defect-pair energetics, orbital redistribution, and local population changes rather than as a large additional band-gap narrowing. DOS/PDOS and population analyses show that C 2p states mainly modify the occupied valence-edge region, Ce 4f/5d states contribute near the band-edge and conduction-band regions, and Ce-C co-substitution induces finite spin population on C together with a nonzero Ce-C bond population. The scissors-corrected optical spectra show increased low-frequency dielectric and refractive responses, with ε₁(0)/n(0) changing from 3.805/1.951 for intrinsic AlN to 4.449/2.109 for AlN:Ce-C, while AlN:C gives the largest low-frequency values of 4.530/2.128. Additional low-energy interband absorption and attenuation features appear especially in AlN:C and AlN:Ce-C, associated with defect-related transitions involving C 2p and Ce-related states. These changes are interpreted as calculated interband optical-response redistribution within the present neutral-defect supercell framework, not as direct evidence of device-level optoelectronic performance. First-principles calculations were performed using the CASTEP module in Materials Studio. The exchange-correlation interaction was described using the generalized gradient approximation with the Perdew-Burke-Ernzerhof functional, and on-the-fly-generated ultrasoft pseudopotentials were employed. Intrinsic AlN, AlN:Ce, AlN:C, and AlN:Ce-C were constructed from a fully relaxed 2 × 2 × 2 wurtzite AlN supercell containing 32 atoms. Single-doped models were constructed by replacing one Al or one N atom, corresponding to 6.25% substitution on the relevant sublattice. The co-doped model contains one CeAl-CN pair, corresponding to xCe = yC = 0.0625 in Al1-xCexN1-yCy, or a combined sublattice substitution level of 12.5%. A plane-wave cutoff energy of 700 eV and a 4 × 4 × 3 k-point mesh were used. Intrinsic AlN was calculated using non-spin-polarized GGA-PBE, C-doped AlN using spin-polarized GGA-PBE, and the Ce-containing systems using spin-polarized GGA-PBE + U. A Hubbard U correction of 5 eV was applied only to the Ce 4f orbitals. Band structures, TDOS/PDOS, Mulliken and Hirshfeld population analyses, representative bond populations, and optical properties were calculated. The dielectric function, complex refractive index, absorption coefficient, and reflectivity were obtained within the linear-response framework using a 2.01 eV scissors correction only for optical-property calculations.

Despite the great success that Kohn-Sham density functional theory (KS-DFT) has achieved, the delocalization error remains a major challenge for commonly used density functional approximations, resulting in systematic errors in ionization energies, electron affinities, band structures, and charge distributions. A recently developed localized orbital scaling correction (LOSC) method, namely, linear response LOSC (lrLOSC), addresses these challenges by incorporating a functional correction that includes the screening effect and orbital localization within the LOSC framework. The method has been shown to provide accurate descriptions of bulk systems and core-level binding energies in small molecular systems. In this work, we extend the applicability of lrLOSC to a broader range of molecular systems, spanning various sizes, with a focus on the corrections to valence orbital energies and total energies. To enable the calculation of large chemical systems, we developed an efficient implementation of lrLOSC with computational costs comparable with standard KS-DFT calculations. Numerical results show that while screening provides modest improvements for small molecules, it becomes critical for achieving high accuracy in larger molecules, from linear to three-dimensional systems. With the screening effect being well captured in a unified way, lrLOSC provides accurate descriptions for a wide range of chemical systems, including organic molecular systems of varying sizes and transition-metal oxide complexes, establishing it as a powerful tool for enhancing the reliability of computational simulations of chemical systems.

Both glucagon-like peptide-1 (GLP-1) receptor agonists and bariatric surgery (BS) are interventions that result in weight loss prior to total knee arthroplasty (TKA). We sought to compare 90-day postoperative complications between TKA patients with a history of GLP-1 use versus those who underwent BS prior to TKA. Patients undergoing primary TKA for osteoarthritis from 2005 to 2025 were identified from the TriNetX Research Network. Patients who underwent BS 6 months to 1 year prior to TKA were propensity score-matched 1:1 to patients who initiated GLP-1 therapy during this same time period based on age, sex, race, chronic kidney disease, rheumatoid arthritis, hypertension, heart disease, diabetes and body mass index (BMI) measured 6 weeks prior to weight-loss intervention. A total of 1650 patients were included in each cohort with 90-day follow-up. The risk of various 90-day complications associated with each weight-loss intervention was compared utilizing univariate analyses. Rates of individual medical and surgical complications were largely comparable between cohorts; however, compared with the BS group, the GLP-1 cohort had significantly lower rates of deep vein thrombosis/pulmonary embolus (2.18% vs. 4.42%, p&#x2009;<&#x2009;0.001), transfusion (0.30% vs. 1.03%, p&#x2009;=&#x2009;0.016), any surgical complication (1.64% vs. 3.45%, p&#x2009;=&#x2009;0.001), any medical complication (9.09% vs. 12.30%, p&#x2009;=&#x2009;0.003) and readmission/emergency department visit (21.33% vs. 25.33%, p&#x2009;=&#x2009;0.007). Compared to obese controls without intervention prior to TKA, both the BS and GLP-1 cohorts had comparable rates of all medical and surgical complications. There were largely comparable rates of complications between patients who underwent BS and those who initiated GLP-1 agonists prior to TKA, although GLP-1 use was associated with lower rates of select complications. Patients who choose GLP-1 agonists or BS can expect similar complication rates and comparable outcomes relative to obese patients who elect for no preoperative intervention prior to TKA. Level III, retrospective cohort study.

Caregivers of individuals with spinal cord injury (SCI) frequently assume demanding roles immediately after SCI, placing them at risk for burden, depression, and diminished well-being. Few interventions have been tailored to support caregivers during this critical initial transition period. This randomized clinical trial developed and tested the Transition Assistance Program (TAP), which provides structured telehealth support targeting caregiver psychosocial adjustment and care quality as they learn to be caregivers for the first time. The study recruited caregiver-care recipient dyads from two acute SCI units at an academic medical center and a Veterans Affairs hospital. Dyads (N&#x2009;=&#x2009;31 completing follow-up) were randomized to TAP or usual care. The TAP consisted of five sessions (one in person before discharge, four via telehealth-to-home) combining structured education, a caregiver guidebook, and supportive problem-solving. Primary outcomes - caregiving quality, depression, relationship satisfaction, and positive affect and well-being - were assessed at baseline, 2, and 4 months post-discharge. Caregivers in the TAP group reported higher caregiving quality across the two follow ups (P&#x2009;=&#x2009;.041, &#x3b7;p&#xb2;&#x2009;=&#x2009;.141), a large effect. For all other caregiver and patient outcomes, TAP participants consistently demonstrated more favorable scores with small-to-medium effect sizes, though differences did not reach statistical significance. The TAP improved caregiver-reported caregiving quality and showed promising effect sizes across multiple psychosocial outcomes. Findings support the feasibility and potential utility of telehealth-based caregiver interventions during the transition from inpatient rehabilitation to home, warranting larger-scale trials.Trial registration: ClinicalTrials.gov identifier: NCT03244098.

The determination of quartic force fields for use in vibrational second-order perturbation (VPT2) calculations, currently available in numerous electronic structure packages, becomes very expensive as the size of the molecule increases, especially if high-level coupled-cluster theory is used. Machine-learned potentials (MLPs) for large molecules and clusters offer a viable alternative to obtaining the quartic force field (QFF). Here, we report Fortran and Python software to determine the QFF and perform VPT2 calculations of energies from the MLPs. We describe this software and then apply it to H2O and protonated oxalate as the test cases. The Fortran software is applied to 21-atom aspirin using a fast MLP reported by us. Despite the fact that there are 32,509 unique cubic force constants for aspirin, the computer time to calculate them using this MLP is trivial, i.e., around 1 min. The new software provides an efficient way to calculate quantum anharmonic energies, using the established VPT2 methodology, for machine learned potentials of large molecules.

End-of-life (EOL) costs account for a disproportionately large share of total Medicare expenditures. However, there is a lack of research examining EOL costs of patients in the US across the full spectrum of ages. To report EOL costs and the monthly health care cost trajectory in the year before death across age groups in the US. This cohort study included individuals aged 0 to 75 years or older identified from the MarketScan Mortality Detail file who died from January 2016 to December 2024. Data were linked to the MarketScan Commercial Claims and Encounters and MarketScan Medicare databases. Age at death, categorized as 18 years or younger, 19 to 49 years, 50 to 64 years, 65 to 74 years, or 75 years or older. Total and out-of-pocket (OOP) health care costs (in 2025 US dollars) in the 365 days before the date of death for patients who died in a hospital and in the month of death and the 11 months prior for patients who did not die in a hospital. Both actual and standardized (ie, Medicare pricing) costs were determined. A generalized linear model with &#x3b3; family and log link and quantile regression were applied to compare mean and median costs, respectively, across age groups. Among 313&#x202f;649 individuals who died from 2016 to 2024 (51.1% male; mean [SD] age at death, 77.5 [14.3] years), median actual EOL costs from the unadjusted analysis were $50&#x202f;599 (IQR, $21&#x202f;258-$109&#x202f;121) overall; the adjusted actual median costs were highest for the youngest age group (&#x2264;18 years; $165&#x202f;030 [95% CI, $160&#x202f;110-$169&#x202f;951]) followed by the group aged 50 to 64 years ($132&#x202f;542 [95% CI, $131&#x202f;698-$133&#x202f;386]) and were lowest in the oldest age group (&#x2265;75 years; $48&#x202f;308 [95% CI, $47&#x202f;945-$48&#x202f;671]). After standardizing costs to Medicare pricing, adjusted median EOL costs were $49&#x202f;259 (IQR, $20&#x202f;889-$103&#x202f;317) overall and were highest in the youngest age group (&#x2264;18 years; $104&#x202f;386 [95% CI, $100&#x202f;144-$108&#x202f;628]) followed by the group aged 50 to 64 years ($99&#x202f;182 [95% CI, $98&#x202f;454-$99&#x202f;909]), with the lowest median costs observed in the oldest age group (&#x2265;75 years, $48&#x202f;308 [95% CI, $47&#x202f;945-$48&#x202f;671]). Unadjusted OOP costs were also higher in younger age groups: 18 years or younger, $4274 (IQR, $1979-$6713); 19 to 49 years, $4063 (IQR, $1640-$6638); 50 to 64 years, $4048 (IQR, $1954-$6556); 65 to 74 years, $1793 (IQR, $1081-$2580); 75 years or older, $1509 (IQR, $793-$2299). Monthly cost trajectories showed EOL costs were persistently higher in younger age groups, with the sharpest increase within 3 months of death and peaking in the month of death (eg, mean total cost of $220&#x202f;819 [95% CI, $195&#x202f;716-$245&#x202f;923] in the last month for patients aged &#x2264;18 years). A much higher percentage of the youngest group (82.3%) died in a hospital compared with the oldest group (20.8%). In this cohort study of EOL costs across age groups, total and OOP costs were substantially higher in patients younger than 65 years vs 65 years or older, even after standardizing to Medicare pricing. Death in a hospital was more common in the younger age groups. The findings suggest attention to EOL care should be expanded beyond Medicare beneficiaries to patients who die young.

This study evaluates the techno-economic and environmental performance of a sequential system based on fixed-bed column adsorption using magnesium-impregnated rice husk biochar (RHB-Mg) for nutrient removal from wastewater, coupled with a prospective assessment of its reuse as a soil amendment in irrigated rice systems. Scale-up based on laboratory data resulted in a treatment capacity of 4.32&#x2009;m3/day and a biochar requirement of 56.91&#x2009;kg/day. The system effectively reduced nitrate and phosphate concentrations below regulatory limits under continuous operation, demonstrating high adsorption performance. The techno-economic analysis over a 20-year period revealed that operational costs are primarily driven by magnesium chloride consumption, which strongly influences overall economic feasibility. Life cycle assessment (LCA) identified biochar production as the main environmental hotspot, contributing the highest impacts across multiple categories due to energy demand. Furthermore, literature-supported and LCA-based evidence indicates that the reuse of nutrient-enriched biochar could potentially reduce fertilizer demand (prospective scenario), decrease irrigation requirements, and contribute to a potential climate change benefit through carbon storage, with an estimated reduction of -1.34-kg CO2 eq per kg of RHB-Mg applied to soil. However, this stage was evaluated as a prospective scenario and was not experimentally validated. Overall, the proposed system demonstrates strong potential within a circular-economy framework; however, process optimization-particularly in reagent consumption and energy integration-is required to enhance large-scale sustainability and economic viability.

Autism spectrum disorder (ASD) has been repeatedly linked to gut microbiota alterations, yet mechanistic insight remains limited by the scarcity of ASD-specific cultured isolates. Here, we performed large-scale gut microbial culturomics on fecal samples from 41 children with ASD and 12 typically developing (TD) controls, generating 1,724 isolates across six phyla. Longitudinal culturomics profiling was further conducted in 17 ASD children undergoing a 9-week fecal microbiota transplantation (FMT) intervention. All isolates underwent 16S rRNA sequencing and non-redundant clustering to assess species-level diversity, ASD-TD differences, and microbial dynamics associated with clinical response. ASD children harbored a distinct culturable microbiota enriched for Shigella flexneri and Shigella boydii, whereas TD children were enriched in beneficial taxa, such as Bifidobacterium catenulatum subsp. and other health-associated species. Notably, 20 species isolated from ASD children and 20 from TD children were absent from major existing gut microbiota biobanks, thereby expanding the cultivable repertoire. Among FMT participants, clinical responders exhibited increased alpha diversity, progressive enrichment of TD-associated beneficial taxa, such as Bacteroides fragilis, Anaerostipes hadrus, Parabacteroides merdae, and Turicibacter sanguinis, and a marked reduction of ASD-associated Shigella flexneri and Shigella boydii, whereas non-responders showed minimal shifts. Acquisition of TD-enriched strains at week 9 was strongly correlated with clinical improvement, suggesting that species-level ecosystem remodeling may contribute to FMT efficacy. This work establishes one of the first ASD-focused gut microbial culturomics resources, identifies Shigella as a potential ASD-associated taxon, and provides foundational evidence and testable mechanistic hypotheses for future microbiome-based interventions in ASD.IMPORTANCEMost autism spectrum disorder (ASD) microbiome studies rely on sequencing, which identifies associations but lacks live strains needed for mechanistic tests. We cultured 1,724 isolates from ASD and typically developing (TD) children, providing an ASD-focused, strain-level resource. ASD samples showed a significantly higher prevalence of Shigella flexneri. Longitudinal profiling during fecal microbiota transplantation (FMT) showed that clinical responders gained TD-enriched taxa and lost Shigella spp., and these shifts correlated with symptom improvement. This resource enables functional assays and gnotobiotic studies with ASD-relevant strains and provides a foundation for rational microbiome-based interventions.

Experimental medicine studies, small, mechanistically focused investigations, have historically driven key discoveries in human physiology and pharmacology. Despite their foundational role, these studies are increasingly marginalised in today's drug development environment due to economic pressures, regulatory conservatism, and an overemphasis on statistical endpoints from large-scale trials. This article traces the historical roots and enduring value of experimental medicine, distinguishes it from current early phase drug development studies, and explores the structural forces behind its decline. N-of-1 trials are discussed as a systematic extension of these principles, offering precision insights at the individual level. We apply this discussion to chronic kidney disease (CKD), a field where slow progression and heterogeneous pathophysiology make early mechanistic studies especially valuable. We argue that bypassing such studies in favour of speed represents a strategic gamble that may misdirect costly late-phase trials. Integrating mechanistic insights with statistical power is not superfluous, but essential, particularly in complex diseases like CKD where understanding why and how interventions work may matter as much as whether they do. We acknowledge that achieving this vision necessitates overcoming significant structural, economic, and cultural barriers within the current drug development environment; however, the costs of inaction, manifest as trial failures, patient harm, and missed therapeutic opportunities, are potentially much greater.

Comorbid insomnia and sleep apnea (COMISA) is a highly burdensome phenotype with additive effects on symptoms, quality of life, and health outcomes. Although obstructive airway diseases (OAD)-including asthma and chronic obstructive pulmonary disease-commonly coexist with sleep complaints, the association between OAD and COMISA in large sleep-clinic cohorts remains unclear. We investigated whether OAD is independently associated with COMISA in a nationwide cohort undergoing full-night polysomnography (PSG). We analyzed 12,715 adults in the Turkish Sleep Apnea Database (TURKAPNE), a prospective, multicenter registry. Demographics, comorbidities, insomnia symptoms, and PSG parameters were compared between individuals with and without OAD, defined as self-reported, physician-diagnosed asthma or COPD. COMISA was defined as the coexistence of obstructive sleep apnea (apnea-hypopnea index&#x2009;&#x2265;&#x2009;5 events/h) and insomnia symptoms occurring "often" or "very often." Multivariable logistic regression was used to determine the independent association between OAD and COMISA. OAD was present in 12.2% of participants (n&#x2009;=&#x2009;1,546). COMISA prevalence was higher in those with OAD than in those without OAD (16.1% vs 10.8%, p&#x2009;<&#x2009;0.001). After adjustment for age, sex, body mass index, education, smoking status, and comorbidities, OAD remained independently associated with COMISA (adjusted odds ratio 1.19; 95% CI 1.06-1.35; p&#x2009;=&#x2009;0.004). Among participants with COMISA, individuals with OAD were older, more frequently female, more obese, and demonstrated shorter total sleep time, longer wake after sleep onset, higher periodic limb movement index, and poorer nocturnal oxygenation. In this nationwide sleep-clinic cohort, OAD was independently associated with COMISA. COMISA patients with OAD exhibited more adverse clinical and polysomnographic features. These findings highlight the multidimensional sleep burden in OAD and support integrated, personalized management strategies.

Hepatitis B virus (HBV) reactivation is a potentially severe and preventable complication of immunosuppressive therapy, particularly with anti-CD20 agents such as rituximab, underscoring the need for effective screening and prophylaxis to reduce adverse outcomes. We conducted a retrospective population-based cohort study using the Clalit Health Services database in northern Israel. Adult patients aged&#x2009;&#x2265;&#x2009;18&#xa0;years who received rituximab between 2005 and 2022 were included. HBV screening (HBsAg and anti-HBc), antiviral prophylaxis, and HBV reactivation events were evaluated. Timely screening was defined as testing performed within 90&#xa0;days before rituximab initiation. Temporal trends were analyzed using the Cochran-Armitage test, and predictors of reactivation were evaluated using Cox proportional hazards models, with the per-patient analysis considered the primary model. After exclusion of patients younger than 18&#xa0;years, a total of 11,888 adult patients received rituximab during the study period (mean age 61.6&#x2009;&#xb1;&#x2009;15.6&#xa0;years; 54.7% female). Only 10.5% of patients underwent timely HBV screening before treatment initiation, while 47.4% were never screened without time restriction and 89.5% had no HBV serology within 90&#xa0;days before rituximab initiation. Among screened patients, approximately 6.0% had evidence of current or prior HBV infection. Screening rates improved significantly over time (P&#x2009;<&#x2009;0.0001) but remained suboptimal across clinical settings. Antiviral prophylaxis increased over the study period but plateaued at approximately 50% among eligible patients. A total of 159 HBV reactivation events were identified, corresponding to an incidence of 1.06% per treatment event and approximately 1.3% per patient. Reactivation occurred predominantly among patients who had not undergone HBV screening. Multivariable analysis identified male sex as an independent predictor of HBV reactivation. Despite gradual improvement over nearly two decades, HBV screening before rituximab therapy remains insufficient in real-world clinical practice. Given that HBV reactivation is largely preventable with appropriate screening and antiviral prophylaxis, system-level interventions are needed to improve adherence to guideline-recommended care.

The need for accurate, cost-effective, non-invasive screening tests for colorectal cancer (CRC) persists. Repetitive genomic elements like Long Interspersed Nuclear Element-1 (LINE-1), due to their high copy number and cancer-associated alterations, present a promising but unexplored target in stool DNA for CRC detection. In this cross-sectional study, stool DNA was extracted from 38 patients with histologically confirmed CRC and 39 healthy controls. The concentration of human DNA was quantified via quantitative PCR targeting two short LINE-1 amplicons (55-bp and 60-bp). Diagnostic performance was evaluated using ROC curve analysis to determine sensitivity, specificity, and predictive values. The concentration of stool DNA, measured by LINE-1 qPCR cycle threshold (Ct) values, was significantly higher in CRC patients compared to controls (p&#x2009;<&#x2009;0.001 for both amplicons). The 60-bp LINE-1 amplicon demonstrated superior diagnostic accuracy with an area under the ROC curve (AUC) of 0.92 (95%CI 0.85-0.98), compared to 0.83 (95%CI 0.73-0.93) for the 55-bp amplicon. At the optimal cut-off (Ct&#x2009;&#x2264;&#x2009;24.19), the 60-bp marker achieved a sensitivity of 87.0%, specificity of 78.4%, a positive predictive value (PPV) of 71.4%, and a negative predictive value (NPV) of 90.6%. The 55-bp amplicon showed higher sensitivity (95.7%) but lower specificity (59.5%). Quantitative analysis of LINE-1 repetitive elements in stool DNA, particularly using a 60-bp amplicon, demonstrates excellent diagnostic accuracy for detecting CRC. This single-marker, qPCR-based assay represents a simple and potentially low-cost non-invasive strategy, warranting further validation in large-scale screening populations and assessment of its efficacy for detecting precancerous lesions.