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Temporal trends of metastatic prostate cancer (mPCa) in the prostate-specific membrane antigen positron emission tomography (PSMA PET) era in the United States are not known. In the Surveillance, Epidemiology, and End Results (SEER) database (2018-2022), all PCa patients were identified. Estimated annual percentage change (EAPC) and multivariable logistic regression (MLR) models tested the effect of the PSMA PET era (2021-2022) on mPCa rate and its substages (M1a, M1b, M1c) rates. Overall, 236,723 PCa patients were identified. Of those, 20,450 (8.6%) harbored mPCa. mPCa rate increased from 7.9% in 2018 to 9.4% in 2022 (EAPC: +4.7%, p = 0.019). In MLR model, PSMA PET era independently predicted 1.1-fold (p < 0.001) increase in mPCa. Within mPCa patients, 1,564 (8.0%), 14,806 (72.0%), and 4,080 (20.0%) harbored M1a, M1b, and M1c substages. M1a and M1b substages rates increased in PSMA PET era (M1a: from 6.3% in 2018 to 9.1% in 2022, EAPC: +9.3%, p = 0.009; M1b: from 70.3% in 2018 to 74.7% in 2022, EAPC: +1.7%, p = 0.043), but not M1c (from 23.3% in 2018 to 16.2% in 2022, EAPC: -8.7%, p = 0.036). In MLR models, PSMA PET era independently predicted 1.3-fold increase (p < 0.001) in M1a, 1.2-fold increase (p < 0.001) in M1b, but 0.7-fold (p < 0.001) decrease in M1c. The introduction of PSMA PET resulted in an increase in the proportion of mPCa patients in the United States. Within those, M1a and M1b substages increased, but M1c decreased. These observations suggest a stage migration phenomenon, where low burden mPCa (M1a and M1b) is diagnosed more frequently at the expense of high burden mPCa (M1c).
Recent events, including increases in cost-of-living, may have influenced gambling behaviour and harm in Great Britain. This study aimed to describe trends in gambling frequency, harm from gambling, self-identified gambling problems, and treatment among British adults from 2021 to 2024. It also examined trends in weekly gambling and harm from gambling within priority sociodemographic groups. Data (pooled N = 50,872) came from the annual repeat cross-sectional online panel ASH Smokefree Great Britain Survey, weighted to reflect the British population. Time trends were assessed using multinomial and log-binomial regression, with survey year as predictor. Additional models assessed trends in subgroups (non-homeowner, socioeconomically disadvantaged, mental health treatment, smoking, vaping, cannabis use, exceeding drinking guidelines, age, gender, nation). Approximately half of adults gambled in the past year. Daily gambling increased from 1.1% (95% CI: 1.0-1.3) in 2021 to 1.7% (1.5-1.9) in 2024; treated gambling disorder also increased, from 0.9% (0.6-1.2) in 2021 to 1.6% (1.3-2.0) in 2024. The highest prevalence of weekly gambling was among those exceeding drinking guidelines (in 2024: 28.7%; 16.7-30.9) and those using cannabis (in 2024: 28.4%; 25.7-31.2). Younger people gambled less frequently but experienced higher rates of harm from others' gambling than older people. There was an increase in gambling activity and related harm. In absolute terms and assuming figures are representative, approximately 366,000 more adults in Great Britain had a gambling disorder in 2024 than in 2021, though data for 2021 may be disproportionately impacted by the Covid-19 pandemic. Monitoring these trends and investing in harm prevention and support strategies is crucial.
To identify risk factors for failure after operative treatment of displaced femoral neck fractures in patients 60 years of age and younger. Design: Retrospective cohort study. Single level 1 academic trauma center. All patients ages 18-60 years who underwent operative fixation of a displaced femoral neck fracture (AO/OTA 31B) between 2005 and 2024 were eligible for inclusion. Patients who were lost to follow-up prior to 6 months, or who had clear indications for hemiarthroplasty but underwent fixation due to medical and or social circumstances, were excluded. The primary outcome was treatment failure, defined as femoral neck nonunion/fixation failure, development of avascular necrosis (AVN), and/or malunion (shortening ≥ 15mm or varus angulation). Patient, injury, and treatment factors were examined as risk factors for failure. Two hundred and twenty-three patients were included. The average age was 39 years (SD 12, range 18-60) and 78% were male. The rates of nonunion/fixation failure, AVN, and malunion were 13%, 19%, and 5%, respectively. The overall failure rate was 30%. In multivariable analysis, increased initial fracture displacement (OR 7.1, 95% CI 1.5-33.5, p=0.013), treatment with cannulated screws versus a fixed angle implant (OR 3.7, 95% CI 1.4-10.0, p=0.009), and good (rather than excellent) reduction (OR 5.6, 95% CI 2.0-15.7, p=0.001) were independently associated with nonunion/fixation failure. In multivariable analysis, medial fracture exit <1cm from the cranial edge of the lesser trochanter was associated with a decreased risk of AVN (OR 0.13, 95% CI 0.03-0.64, p=0.011), while increasing age (OR 1.07, 95% CI 1.01-1.15, p=0.036) and low energy mechanism (OR 9.5, 95% CI 2.4-38.6, p=0.002) were associated with increased risk of malunion. In univariable analysis, treatment with a static vs dynamic implant was not associated with risk of AVN, nonunion/fixation failure, or malunion (p>0.05 for all). In patients aged 18-60 with displaced femoral neck fractures treated with operative fixation, the overall failure rate (including AVN, nonunion, and malunion) was 30%. Medial fracture exit < 1cm from the cranial edge of the lesser trochanter was protective against the development of AVN. Increased initial fracture displacement, treatment with non-fixed angle implants, and achieving only good (rather than excellent) reduction were independently associated with increased risk of nonunion. III.
Systemic lupus erythematosus (SLE) is a known risk factor for femoral head osteonecrosis (FHON), but its impact on FHON risk following hip trauma has not been well characterized. We evaluated whether adults with SLE have an increased risk of FHON after hip trauma compared with patients without SLE. We conducted a retrospective cohort study using de-identified electronic health record data from the TriNetX Research Network. Adults aged 18 to 65 years with an incident hip trauma diagnosis and no prior FHON were included. SLE was defined by the presence of an ICD-10 diagnosis code for SLE documented in the electronic health record. Patients with and without SLE were matched 1:1 using propensity scores incorporating demographics, baseline comorbidities, and systemic glucocorticoid exposure. The primary outcome was incident FHON within 5 years following hip trauma, with a secondary analysis evaluating FHON risk in matched cohorts without hip trauma. Kaplan-Meier and Cox proportional hazards analyses were performed. Among adults with incident hip trauma, patients with SLE had a higher 5-year incidence of FHON than patients without SLE. In propensity score-matched time-to-event analyses, SLE was associated with an increased hazard of osteonecrosis (hazard ratio: 2.9; 95% CI: 2.0-4.3; log-rank p < 0.001). These findings were consistent with a similarly elevated baseline risk of FHON observed in patients with SLE in analyses without hip trauma. SLE is associated with an increased FHON risk both with and without hip trauma. The modest absolute post-trauma risk difference supports symptom-guided vigilance rather than routine imaging after trauma. Persistent, progressive, or atypical hip symptoms after trauma in patients with SLE warrant clinical vigilance for osteonecrosis, but these findings do not support routine imaging of all patients with SLE after trauma.
Driving under the influence of drugs is a major cause of road traffic accidents, and alcohol markedly increases crash risk. A clinical test of impairment (CTI) is in some countries performed alongside blood sampling in apprehended drivers, yielding a conclusion of either "impaired" or "not impaired". While the relationship between CTI results and blood drug concentrations has been examined, no previous studies have evaluated CTI outcomes in relation to traffic accidents. This study assesses whether ethanol-positive drivers judged as "impaired" have a higher risk of traffic accident involvement than those assessed as "not impaired", and whether accident involvement increases with impairment severity and ethanol concentration. Drivers positive for ethanol alone were included if a valid CTI conclusion was available and blood sampling occurred 0.25-3 h after the incident. Cases were categorized as either traffic accident group or non-accident controls, the latter including police stops unrelated to accidents (e.g., routine checks, license issues, erratic driving). Age, sex, blood ethanol concentration and CTI results were compared between groups. Associations between impairment level and accident risk were analyzed using multivariable logistic regression. The accident included group 5,290 cases and the non-accident group included 17,596 cases. Accident-involved drivers were younger (median 30 vs. 34 years, p < 0.001), had higher ethanol concentrations (median [IQR] 1.60 g/kg [1.06, 2.05] vs. 1.29 g/kg [0.63, 1.89], p < 0.001) and were more often assessed as "impaired" (94.8% vs. 90.3%, p < 0.001) compared to non-accident drivers. After adjusting for age, sex, ethanol concentration and driving time, CTI-assessed impairment remained significantly associated with accident involvement (OR 1.47; 95% CI 1.28, 1.69). Accident odds increased progressively with both impairment severity and ethanol concentration (ptrend < 0.001). Ethanol-positive drivers assessed as "impaired" by the CTI had 47% higher odds of being involved in traffic accidents compared with drivers apprehended for other reasons, independent of ethanol concentration and demographic factors. Being assessed as "impaired" by the CTI therefore appear to be independently associated with accident risk among alcohol-positive drivers.
This study investigated the effects of five modification methods, including ultra-high pressure, ultrasonic, alkaline protease, ultra-high pressure-alkaline protease, and ultrasonic-alkaline protease treatment, on walnut protein (WP) and their application in milk coffee. The results demonstrated that modification effectively altered key physicochemical properties of WP, including reduced molecular weight and surface hydrophobicity. The treatments induced partial reversible cross-linking, increased pore formation and β-turn content, and significantly improved protein solubility. Notably, enzyme-assisted modification increased solubility by more than threefold. Foam stability of WP aqueous solutions over 30 min was improved due to reduced and more uniform bubble size, accompanied by enhanced rheological properties. In particular, WP modified by ultrasound combined with alkaline protease significantly enhanced the foaming capacity by 282.67%. Within 30 min, this treatment also exhibited the highest foam stability, the largest foam volume, and the smallest foam diameter. After mixing with coffee, the addition of modified WP improved product appearance and reduced zeta potential, while also enhancing the sweetness perception. In addition, electronic nose response intensity and overall volatile compound levels were decreased. However, modified WP increased the release of characteristic coffee aroma compounds, including methyl acetate.
For patients with unfavorable intermediate or high risk localized prostate cancer receiving definitive radiotherapy, androgen deprivation therapy reduces recurrence and improves survival but is underutilized due to toxicity concerns. Patients who forgo initial ADT may later require salvage ADT. Robust real world risk estimates can guide counseling. We conducted a retrospective cohort study using SEER-Medicare. Men aged 66 years diagnosed from 2010 to 2021 and treated with external beam radiotherapy were included. Exposure was concurrent ADT with radiotherapy versus radiotherapy alone. Salvage ADT was defined as initiation after the initial treatment period. We estimated cumulative incidence of salvage ADT accounting for death as a competing risk and used Fine-Gray models to obtain adjusted sub-distribution hazard ratios, controlling for demographics, tumor characteristics, and facility factors. Among 5,092 patients with unfavorable intermediate-risk disease, 61.17% received concurrent ADT with definitive RT. Among 6,970 patients with high-risk disease, 89.60% received concurrent ADT with definitive RT. At 5 years, the adjusted cumulative incidence of salvage ADT was 3.53% (RT with ADT) versus 6.07% (RT alone) for unfavorable intermediate-risk, and 5.92% vs 19.17% for high-risk patients. On multivariable analysis, concurrent ADT with definitive RT was associated with a lower risk of salvage ADT in both the unfavorable intermediate-risk group (SHR, 0.56; 95% CI,A 0.45-0.70; p < 0.01) and the high-risk group (SHR, 0.26; 95% CI, 0.21-0.31; p < 0.01). Higher PSA was also associated with increased risk for salvage ADT for both risk groups, and higher Gleason score was also associated with increased salvage ADT in high-risk patients. Omission of initial ADT during RT is associated with an increased risk of salvage ADT in unfavorable intermediate-risk and high-risk prostate cancer. These real-world, population-based estimates help inform patient counseling and facilitate personalized treatment decisions.
Subarachnoid hemorrhage (SAH) is associated with high mortality and long-term morbidity, as well as a considerable economic burden. Screening for unruptured intracranial aneurysms (UIAs) has the potential to reduce mortality and disability related to SAH, but whether the related costs are justified and provide true health benefits-either in general or specific high-risk populations-remains unclear. Therefore, we conducted a systematic review to determine whether screening of UIAs has been estimated to be cost-effective in any population. We conducted a literature search in PubMed, Scopus, and Web of Science for studies reporting economic analyses of UIA screening. Eligible studies assessed screening in the general population or in populations with an increased risk of SAH or UIAs. Data were extracted on input parameters, type of model, perspective, and cost-effectiveness outcomes. Study quality was assessed using a modified ECOBIAS checklist. We included 15 modelling studies from 8 countries, published during 1996-2025. Nine studies evaluated high-risk populations (autosomal dominant polycystic kidney disease, bicuspid aortic valve, coarctation of the aorta, family history, and female smokers), 5 evaluated the general population and 1 examined both. Model input parameters varied widely across studies; assumed UIA prevalence ranged from 0.5% to 19% and annual rupture rates from 0.16% to 12.9%. Twelve studies reported screening as cost-effective (n = 8) or cost-saving (n = 4). All 10 studies evaluating high-risk populations found screening cost-effective. Of 6 studies analyzing screening of general population, 3 concluded it was not cost-effective or was dominated by no screening. All 15 studies were classified as of low quality according to the risk of bias assessment. Current economic analyses suggest that screening is cost-effective for high-risk populations, whereas evidence for general population remains conflicting. However, the evidence consists exclusively of modelling studies, many with important methodologic limitations. Until prospective data better define SAH risk in screened populations and models more accurately reflect the natural history of aneurysms, the economic analyses of screening should be interpreted with caution. Future research should address these limitations and restrict screening strategies to populations with a demonstrated increase in the incidence of SAH rather than with elevated UIA prevalence alone.
Autologous fat grafting (AFG) is limited by variable long-term retention. Type III collagen (Col III) may support angiogenesis, adipocyte viability, and immunomodulation. We evaluated whether recombinant humanized type III collagen (rhCol III) improves fat graft survival in a concentration-dependent manner. Human lipoaspirate was mixed 1:1 (v/v) with rhCol III at 0 (normal saline, NS), 2, 4, or 8 mg/mL and grafted subcutaneously to the dorsum of female BALB/c nude mice. At postoperative weeks 1, 2, 4, and 12, we assessed volume retention, histology (H&E), collagen deposition, adipocyte viability, vascularization, and expression of PPARG, CEBPA, VEGFA, and FGF2. RNA-seq at week 2 profiled rhCol III-associated transcriptional changes. In vitro, human ADSC proliferation, adhesion, migration, and adipogenesis were tested under rhCol III exposure. rhCol III reduced volume loss from week 2 onward, with maximal retention at 4 mg/mL. Histology showed superior structural integrity at 4 mg/mL. Collagen content increased dose-dependently (greatest at 8 mg/mL). Perilipin 1 and platelet endothelial cell adhesion molecule-1 (CD31) were elevated with rhCol III, with sustained increases at 4 mg/mL, paralleling upregulation of PPARG, CEBPA, VEGFA, and FGF2. In vitro, rhCol III enhanced ADSC proliferation, adhesion, migration, and adipogenesis, optimal at 4 mg/mL. RNA-seq indicated immune, adhesion, and extracellular matrix programs centered on PI3K-Akt and integrin/matrix-receptor signaling. rhCol III enhances fat graft retention by promoting angiogenesis, adipocyte viability, and favorable immune remodeling, with an optimal concentration near 4 mg/mL. rhCol III shows promise as a biomaterial adjunct to improve and standardize AFG outcomes.
Objectives. To examine trends in sexual behaviors, condom use, and pregnancy prevention methods among female adolescents. Methods. We analyzed national and state Youth Risk Behavior Surveillance System data (2007-2023) among US female high school students (≥ 14 years). Outcomes included current sexual activity, condom use, and use of pregnancy prevention methods. We estimated weighted prevalence and trends overall and by region, age, and race/ethnicity and examined adolescent birthrates using Centers for Disease Control and Prevention data. Results. The proportion of respondents who were currently sexually active declined (2007-2011: 35.1%; 2019-2023: 23.8%; P < .01). Among those sexually active, nonuse of condoms increased (45.8% to 52.4%; P < .01), whereas nonuse of moderately or highly effective pregnancy prevention decreased (73.0% to 63.0%; P < .01), reflecting increased uptake of effective methods. The proportion using no pregnancy prevention method remained stable. Declines in sexual activity reduced population-level sexual risk indicators. Racial/ethnic disparities persisted. Birthrates declined substantially. Conclusions. Declines in adolescent birthrates are driven largely by reduced sexual activity, whereas condom use has declined and disparities in contraceptive use persist, indicating uneven improvements in sexual health behaviors. Public Health Implications. Efforts should strengthen comprehensive sexual health education and access to effective contraception and condoms, with targeted strategies for younger adolescents, the South, and non-Hispanic Black and Hispanic populations. (Am J Public Health. Published online ahead of print July 2, 2026:e1-e10. https://doi.org/10.2105/AJPH.2026.308511).
Postoperative recovery after colorectal cancer surgery is highly heterogeneous and incompletely explained by tumor stage or operative factors. Whether early postoperative inpatient stress exposure and subsequent multisystem recovery dynamics are associated with ctDNA-defined molecular residual disease and long-term oncologic outcomes remains unclear. In this prospective longitudinal cohort study, 1200 patients undergoing curative-intent resection for stage II-III colorectal cancer (2018-2020) were followed for up to 60 months. Early postoperative hospital exposome stress was quantified using a prespecified composite Hospital Exposome Stress Load (HESL) assessed during postoperative days 0-7. HESL was conceptualized as a composite inpatient recovery exposure based on routinely captured proxy indicators, rather than as a direct physical measurement of the ward environment. To address potential reverse causation, environmental/nocturnal disruption components were distinguished from care-process or clinical-intensity components in sensitivity analyses. Multisystem recovery trajectories were derived from repeated physiological and inflammatory measures using latent class mixed modeling. Trajectory classification was based on standardized recovery scores at POD3 and POD7 and did not include postoperative length of stay or downstream oncologic outcomes. Outcomes included clinically significant postoperative complications, ctDNA-defined molecular residual disease (MRD), and disease-free survival (DFS). Higher HESL was associated with increased risk of postoperative complications and a greater likelihood of maladaptive recovery trajectories. MRD positivity increased stepwise across HESL tertiles (9.8%, 14.9%, and 22.4%, respectively), and both high HESL (adjusted OR 2.12, 95% CI 1.36-3.30) and maladaptive recovery phenotypes (adjusted OR 2.89, 95% CI 1.78-4.70) were associated with MRD positivity. Over long-term follow-up, elevated HESL (adjusted HR 1.68, 95% CI 1.32-2.14) and maladaptive recovery trajectories (adjusted HR 2.21, 95% CI 1.63-2.99) were associated with inferior DFS. Findings were robust across multiple sensitivity analyses. Early postoperative hospital exposome stress and multisystem recovery trajectories were associated with molecular residual disease and long-term oncologic outcomes after curative colorectal cancer surgery. Because HESL included both environmental/nocturnal disruption proxies and care-process intensity indicators, these findings should be interpreted as prognostic and hypothesis-generating rather than causal.
Disability trajectories in aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are primarily driven by attack-related damage. Confirmed disability worsening (CDW) independent of attacks has been described but occurs infrequently in AQP4-IgG+ NMOSD and MOGAD. Confirmed disability improvement (CDI) has not been evaluated in large cohorts. We determined the frequency of CDI and CDW independent of attacks and identified clinical factors associated with these outcomes in AQP4-IgG+ NMOSD and MOGAD. This retrospective, multicenter cohort study analyzed data from the German Neuromyelitis Optica Study Group (NEMOS) registry. Adult patients with AQP4-IgG+ NMOSD or MOGAD and longitudinal Expanded Disability Status Scale (EDSS) assessments were included. EDSS episodes were defined as periods with ≥3 EDSS assessments without attacks, obtained ≥90 days after attack. CDW and CDI were defined as sustained EDSS increase or decrease (≥1.5 for baseline EDSS 0; ≥1.0 for EDSS 1.0-5.5; ≥0.5 for EDSS ≥6.0) confirmed after at least 6 months. The primary outcomes were annualized CDI and CDW rates. Risk factors were assessed using multivariable Anderson-Gill regression models. A total of 338 EDSS episodes of 307 patients (n: 202/105, median age at EDSS change: 56/41 years, 88/49% female, both p < 0.001; AQP4-IgG+ NMOSD/MOGAD) were included. Adjusted annualized CDI and CDW rates did not differ between AQP4-IgG+ NMOSD (CDI: 0.083, 95% CI 0.029-0.233; CDW: 0.025, 95% CI 0.007-0.092) and MOGAD (CDI: 0.057, 95% CI 0.012-0.277; CDW: 0.036, 95% CI 0.002-0.513). In AQP4-IgG+ NMOSD, a lower number of prior attacks was associated with higher CDI rates (hazard ratio [HR] 0.89, 95% CI 0.82-0.97). Younger age was associated with increased CDI rates in both AQP4-IgG+ NMOSD and MOGAD (HR 0.96, 95% CI 0.94-0.99, for both). CDI and CDW independent of attacks, although rare, occur in AQP4-IgG+ NMOSD and MOGAD. The association between fewer prior attacks and higher CDI rates in AQP4-IgG+ NMOSD underscores the importance of early attack prevention. Limitations include the retrospective design, and the limited number of CDI and CDW events.
Polymer-based delivery vehicles are a promising nonviral alternative for nucleic acid therapeutics; however, current formulations often have low transfection efficiency or if effective, have high toxicity. Herein, we investigate the use of blended polymeric micelles, an ordered assembly of amphiphilic block copolymers in solution, for the delivery of mRNA. Three cationic amphiphiles consisting of a primary amine (C1), dimethylamine (C2), or diethyleneimine (C3) were synthesized. Neutral amphiphiles containing morpholino (M), hydroxy (H), dihydroxy (DH), brush PEG (PB), or two linear PEGs (P5K, P10K) were also created. Seventy-five micelles were formed by blending each cationic and neutral amphiphile at 5 compositions. In the absence of serum, C2 micelles with PEG incorporations above 10% had the highest transfection efficiency; however, C3 formulations were more optimal, having more moderate transfection efficiencies and improved viability. In the presence of serum, C3 formulations with 5 and 10% neutral group incorporations were the most effective, maintaining cell viabilities on par with untreated controls and transfection efficiencies superior to purely cationic micelles. Higher neutral loadings of 20 and 40% reduced transfection efficiency. IL-1β release from macrophages during transfection was also measured as an indicator for potential inflammatory responses. Neutral group loadings of 10% with C1 and C2 significantly reduced cytokine release. In contrast, 10% neutral loadings for C3 micelles slightly increased cytokine release; however, these levels were still below those measured for C2 formulations, indicative of improved biocompatibility of C3 relative to C2. One notable exception was 10% M in C3 micelles, which produced levels on par with Nigericin, a microbial toxin known to include inflammasome activation. Neutral loadings of 40% reduced cytokine release across the formulation space, indicative of improved biocompatibility. Overall, this work demonstrates that changes in formulation chemistry can produce polymeric systems of improved transfection efficiency, without a coinciding increase in toxicity and immunogenicity, to yield more desirable vehicles for nucleic acid delivery.
Global climate change has intensified extreme heat and drought events worldwide. Leaf potassium (K), calcium (Ca) and magnesium (Mg) are critical for maintaining plant physiological functions and stress resistance. However, the large-scale distributions, stoichiometric relationships and future climate-change dynamics of these three elements in plants remain unclear. Here, we explored the spatial and temporal variations in leaf K/Ca/Mg concentration and their stoichiometry of woody angiosperm plants in China, and the underlying potential drivers, based on climate and soil variables and CMIP6 future climate data. We found that leaf K and Mg concentrations increased from south-eastern to north-western China, primarily regulated by precipitation, with soil showing limited contribution. Leaf Ca peaked in central China and showed a unimodal relationship with temperature and precipitation, with drought and cold reducing Ca uptake by limiting transpiration. Leaf K and Mg were strongly coupled across China, whereas Ca was coupled with them only in humid and warm regions but became decoupled in arid and cold regions. Under future climate, scenario-based projections suggested that the overall patterns and relationships of leaf K-Ca-Mg may remain similar to current ones, while leaf Ca concentration may increase and become increasingly decoupled from leaf Mg. These findings contribute to our understanding of the nutrient-adaptive strategies of woody plants and provide critical insights for evaluating potential changes in nutrient cycling and forest productivity under global change.
Incorporation of structured data elements within the electronic health record generates real-time data for many potential uses. However, this requires a change in documentation practices, which may increase documentation effort. The best strategies to support structured documentation interventions have not been thoroughly investigated. Herein, we report the results of extending a data capture tool across multiple disease sites and practice locations. A note-based data capture tool was developed to collect five data elements using minimum common oncology data elements language. Soft-stop close visit validation (CVV), offloading of data entry tasks to allied health staff, group education, individualized e-mails, and one-on-one assistance were used to support utilization. Baseline and follow-up surveys were collected. For each provider, we compared data capture in the 6 months before and after their CVV go-live. Forty-five providers participated (31 physicians, 14 nurse pracationers and physician assistants [NPPAs]), resulting in 23,274 encounters pre-CVV go-live and 23,146 post-CVV go-live visits. Median percentage of all data elements captured increased from 69.5% to 82.6% across all providers. The effect of CVV was immediate and sustained. When surveyed, most respondents agreed with the value propositions of understanding practice population, outcomes, selecting trials to open, and identifying patients for trial enrollment. Most respondents (15/20, 75%) felt the soft stop was a helpful reminder. Structured data can be successfully collected in provider notes with >80% data capture. Personalized assistance incorporating the structured data elements into users' preexisting templates and soft-stop CVV, along with monitoring the results of implementation and personalized follow-up, was used to support the structured data capture intervention.
Microalgal-bacterial systems provide a promising strategy to enhance the nitrate removal performance of denitrifiers via the traditionally assumed provision of electron donors or enrichment of functional microorganisms, while the single-species regulatory mechanism remains unclear. Chlorella vulgaris (C. vulgaris) could markedly improve the nitrate removal by Paracoccus denitrificans (P. denitrificans) even under nutrient-replete conditions, contributing to a 2.48-fold increase in the nitrate removal rate constant compared to the sum of monocultures, indicating non-nutritional regulatory effects. Transcriptomics showed glycolytic genes in P. denitrificans were upregulated by 1.65 to 10.1-fold, accompanied by a 51.0% increase in NADH production. Lactate, as a key intermediate, activated the bacterial electron transport chain (ETC), with ETC-related gene expression upregulated by 2.83 to 2.95-fold. Furthermore, bacterial ammonium induced microalgal glutamate synthesis and release, which likely acted as a signaling molecule to upregulate bacterial nitrate reductase expression. These interactions redirected electrons toward nitrate reduction, increasing carbon utilization efficiency for nitrate removal by 82.75%. Microalgae coordinately optimized bacterial carbon and nitrogen metabolism, reprogramming electron generation, transfer, and allocation to achieve efficient nitrate conversion. This work provides molecular-level mechanistic insights and supports the design of controllable strategies for environmental remediation.
The dihydrofolate reductase (DHFR)-based selection system widely used to develop Chinese hamster ovary (CHO) cell lines for the production of therapeutic proteins is limited by low selection stringency, reliance on stepwise gene amplification, and restricted capacity for efficient multigene selection. In this study, we developed a highly stringent split DHFR selectable marker by integrating a computationally guided split-site design with split intein-mediated protein ligation (SiMPl) in CHO cells. Using the synthetic SiMPl-DHFR selection system, the proportion of Fc-fusion glycoprotein-producing cells in stable cell pools reached 98.5%, and specific protein productivity increased 22.5-fold compared with the wild-type DHFR (WT-DHFR) selection system. When combined with dhfr/methotrexate-mediated gene amplification, the SiMPl-DHFR system further increased mRNA expression levels and Fc-fusion glycoprotein production. Notably, dhfr-nonamplified cell pools generated using the SiMPl-DHFR selection system exhibited higher expression levels than all dhfr-amplified cell pools established using the WT-DHFR selection system. Furthermore, the SiMPl-DHFR selection system permitted the efficient generation of stable monoclonal antibody- and bispecific antibody-producing CHO cell pools that require coordinated expression of two and four genes, respectively. Overall, this study establishes a synthetic selectable marker architecture based on intein-mediated protein splicing that rewires DHFR selection logic and provides a highly stringent and extensible platform for mammalian cell line development.
Obesity affects one third of patients with interstitial lung disease (ILD) and increases both fatigue and dyspnea in the general population. Fatigue and dyspnea are commonly reported by patients with ILD and are difficult to treat. We hypothesized that higher body mass index (BMI) would associate with greater fatigue and dyspnea, worse health-related quality of life (HRQoL), and greater changes in symptoms over time in a real-world ILD cohort. We performed a retrospective analysis of a cohort study of participants in the Pulmonary Fibrosis Foundation Registry with BMI and at least one questionnaire available at enrollment. Symptoms were assessed at enrollment, 6, and 12 months using the Fatigue Severity Scale, UCSD Shortness of Breath, and Short-Form Six-Dimension questionnaires. Linear mixed models with random intercept for participant and interaction between time and BMI evaluated whether BMI correlated with symptoms and changes in symptoms over time. We used random-intercept cross-lagged panel models to evaluate the reciprocal relationship between BMI and symptoms. All models were adjusted for baseline age; sex; ILD diagnosis, diabetes, hypertension, coronary artery disease, and depression diagnoses; use of antifibrotics and corticosteroids; use of supplemental oxygen, and pulmonary function, with forced vital capacity and diffusing capacity of the lung for carbon monoxide as time-varying covariates. 1544 participants were included, 1029 (67%) had 12-month data, with mean (standard deviation) age of 68 (10.3) years, 35% were female, 63% had IPF, percent predicted forced vital capacity of 68% (18.1%), and BMI of 29 (5.8) kg/m2; 87% were using anti-fibrotic therapy at enrollment. Higher BMI was associated with greater fatigue and dyspnea but not with HRQoL. BMI did not moderate changes in fatigue (p-value = 0.29), dyspnea (p-value = 0.98), or HRQoL (p-value = 0.91) over time. BMI and fatigue had bidirectional associations over time wherein lower BMI was associated with greater subsequent symptoms, and greater symptoms were associated with lower subsequent BMI. Higher BMI is associated with greater fatigue and dyspnea on average in patients with ILD, independent of comorbidities and medications. Longitudinally, BMI did not moderate change in these symptoms over time. Further work should investigate whether intentional weight loss can improve fatigue and dyspnea in patients with obesity and ILD.
Peritoneal metastasis (PM) of gastric cancer (GC) is frequently resistant to systemic chemotherapy, which leads to a poor prognosis. This study was designed to compare the safety and tolerability of hyperthermic intraperitoneal chemotherapy (HIPEC) with recombinant mutant human tumor necrosis factor-α (rmhTNF) versus paclitaxel after radical surgery for GC. Patients with locally advanced or metastatic GC who underwent surgical exploration at the Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University were prospectively enrolled and randomly assigned to three groups. All patients received HIPEC on the 1st and 3rd postoperative day. The HIPEC regimens were as follows: rmhTNF (Group A), paclitaxel (Group B), and rmhTNF + paclitaxel (Group C). A total of 30 patients were enrolled in this study, with 10 patients each in groups A, B and C. There were no statistically significant differences in postoperative first activity, gastrointestinal function recovery, catheter removal, and length of hospital stay (P > 0.05). Postoperative complications, including abdominal distension, discomfort, anastomotic leakage, myelosuppression, infection, and fever, did not demonstrate statistically significant differences among the three groups (P > 0.05). Similarly, no statistically significant differences were observed in hematology, liver and kidney function, and postoperative coagulation function among the three groups of patients before surgery, after the first HIPEC treatment, before the second HIPEC treatment, and after the second HIPEC treatment (P > 0.05). After a median follow-up of 14 months, a total of 10 patients (34.5%) experienced recurrence. The safety and tolerability of rmhTNF for HIPEC in GC were confirmed. Additionally, rmhTNF did not impede gastrointestinal recovery or increase postoperative complication rates.
Chlorination is a cornerstone of drinking water disinfection; however, the persistent oxidative stress it imposes may inadvertently select for metabolically resilient microorganisms within distribution systems. In this study, we investigated the universally conserved metabolic mechanisms underlying chlorine tolerance in a representative environmental bacterial isolate recovered from a full-scale drinking water distribution network. By integrating transcriptomic profiling, targeted metabolomics, and constraint-based flux balance analysis (FBA) within a proof-of-concept framework, we identified a coordinated metabolic reprogramming in response to chlorine exposure. Specifically, chlorine stress promoted increased flux through central carbon metabolism, including glycolysis, the tricarboxylic acid (TCA) cycle, and the oxidative pentose phosphate pathway (PPP), collectively enhancing intracellular NAD(P)H regeneration and redox buffering capacity. Model-guided simulations further revealed a subset of redox-associated metabolic nodes that are critical for maintaining cofactor balance and energy homeostasis under oxidative stress. Experimental validation via targeted gene disruption confirmed the model predictions, with key knockouts (e.g., mdh, narG) resulting in up to an 85% reduction in NAD(P)H production, accompanied by significant declines in metabolic activity, chlorine tolerance, and cross-resistance to multiple antibiotics. Collectively, these findings define a chlorine-responsive metabolic network that mechanistically links disinfection-induced oxidative stress to bacterial persistence and antimicrobial cross-resistance, providing critical insights into microbial survival strategies in drinking water systems.