Introduction Objective: Combination therapy is considered an effective strategy to improve cancer treatment outcomes. This study aimed to develop a Pluronic F127-based nano-codelivery system (FDC) encapsulating docetaxel (DTX) and chlorin e6 (Ce6) to enhance the efficacy of PDT using Ce6 and the chemotherapy effect of docetaxel (DTX). FDC was prepared by the thin film hydration method. Particle size, polydispersity index (PDI), zeta potential, drug loading efficiency, and 7‑day colloidal stability were characterized. Cellular uptake, reactive oxygen species (ROS) generation (using DCFH‑DA and SOSG probes), cytotoxicity (MTT assay), apoptosis (flow cytometry), and live/dead staining were evaluated in 4T1 breast cancer cells under light irradiation (630 nm, 29.8 mW/cm², 5 min). Statistical comparisons used Student's t‑test or one‑way ANOVA, with p < 0.05 considered significant. FDC exhibited a uniform hydrodynamic diameter of 200.33 ± 7.71 nm, a PDI of 0.392 ± 0.03, high drug loading efficiency, and good stability over 7 days. Compared with free Ce6, FDC significantly enhanced cellular uptake of Ce6 and markedly increased ROS generation upon light irradiation (p < 0.01). Cytotoxicity assays, apoptosis analysis, and live/dead staining also showed that FDC plus light induced the strongest anti-tumor effect, showing better antitumor effect than free Ce6, free DTX, and the physical mixture of Ce6+DTX Discussion: The improved anti-tumor effect of FDC may be related to enhanced cellular uptake of Ce6 and the co-delivery of DTX and Ce6. The FDC nano-co-delivery system represents a promising strategy for chemotherapy combined with photodynamic therapy against breast cancer.
Aim: To evaluate the clinical effectiveness of a digitally delivered balance program relative to an attention-control comparison group in older adults at risk for falls. Materials & methods: This nonrandomized controlled trial recruited adults aged 65 years and older with moderate-to-high fall risk. Participants were assigned to a digital balance program (exercise therapy, education and health coaching) or an attention-control group (education materials). Outcomes were assessed via self-report surveys at baseline and 3 months. Analyses including all assigned participants evaluated changes in fall rate, fall severity, physical function and medical care utilization. Results: A total of 687 participants were included in the analysis (intervention: n = 344; attention-control: n = 343). The mean age was 68.8 years, and 74.1% of participants were female. In the primary analysis, adjusting for baseline factors, the intervention group demonstrated a 37% lower fall rate compared with the attention-control group at 3 months (IRR: 0.63, 95% CI: 0.48-0.82, p < 0.001). The intervention group also demonstrated significant improvement in physical functioning (β = 6.86, 95% CI: 3.80-9.92, p < 0.001) and lower odds of emergency department visits (OR: 0.43, 95% CI: 0.24-0.76, p = 0.004). Intervention participants engaged in an average of 25.2 exercise therapy sessions over the 12-week period. Conclusion: Findings suggest that participation in the digital balance program was associated with reductions in self-reported fall rates, improvements in self-reported physical function, and lower odds of emergency department utilization. High engagement levels further indicate that digitally delivered programs offer a viable option for improving health outcomes in this population. Trial Registration: Clinicaltrials.gov NCT06868680 retrospectively registered 6 March 2025. What is this article about? Falls are a major cause of injury for adults aged 65 and older. While exercise can help prevent falls, many older adults find it difficult to attend in-person classes due to transportation or mobility issues. This study looked at whether a digital balance program (delivered through an app on a smartphone or tablet) could help reduce falls. The program included exercise therapy, education and support from a health coach and physical therapist. Researchers compared 344 participants who used the app to 343 participants who received only educational emails to see if the app helped reduce falls and improve overall health. What were the results? After 3 months, participants using the digital program reported significantly fewer self-reported falls compared with the group that only received educational emails. As part of an exploratory analysis, participants using the app also reported significant improvements in their physical ability to move and do daily tasks. In another exploratory finding, those in the digital program group reported fewer emergency department visits during the study. Participants were highly engaged with the app, completing an average of two exercise sessions per week. What do the results mean? These findings suggest that digital exercise programs can be an effective and accessible way for older adults with baseline digital literacy and device access to improve their balance and physical health from home. By reducing patient-reported fall risks and emergency hospital visits, such programs may help tech-proficient older adults live independently for longer while reducing the burden on the healthcare system.
Prehabilitation has become increasingly prominent in the context of cancer surgery. While prehabilitation offers significant benefits, it can also inadvertently broaden inequalities because it is often more accessible to some than others. To explore the connection between health inequalities and prehabilitation before cancer surgery, we designed a qualitative study based on case study methodology. Diverse prehabilitation services were purposively sampled. We conducted orientation interviews with service leads; semi-structured interviews with professionals, patients and carers; and observations of prehabilitation practice. These were conducted following topic guides informed by implementation science theory. We employed an inductive thematic approach to allow themes to emerge, highlighting connections between prehabilitation and health inequalities. Six prehabilitation services across England and Wales were included, comprising a combination of established and new services, urban and semi-rural settings and varied healthcare delivery models. We conducted 47 interviews with professionals, 47 interviews with patients (including eight with carers) and 28 observations of practice. We developed six themes, which illuminated how: patients' circumstances influence their ability to engage; the value of prehabilitation to patients depends on how it is introduced and understood; services can address, but also exacerbate, health inequalities; services may offer more and/or less than the prototypical prehabilitation model; services use and develop an incomplete evidence base; and services work with limited resources to provide the most benefit. Our findings highlight that while prehabilitation is often presented as a simple concept in the literature, in practice it is a complex intervention that must integrate with other ongoing treatments (e.g. surgery, chemotherapy, radiotherapy) during an already challenging period in patients' lives. Our qualitative findings from real-world settings illustrate how and why disparities arise in practice and offer insights for more equitable prehabilitation. We studied six services in England and Wales that help people get ready for cancer surgery. These programmes, called prehabilitation services (often called ‘prehab’), support patients before treatment. We interviewed healthcare workers, patients and carers, and we also watched how the services worked in practice. Not everyone has the same chance to use prehabilitation services. People's health, where they live, and their personal circumstances can affect whether they can take part. We wanted to understand why these differences happen and how services could be made fairer for everyone. We found that prehabilitation is not the same for every patient. Some people found it easier to access and benefit from the support than others. Services often had to adapt to meet different patients' needs, and many work with limited staff and resources. We also found that cancer treatment can be a difficult and stressful time, making it harder for some people to take part. The study showed that more work is needed to make prehabilitation services fair and accessible for all patients.
Natural killer (NK) cells are innate lymphocytes that play a critical role in protective immunity against diverse intracellular pathogens and cancers. Their primary function is to kill target cells that are infected, malignantly transformed, or coated by antibodies via antibody-dependent cellular cytotoxicity (ADCC). NK cells can also be genetically engineered to express chimeric antigen receptors (CARs) that enable targeted recognition of specific antigens. Quantitative measurement of NK-cell cytotoxicity is essential for assessing baseline functionality and for preclinical evaluation of monoclonal antibodies and CAR-engineering strategies. However, in vitro functional assays remain highly variable across laboratories due to differences in cell preparation, target cells, effector-to-target ratios, co-incubation times, and readout methods, limiting reproducibility and cross-study comparisons. This article presents a standardized protocol for quantitative assessment of NK-cell cytotoxicity using flow cytometry and real-time, live-cell imaging. Primary human NK cells and CAR-expressing NK-92 cells were evaluated for their ability to kill cancer cells and antibody-coated target cells in a 96-well plate format to measure natural cytotoxicity, CAR-mediated killing, and ADCC. Target-cell survival was measured either continuously using live-cell imaging or at a defined time point by flow cytometry, which also enabled phenotypic characterization of NK cells and target cells. These protocols provide a robust framework using routine tissue culture, imaging, and flow cytometry methods to enable reproducible quantification of NK-cell effector functions for studies of innate immunity and NK cell-based immunotherapies.
The optimal embryo transfer strategy for women with a history of cesarean delivery (CD) remains highly controversial. CD causes uterine microenvironmental damage, especially cesarean scar niche formation and chronic low-grade inflammation, both of which severely impair endometrial receptivity. Supraphysiological hormones during controlled ovarian stimulation (COS) further exacerbate these harmful conditions, creating a "double hit" that compromises implantation. This study aimed to compare the reproductive outcomes of fresh embryo transfer (fresh ET) versus a "freeze-all" frozen-thawed embryo transfer (FET) strategy in this specific population. A large-scale retrospective cohort study was conducted including women with a history of a single CD undergoing their first or second in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. To minimize selection bias and balance baseline and embryological covariates, a 1:1 propensity score matching (PSM) was performed. The primary outcome was the live birth rate (LBR) per transfer. Following PSM, 412 well-matched pairs (n = 824 cycles) were analyzed. The FET group was found associated with a significantly higher LBR compared to the fresh ET group (42.2% vs 33.5%; odds ratio [OR] 1.45, 95% confidence interval [CI]: 1.12-1.88, P = 0.006) per transfer. Similarly, the clinical pregnancy rate (CPR, 51.5% vs 41.0%, P = 0.003) and implantation rate (35.8% vs 28.6%, P < 0.001) were found associated with the FET cohort, with no significant differences in miscarriage or adverse neonatal outcomes. Multivariate logistic regression found FET to be independently associated with live birth as a protective predictor (adjusted OR 1.48, 95% CI: 1.15-1.92, P = 0.003). Crucially, subgroup analysis found that the superiority of FET was predominantly associated with patients with a sonographically confirmed cesarean scar niche (OR 2.15, 95% CI: 1.45-3.20, P < 0.001), whereas the benefit was marginal in those with an intact scar (P = 0.125). For women with a previous CD, a "freeze-all" strategy significantly improves LBR and implantation potential compared to fresh ET. This approach is strongly recommended, particularly for patients with a cesarean scar niche, who are the key population benefiting most from FET cesarean.
REBYOTA and VOWST are the first FDA-approved live biotherapeutic products (LBPs) for recurrent Clostridioides difficile infection (rCDI). Prior FDA safety alerts (2019-2020) regarding invasive infections from investigational fecal microbiota transplantation underscore the need for post-marketing surveillance of these novel products. To characterize the real-world safety profiles of REBYOTA and VOWST using the FDA Adverse Event Reporting System (FAERS) and compare them against established CDI therapeutics. We performed disproportionality analysis of FAERS data (Q1;2020-Q4;2025). REBYOTA and VOWST were identified as primary suspect drugs using BLA numbers and drug name matching. Comparators included fidaxomicin, bezlotoxumab, and vancomycin (CDI-filtered). Four methods were applied: reporting odds ratio (ROR), proportional reporting ratio, information component, and empirical Bayes geometric mean. Signals required ≥2 methods agreement. We identified 231 REBYOTA and 813 VOWST primary suspect reports, yielding 18 and 54 disproportionality signals, respectively. Both products' signals were consistent with known gastrointestinal adverse events. No signals were detected for bacteremia, septic shock, or anaphylaxis. Death was reported at lower-than-expected frequency for VOWST (ROR 0.29; 95% CI 0.15-0.53). A VOWST-specific UTI cluster (Klebsiella UTI ROR 405.73; Pseudomonal UTI ROR 168.54) was identified; head-to-head comparison showed no significant UTI difference versus REBYOTA (ROR 1.39, NS), suggesting stimulated reporting bias rather than a biological signal. Route-dependent adverse event profiles differed between oral VOWST and rectal REBYOTA. FDA-approved LBPs demonstrate reassuring post-marketing safety profiles without transmitted infection signals. The extreme VOWST UTI signal is likely attributable to FDA-mandated expedited reporting obligations rather than a causal drug effect.
Cytoskeletal filaments and their associated organelles/proteins form a system-level network that organizes cellular architecture and activity, yet chemical tools for spatiotemporal control and proteome-wide mapping of these networks in living cells remain scarce. Here we present a modular strategy to generate small-molecule, singlet-oxygen-generating (1O2-genic) photosensitizers for controlling and decoding cytoskeletal networks. Single-step installation of a sulfamide-PEG2-ligand onto rhodamine photosensitizer scaffolds yields binding-activated probes that mainly exist as the non-excitable spirolactams in solution but largely switch to 1O2-producing zwitterions upon binding to microtubules or F-actin. Continuous illumination in confocal microscopy generates a burst of 1O2, driving highly localized oxidation and second-timescale collapse of filament-organelle/protein networks, revealing key roles for microtubules in lysosome transport and mitochondrial dynamics. In parallel, light-tunable mild 1O2 generation enables selective proteome-wide proximity labeling of microtubule- and F-actin-associated networks, unveiling previously uncharacterized dual interactors at the microtubule-F-actin interface. This modular platform provides an effective tool for genetic-manipulation-free mapping and spatiotemporally controlled, localized oxidative perturbation of endogenous networks.
Rh isoimmunisation remains a major cause of hemolytic disease of the fetus and newborn, particularly when fetal anaemia develops early in gestation. Antenatal intravenous immunoglobulin (IVIG) has been proposed to improve fetal outcomes, but evidence remains limited, especially from low- and middle-income settings. This study was conducted at a tertiary care centre in India and included pregnant women with severe anti-D isoimmunisation managed between 2023 to 2025. Inclusion criteria was pregnant women, with a previous pregnancy complicated by hydrops with perinatal death and/or requirement of intrauterine transfusion (IUT) before 24 weeks. They received antenatal IVIG (1 g/Kg/week from 13-14 weeks for 4-6 doses) and were compared with cases managed without IVIG. Outcomes analysed included presence of fetal hydrops, the requirement for IUT and the total number of IUTs, gestational age at first IUT, gestational age at delivery, and pregnancy outcome (live birth, stillbirth, or abortion) and neonatal outcomes. Thirty four pregnancies were included with17 managed with IVIG and 17 managed without IVIG based on the timing of referral. The incidence of fetal hydrops was significantly lower in the IVIG group [5.9% vs 52.9%, p = 0.008], and preterm delivery occurred less frequently [70.5% vs 100%, p = 0.04]. The need for IUT, gestational age at first IUT, number of IUTs, gestational age at delivery, and birth weight were comparable between groups. Live birth rate and survival at discharge were higher in the IVIG group, though differences did not reach statistical significance. Infusion-related reactions occurred in 17.6% of IVIG-treated patients and were mild. Antenatal IVIG was associated with reduced fetal hydrops and preterm delivery in severe Rh isoimmunised pregnancies. However, these findings should be interpreted with caution, as improved outcomes may also reflect earlier referral, surveillance, and intervention.
In Pakistan, one-third of under-5 deaths (58/1000 live births) are attributable to the high prevalence of stunting (40%), underweight (23%), and wasting (17.7%). Given the suboptimal prevalence of exclusive breastfeeding (EBF; 48%) and the alarmingly low consumption of a minimum acceptable diet (3.6%), mitigation of early-life nutritional risk provides a critical window of opportunity for intervention. Mobile health (mHealth) provides an innovative and low-cost option to improve infant and young child feeding practices (IYCFPs) among mothers. This study aims to assess the efficacy of a context-specific mHealth coaching app in promoting EBF and IYCFPs compared to face-to-face (F2F) counseling. This is a prospective, parallel-arm randomized controlled trial planned at a secondary care hospital in Karachi, Pakistan. The study will enroll 300 booked singleton pregnant women in the third trimester, who plan to stay in their respective areas for at least 1 year postdelivery, are registered for child immunization at the associated Family Health Center, own smartphones with internet access, are able to read Urdu, and provide consent. Participants in the intervention arm will receive the Pehli Ghiza mHealth app along with routine standard-of-care F2F counseling. The app will deliver context-specific educational content on breastfeeding and IYCFPs through short videos and messages sent 3 times per week, tailored to the stage of pregnancy and infant age. Participants in the control arm will receive only routine F2F counseling. The standard of care will be delivered at each follow-up visit, which is scheduled at birth, at 6, 10, and 14 weeks, and at 6, 9, and 12 months of the infant's age. Data will be collected at enrollment and at each follow-up visit using structured questionnaires. Primary outcomes are EBF and the introduction of age-appropriate complementary feeding. Secondary outcomes include early initiation of breastfeeding, continued breastfeeding at 1 year, minimum dietary diversity, meal frequency, minimum acceptable diet, and child health outcomes. Analysis will follow the intention-to-treat principle to detect a 20% absolute improvement in primary outcomes between the intervention and control groups over time and to evaluate between-group differences in feeding practices. Compliance will be determined by the proportion of participants who complete the 6-month coaching program. Usability will be assessed based on features related to design, interface, content, coaching, perception, and personal benefit. The study was approved by the Ethics Review Committee of the Aga Khan University and the National Ethics Committee. Participant recruitment started on February 2, 2026. As of May 18, 2026, 241 participants have been recruited. Follow-ups and outcome assessments are expected to be completed by June 2027. If effective, the Pehli Ghiza intervention could support the integration of digital health tools into standard of care in Pakistan and similar low- and middle-income country settings.
Slow-transit constipation (STC) is characterized by reduced colonic motility, impaired smooth muscle function, and altered mucosal signaling. Among these pathways, mucosal serotonin (5-HT), mainly produced by enterochromaffin cells, contributes to intestinal motility regulation. In a loperamide-induced constipation model in male C57BL/6J mice, we evaluated the effects of Lactiplantibacillus plantarum NCHBL-004 on bowel function and associated molecular changes. Compared with loperamide-treated mice, live NCHBL-004 at 1×10⁹ CFU improved fecal output and gastrointestinal transit and partially preserved fecal water content, whereas the lower live dose and heat-killed preparation showed no significant effects. These functional changes were accompanied by preservation of colonic muscularis thickness and increased expression of smooth muscle-associated markers, including Acta2 and Myh11. NCHBL-004 also modulated mucosal serotonergic gene expression, as indicated by increased Tph1, which encodes a key enzyme for 5-HT synthesis, and decreased Slc6a4, which encodes the serotonin transporter involved in 5-HT reuptake. Overall, these findings suggest that live NCHBL-004 improves intestinal motility in loperamide-induced constipation, with associated changes in colonic smooth muscle phenotype and mucosal serotonergic regulation.
Foreign-born women face a higher risk of adverse pregnancy outcomes, including stillbirth, compared to Swedish-born women, and this disparity cannot be fully explained by known risk factors. This study investigates differences in pregnancy-related health care by maternal origin and whether such differences may contribute to disparities in stillbirth risk. This was a retrospective cohort study including all singleton births in the Stockholm region between 2000 and 2020 (n = 518 792 births). Data from the National Medical Birth Register was linked to data from Statistics Sweden and the VAL databases using the personal identity number of the mother. Maternal and fetal characteristics, inpatient care occasions, length of hospital stay, outpatient visits, and antenatal care visits were compared between women divided by maternal origin, experiencing live births, and stillbirths. Regression models using a forward selection strategy were performed, adjusting for different potential mediators on the causal pathway from maternal country of origin to stillbirth. Among women with live births, those originating from Middle East/Northern Africa, sub-Saharan Africa, and South America had significantly higher proportions of inpatient care occasions than women originating from high-income Western Countries. Women with live births originating from other regions than high-income Western Countries had significantly less antenatal care visits, regardless of parity. Among women with stillbirths, women originating from sub-Saharan Africa had significantly more inpatient care occasions and fewer antenatal care visits than women originating from high-income Western Countries. After adjusting for maternal risk factors, SGA infants, socioeconomic factors, multiple inpatient care occasions, and few antenatal care visits during pregnancy, women from sub-Saharan Africa had a slightly elevated risk of stillbirth (aOR 1.29, 95% CI 1.00-1.66, p-value 0.047) compared to women from high-income Western Countries. Women originating from other regions than high-income Western Countries, especially those from sub-Saharan Africa, attended fewer antenatal care visits and had more inpatient care occasions compared to women from high-income Western Countries. Reduced attendance in antenatal care could potentially be associated with their elevated stillbirth risk. Improving access to and participation in antenatal care should be prioritized to reduce disparities in stillbirth risk.
Background: More than three decades after the Bosnian war (1992-1995), its psychological consequences persist. While early post-war mental health outcomes have been extensively studied, little is known about the long-term psychological experiences of women who lost multiple family members.Objective: This study aimed to explore the current mental health status and lived psychological consequences of women from Srebrenica and surrounding regions who experienced multiple war-related losses.Methods: Two focus group discussions were conducted with 25 women. Audio-recorded data were transcribed, translated, and analysed using qualitative content analysis to identify central themes and subthemes.Results: Five overarching themes emerged: (1) enduring war trauma, loss, and emotional consequences; (2) justice, institutional responses, and systemic failures; (3) stigma and barriers to mental health care; (4) personal and everyday coping strategies; and (5) external support systems. Participants described persistent traumatic grief, chronic psychological distress, and ongoing somatic and emotional symptoms three decades after the conflict. Narratives revealed diverse coping strategies rooted in meaning-making, work, family, spirituality, and peer support. Institutional neglect, stigma, and limited access to mental health care were identified as major obstacles to recovery, whereas NGO-based and group-based interventions were experienced as particularly valuable.Conclusions: Thirty years after the Bosnian war, women survivors from Srebrenica and surrounding regions continue to live with profound and enduring psychological consequences of trauma and loss. Their narratives highlight the long-term nature of war-related suffering, the central role of social and institutional context, and the importance of culturally embedded, relational forms of support. These findings underscore the need for sustained, survivor-centered, and trauma-informed mental health services in post-conflict settings and contribute to a deeper understanding of long-term female survivor consequences following mass violence. Many women continue to live with the psychological consequences of war-related loss and trauma decades after the conflict.The experience of grief was characterized as unresolved and enduring, influenced by uncertainty and repeated encounters with loss.Women described everyday coping through work, family responsibilities, spirituality, and support from NGOs and peer groups.
Frailty refers to a state of heightened vulnerability to adverse health outcomes. Animal models of frailty provide an opportunity to probe lifetime events and exposures that drive frailty progression and to evaluate intervention strategies that could mitigate frailty development and its consequences in older adults. The relationship between parity-production of live offspring-and later life frailty in women is poorly understood. Here, we utilize companion dogs to test the hypothesis that production of live offspring comes at a physiological cost, leading to increased late-life frailty. We measured deficit accumulation using a 34-item clinical frailty index in a cohort of 95 geriatric female Rottweilers. The study outcome was late-life robustness, defined as the lowest quintile of frailty in the study population. We found no evidence of reproductive cost. Instead, compared to nulliparous females, parous females were 3× more likely to retain late-life robustness [OR, 95% CI = 3.30,1.16-9.38; p = .025], a relationship not attenuated by adjusting for covariates, including owner-reported reason for nulliparity. Moreover, females with largest number of litters had highest late-life robustness. Finally, employing two measures of early-life health/fitness-earlier-in-life health deficits, lifetime morbidity profiles-could not explain results based on selection. This inquiry introduces a new application of the dog model of frailty for the study of reproduction and deficit accumulation. The linkage we observed between parity and higher late-life robustness is congruent with results of several studies in women, suggesting parous females may have the capacity to dampen the development of later-in-life frailty, which should be further investigated at the genetic and epigenetic level.
This study aims to evaluate the discriminatory validity of a randomized, double-blind evaluation protocol based on the Global Evaluative Assessment of Robotic Skills (GEARS) scoring system for cross-specialty competency assessment during robotic surgery training. We conducted a prospective, randomized, double-blind evaluation protocol at a single robotic training center. 49 surgical trainees (17 general surgery, 16 urology, 16 gynecology) with no prior robotic experience completed a 3-week training program-7 days of intensive simulator (dV-Trainer) and porcine-model procedures, followed by 2 weeks of clinical observation. All operation videos were anonymized and randomly assigned to 7 blinded expert reviewers per session, selected from a 12-member panel. To calibrate scoring and detect bias, 17 expert-generated videos were randomly interspersed as internal controls. Validity and inter-scenario consistency were assessed using factor analysis, Cronbach's α, and the Bland-Altman method. The GEARS-based assessment protocol under the randomized double-blind design demonstrated good validity (KMO = 0.836, cumulative variance 85%) and reliability (Cronbach's α = 0.765), effectively distinguishing trainees from experts in simulator and live tissue operations (p < 0.05). The Mscore-Sim correlated significantly with the GEARS dimensions (R²=0.563); the Bland-Altman limits of agreement (-2.1-3.8) validated cross-modal scoring consistency. Subgroup analysis revealed the system's stability across specialties (Δ < 0.4), training robot models (Δ < 0.2), and sexes (p > 0.05). Compared to younger trainees, older trainees showed no difference in live tissue performance, suggesting a compensatory effect of experience. The scoring system objectively differentiates operational abilities of trainees across specialties, demonstrating its potential as a standardized assessment tool for heterogeneous robotic surgery training.
Although several surveys on neural combinatorial optimization (NCO) solvers specifically designed to solve vehicle routing problems (VRPs) have been conducted, they did not cover the state-of-the-art (SOTA) NCO solvers emerged recently. More importantly, to establish a comprehensive and up-to-date taxonomy of NCO solvers, we systematically review relevant publications and preprints, categorizing them into four distinct types, namely learning to construct (L2C), learning to improve (L2I), learning to predict (L2P)-once, and L2P-multiplicity (L2P-M) solvers. Subsequently, we present the inadequacies of the SOTA solvers, including poor generalization, incapability to solve large-scale VRPs, inability to address most types of VRP variants simultaneously, and difficulty in comparing these NCO solvers with the conventional operations research (OR) algorithms. Simultaneously, we discuss ongoing efforts, identify open inadequacies, and propose promising and viable directions to overcome these inadequacies. Notably, existing efforts focus on only one or two of these inadequacies, with none attempting to address all of them concurrently. In addition, we compare the performance of representative NCO solvers from the reinforcement, supervised, and unsupervised learning (UL) paradigms across VRPs of varying scales. Finally, following the proposed taxonomy, we provide an accompanying web page as a live repository for NCO solvers. Through this survey and the live repository, we aim to foster further advancements in the NCO community.
Veterinary schools are tasked with teaching an increasing number of clinical skills to a constantly increasing number of veterinary students. In addition, they are faced with the ethical and logistical challenges of using live animals for teaching. This perfect storm has prompted a shift toward using non-animal teaching models for training and evaluation of student learning. Veterinary school-developed teaching models are becoming more common as educators look for nontraditional methods of teaching important clinical skills. The current commercial large animal reproduction models include bovine and equine dystocia simulators, bovine and equine theriogenology models, and a ewe artificial insemination model. These models are expensive, which may limit accessibility to students. This article presents two low-cost, low- and moderate-fidelity models of the caudal equine reproductive tract that can be used to teach and evaluate student skills in equine endometrial sampling or infusion, both skills commonly performed in clinical practice. The models have been used successfully in student teaching and for Objective Structured Clinical Examinations (OSCEs). The low cost and ease of production allow students to have easy access to the models for self-review. The models described demonstrate instructional value by improving access by students, standardizing OSCE evaluation tools, and reducing live animal usage. These models can be implemented at other veterinary teaching institutions to increase student knowledge and clinical skills.
The growing use of AI to support patient portal message management requires rigorous preclinical evaluation. Directly testing AI within electronic health record (EHR) systems poses significant safety, workflow, and data-governance risks. Here, we present a technical feasibility report on a secure user interface (UI) sandbox designed to enable clinical and technical teams to experiment with AI for portal messaging before clinical integration. In this context, a "sandbox" refers to a controlled, nonproduction environment that allows safe testing, prompt iteration, and evaluation of AI outputs without impacting live EHR systems or patient care. We developed a web UI in Python 3 with a modular backend for data handling and AI task execution that operates entirely within the institutional firewall. The system runs in a secure research environment equipped with an NVIDIA GRID T4-1Q graphics processing unit (GPU) and institutional access controls. We designed a deidentification pipeline to remove or replace personal health identifiers and assessed its precision. The platform supports single-message and batch workflows and exposes example large language model (LLM)-enabled tasks such as authorship identification, message categorization, criticality flagging, and response drafting using zero-shot, one-shot, and few-shot prompting. The system successfully executed end-to-end workflows to ingest messages, run individual or batch AI analyses, and present outputs for review. Personal health information partial masking was applied across the corpus using a deidentification pipeline validated against 110 manually adjudicated entities (sensitivity 95.1%, precision 82.1%). We ran use cases with an institutional review board-approved corpus of a dementia-relevant subset of 6941 patient portal messages categorized as "medical advice requests" from 497 unique patients. With the support of the UI, we tested which prompting strategies yielded interpretable outputs for authorship identification, categorization, and criticality flagging, and whether response drafting produced editable clinician starting points. A token-based cost readout provided transparent operating estimates for LLM-backed tasks. This framework offers a practical, secure path to test AI behavior on real messages without affecting live EHR workflows and thus supports exploratory testing, prompt iteration, and comparative analyses, including LLM prompts versus baseline models, while preserving governance boundaries. We discuss design choices, safety controls, and the limits of a sandbox approach. A secure, UI-based sandbox enables health system teams to evaluate AI for patient portal messaging before clinical integration. The goal is not to assume benefit but to generate evidence about feasibility, risks, and fit to clinical needs in a controlled setting.
To establish a 2026 global benchmark for senior authorship gender representation in high-impact imaging journals and identify structural barriers to digital metadata visibility. An algorithmic audit analyzed 6454 publications from seven leading radiology journals compiled between January 2024 and February 2026. Senior author gender was inferred utilizing the validated gender-guesser name-inference engine. Pearson's Chi-squared test compared gender distributions across journals. A dynamic, web-based dashboard was developed using a Python-Streamlit framework to facilitate continuous, live data exploration. The global female senior authorship rate across successfully classified data was established at 17.70% (1144/3717). Significant variation was found by journal (x2=34.19, p < 0.0001). The Journal of the American College of Radiology (JACR) demonstrated the highest representation (37.17%), while technical subspecialty journals showed lower parity. A profound "Metadata Gap" was identified, with 42.42% (2737/6454) of the total cohort lacking identifiable gender markers or sufficient name strings in professional publishing summaries to allow for algorithmic inference. A profound gender gap persists in global senior research leadership within imaging specialties. Enhancing publishing metadata hygiene is an essential step for accurate institutional equity tracking. Informatics-driven auditing via live dashboards provides a scalable roadmap for modern departmental and institutional accountability.
The global debate over the ethics and purpose of elephants in zoos has resulted in proposed legislation to cease keeping them, unless zoos can demonstrate the species' needs are met. Outdated analyses that fail to provide a current and robust appraisal of elephant survival in zoos fuels the debate. We analysed changes in life expectancy and lifespan equality in zoo elephants between 1960 and 2024, and compared these to wild or semi-wild populations. We found an increase of up to 21% in female zoo elephant life expectancy over time, and up to 44% for males. Lifespan equality increased by up to 14% in both sexes. Improvements in care have resulted in comparable or higher survival measures of zoo elephants compared to evaluated wild populations. Our findings provide information to guide zoos to ensure elephants live long meaningful lives that are, at a minimum, comparable to wild counterparts.
Phenylketonuria (PKU) is a rare inherited metabolic disorder requiring lifelong treatment. While early diagnosis and dietary management have substantially improved neurocognitive outcomes, less is known about how PKU affects sexual life, intimate relationships, and reproductive decision-making, particularly during the transition to adulthood. This cross-sectional study included 152 adolescents and young adults with PKU and 183 age-matched healthy controls. A questionnaire-based approach was used to assess sociodemographic characteristics, sexual behavior, and reproductive attitudes. Additional analyses within the PKU group examined sex- and age-related differences and factors associated with awareness of maternal PKU syndrome. Individuals with PKU differed from controls primarily in psychosocial and reproductive domains rather than in sexual behavior itself. Participants with PKU were more likely to live with parents, less frequently sexually active, and less likely to have children, particularly men. Among sexually active individuals, no significant differences were observed between groups in age at sexual initiation, number of sexual partners, or condom use. Within the PKU cohort, women were more likely to be sexually active, to live independently, to have children, and to report that PKU influenced decisions related to sexual initiation and parenthood. Awareness of maternal PKU syndrome was uneven and strongly associated with female sex, older age, higher education, sexual activity, and parenthood, indicating substantial knowledge gaps among younger individuals and men. PKU appears to be associated with delayed psychosocial transitions and reduced parenthood rather than altered sexual behavior per se. Marked sex differences in reproductive attitudes and disease-related knowledge highlight an unequal distribution of reproductive responsibility. These findings underscore the need to integrate structured sexual and reproductive health education into lifelong care for individuals with PKU, particularly during adolescence and early adulthood.