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Psoriasis is a chronic inflammatory skin disease with a complex pathogenesis. Initially affecting the skin, it may also involve the nails and joints, often requiring lifelong medication. Despite recent advances in understanding its pathogenesis, the chronic and recurrent nature of psoriasis poses ongoing challenges for long-term drug management. While natural medicines offer higher safety profiles and fewer side effects compared to synthetic drugs, their development as clinical candidates for psoriasis is constrained by low bioavailability, limited solubility, poor permeability, and instability. For instance, specific nanocarriers have been shown to significantly improve therapeutic outcomes; curcumin-loaded PLGA nanoparticles (50 nm) demonstrated a 48.23±0.77% drug loading capacity with over 85% release within 72 hours, while hyaluronic acid-modified ethosomes increased skin retention by 2.3-fold compared to conventional formulations in preclinical models. This paper systematically reviews the structure and advantages of nanocarrier systems, including liposomes, nanoparticles, nanofibers, micelles, nanogels, and nanoemulsions. It focuses on the preparation, preclinical, and clinical progress of nanocarriers for key natural bioactive compounds, including resveratrol, curcumin, oleuropein, psoralen, natural oils, and complex natural mixtures. We aim to highlight the potential of nanotechnology-based on natural drugs as an alternative strategy to improve the therapeutic efficacy of psoriasis while reducing side effects.

This study evaluates the efficacy of a post-discharge follow-up program in patients recovering from acute heart failure (AHF) hospitalized in internal medicine (IM) and in cardiology (CA) wards. Patients hospitalized for AHF between October 2020 and November 2022 at a third-level center were retrospectively analyzed according to their hospitalization ward in CA vs IM. Patients deemed eligible for inclusion were ≥ 18 years-old and hospitalized for AHF. Only patients discharged alive were included in the post-AHF follow-up program. The primary endpoint was a composite of time to first HF hospitalization or cardiovascular (CV) death at 6 months, while secondary endpoints were its individual components, all-cause death and a composite of time to first HF hospitalization or all-cause mortality at 6 months. Out of 230 patients, 122 were hospitalized in CA and 108 in IM wards. Patients hospitalized in CA were younger and less frequently affected by extra-cardiac comorbidities compared to patients managed in IM. At 6 months, no difference in the primary endpoint was registered in the two groups (IM 16.6% N = 18 vs CA 13.1% N = 16, log-rank p = 0.425; IR 37.5 per 100 p/y CI 23.7-59.6 vs 28.4 per 100 p/y CI 17.4-46.5; p = 0.523). Moreover, the cohorts did not differ for any of the secondary endpoints. A secondary analysis according both to ward of hospitalization and ejection fraction (> 40% vs ≤ 40%) did not show any significant difference in the primary composite outcome between the subgroups. In this single-center retrospective cohort study, no significant differences in the risk of major adverse CV events were observed between patients hospitalized in CA and IM wards during mid-term follow-up after enrollment in a post-AHF follow-up program.

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Provision of equal access to medical services for all citizens is a challenge for the public healthcare systems of many European countries. In many of them, rural areas and other peripheral regions are gradually turning into so-called 'medical deserts', whose inhabitants' access to healthcare is obstructed, which, in turn, leads to deterioration of the quality of life and worse healthcare characteristics of the population. This problem, also experienced in Poland, is not only caused by the shortage of doctors but also by the suboptimal dislocation of the medical workforce. Currently, it is also believed that the emergence of medical deserts can be triggered by factors connected both with the demand and supply of healthcare. The aim of the study is determine the preferences of medicine students towards planned specialization and workplace (understood both as a type of institution and a geographical location) as well as to isolate the determinants of choice of the medical profession, in order to explore how these factors may indirectly contribute to the development and persistence of medical desertsMethods: A computer-assisted web interviewing questionnaire study was conducted anonymously with students in their first, third and sixth year of medicine at the Medical University of Warsaw. The research was of a pilot and exploratory nature. Students took part in the research conducted online via the Lime Survey Professional online survey service in January and February 2024. The authored research questionnaire comprised 18 questions concerning motivations for the choice of the medical profession, preferred specialization and workplace. The questionnaire was completed by 434 participants. Motivations for the selection of the medical profession of young people can be divided into those related to the profession and those connected with private life, expected salaries or time management. For some respondents, the most significant incentive was the prospect of work in the area of science (research motivations); for others it was the chance to help others (altruistic motivations). The most important factors influencing career plans were job stability (mean score: 4.5/5), the desire to have a socially meaningful profession (4.3/5), and opportunities for professional self-development (4.2/5). By identifying factors shaping future physicians' career plans, the study contributes to a better understanding of workforce-related mechanisms underlying the development of medical deserts in Poland. These findings may inform future workforce planning and educational strategies aimed at improving the distribution of medical professionals, particularly in underserved areas. However, given the pilot nature of the study and its single-university design, the results should be interpreted with caution, particularly with regard to their generalizability.

Driven by recent advances in artificial intelligence, particularly in medicine, audio-based voice and speech biomarkers are increasingly investigated for various medical applications as a complementary or even alternative modality to traditional medical devices. The adoption of deep learning techniques in recent literature is motivated by their superior performance compared to classical machine learning (ML) methods. However, ethical and regulatory concerns regarding the black-box nature of these models have limited their integration into clinical workflows. Consequently, Explainable AI (XAI) has recently been employed to address this issue by generating explanations for opaque model outputs. Ideally, medical XAI systems aim to provide human-understandable, clinically grounded explanations essential for enhanced AI trustworthiness and, thereby, facilitated adoption into real-world clinical settings. We conduct a systematic literature review of XAI methods applied for explaining deep learning techniques in audio-based voice and speech clinical applications. Our aim is to identify what XAI methods have been used to explain the decisions of deep learning voice and speech AI systems in healthcare, as well as XAI-informed insights. Additionally, we aim to contextualize these findings with respect to clinical applicability and stakeholder relevance. Lastly, we identify opportunities and recommendations for future clinical audio XAI design. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six electronic databases (IEEE Xplore, ACM Digital Library, Scopus, PubMed, Web of Science, and Nature) were systematically searched for articles published between January 2015 and February 2025. Eligible studies applied explainability or interpretability methods to deep learning models for voice or speech audio in healthcare contexts. Risk of bias was assessed using PROBAST+AI. Results were thematically synthesized across explainability categories, input representations, clinical domains, validation strategies, and stakeholder considerations. Thirty studies met the inclusion criteria. These studies employed a range of explainability approaches, including gradient-based methods, perturbation-based techniques, surrogate model-based methods, model-internal representation analyses, concept-based detectors, and attention-based explanations. Applications spanned diverse clinical domains, including voice disorders, neurodegenerative diseases, psychiatric conditions, and traumatic brain injury. Overall, results indicate that most studies relied primarily on qualitative interpretation of explainability outputs, with limited quantitative validation of explanation consistency across external datasets. Furthermore, none of the included studies explicitly conducted human-in-the-loop evaluations with relevant stakeholders, highlighting a substantial gap in stakeholder alignment. Current XAI practices in clinical voice and speech analysis are limited by insufficient validation, lack of domain-specific design, and misalignment with clinical stakeholder needs. This review highlights opportunities for developing validated, audio-aware, and stakeholder-centered XAI approaches to support trustworthy clinical deployment. Interpretation of these findings should consider limitations related to single-reviewer study selection, potential high-risk of bias in model development and evaluation, and the repeated use of benchmark datasets across reviewed studies.

Understanding how individual cancer cells adapt to drug treatment is a fundamental challenge limiting precision medicine cancer therapy strategies. Here, we present a multimodal framework that integrates bulk and single-cell treated and untreated transcriptomics data to identify drug-responsive cell populations in triple-negative breast cancer (TNBC). Our framework defines seven bulk-level "identities," each representing unique combinations of biologically relevant genes. These trackable identities are further mapped onto single cells and uncover global patterns of how cell populations respond to drug treatment. By capturing the evolving nature of cellular states, we show that a select few identities dominate and drive population-level responses during treatment, which allows us to better predict how entire tumors respond to treatment. This insight is essential for designing precise combination therapies tailored to the unique heterogeneity of patient tumors, addressing the single-cell variations that ultimately determine therapeutic outcomes.

Cancer clinical trials are essential for advancing therapeutic innovations; however, patient enrollment remains a persistent challenge globally. Understanding the attitudes and willingness of patients with cancer to participate in clinical trials is critical for improving recruitment strategies. While previous studies have explored barriers and facilitators, few have integrated multiple data sources or used emerging analytical approaches, such as large language models (LLMs), to capture the multidimensional nature of patient decision-making. Furthermore, limited research has examined these perspectives within the Chinese health care context, where cultural, economic, and systemic factors may uniquely influence participation decisions. This study aimed to examine the attitudes and willingness of patients with cancer to participate in drug clinical trials in China by (1) identifying key themes influencing patients' decision-making processes, (2) comparing thematic findings derived from investigator-led qualitative analysis with those generated by 2 LLMs (Gemini Pro 2.5 and DeepSeek R1), and (3) evaluating the complementary value of hybrid analytical approaches in qualitative health research. A multistage qualitative study was conducted using 2 data sources: semistructured face-to-face interviews with patients with cancer (n=11) from a tertiary hospital in Shanghai and publicly available comments from 2 Chinese online health communities (Zhihu and Yuaigongwu). Of the 3148 initial comments, 219 met the inclusion criteria after systematic screening. Three parallel analytical approaches were used: investigator-led thematic analysis, Gemini Pro 2.5-assisted analysis, and DeepSeek R1-assisted analysis. Both LLMs received identical, structured prompts. Thematic outputs were systematically compared to identify convergent and divergent findings. The 3 analytical methods jointly identified 7 core themes: treatment selection, financial burden relief, uncertain therapeutic efficacy, uncertainty regarding control groups, lack of cognition, misconceptions, and physician trust. Substantial thematic overlap was observed between investigator-led and DeepSeek R1 analyses (8 shared themes, including family-involved decisions and service-related factors) and between investigator-led and Gemini Pro 2.5 analyses (3 shared themes, including regional disparities and autonomous decision-making). Method-specific themes included recognition of medical value (investigator only), insufficient clinical data (DeepSeek R1 only), and lack of information resource (Gemini Pro 2.5 only). These findings highlight the multidimensional nature of trial participation decisions, encompassing treatment expectations, economic considerations, risk perceptions, cognitive factors, trust relationships, and structural barriers to accessibility. The willingness of patients with cancer to participate in clinical trials is shaped by a complex interplay of treatment expectations, economic considerations, risk perceptions, cognitive factors, and relational dynamics. The hybrid analytical framework demonstrated complementary strengths: human analysis provided contextual depth and cultural sensitivity, while LLMs offered efficiency and identified additional thematic dimensions. These findings underscore the need for patient-centered communication strategies, transparent trial information, and culturally tailored recruitment approaches. Future research should expand sample diversity and further validate the use of LLMs in qualitative health research.

In this same, May-June 2026, issue of the Hastings Center Report, Brendon Saloner suggests that mandated drug treatment can expand freedom and promote egalitarian social justice so long as three criteria are met. Drawing on our clinical experience in addiction medicine and a critical appraisal of the available evidence, we challenge this claim. We argue that Saloner's three criteria are unlikely to be met within jurisdictions that criminalize drug use and lack supports for people who use drugs. The criterion that mandated treatment be "likely to be beneficial" is undermined by the coercive nature of such interventions and the lack of evidence supporting their effectiveness when compared to voluntary care. Further, the application of mandated treatment risks extending carceral oversight to individuals charged with minor offenses, disproportionately affecting equity-denied populations. Finally, we question whether infringements on liberty through legal oversight can genuinely expand freedom, particularly when such measures exacerbate social instability and undermine the potential for voluntary engagement with care. We contend that meaningful expansion of freedom for people who use drugs is better achieved through voluntary, community-based treatment models supported by robust social infrastructure. A radical reorientation of drug policy-away from coercion and toward supportive, person-centered care-is necessary to achieve the ethical aims of reducing harm, promoting autonomy, and advancing egalitarian social justice.

Anorectal melanoma is a rare and aggressive malignancy arising from melanocytes within the mucosal epithelium of the anorectal region. Because presenting symptoms such as rectal bleeding frequently mimic benign anorectal conditions, diagnosis is often delayed until advanced stages of the disease. Mucosal melanoma is characterized by aggressive local invasion and early metastatic spread. We present the case of a 54-year-old female with metastatic rectal melanoma whose disease course was complicated by extensive pelvic tumor burden, malignant venous compression leading to deep venous thrombosis, obstructive uropathy, and tumor-associated hemorrhage. Cross-sectional imaging demonstrated a massive posterior pelvic mass occupying the rectouterine space with displacement of surrounding structures, additional rectal tumor extension, metastatic lesions in the liver, and locally invasive disease adjacent to the patient's colostomy. Diagnosis was confirmed through sequential biopsy, molecular analysis, and definitive surgical pathology, demonstrating a poorly differentiated malignant neoplasm with melanocytic differentiation and immunohistochemical positivity for S100, SOX10, Melan-A, and HMB45. Despite thrombectomy with iliac vein stenting, percutaneous nephrostomy tube placement, arterial embolization, and multidisciplinary oncologic management, the patient experienced progressive metastatic disease and ultimately transitioned to hospice care. This case highlights the aggressive nature of anorectal melanoma and illustrates how advanced pelvic malignancy may produce complex multisystem complications requiring multidisciplinary management.

Panic attacks (PAs) are acute anxiety episodes that are pervasive, with one in 10 individuals having experienced a PA in the past year. PAs impair daily functioning and are associated with an increase in emergency room visits and suicide attempts. Despite their impact, the unpredictable nature of PAs makes them challenging to manage. PAs are transdiagnostic, occurring in individuals across and without a mental health diagnosis. However, prior work has largely focused on PA indications within individuals with panic disorder. This study identifies PA risk factors from over 6 months of passive sensing data recorded by Oura Rings in 182 young adults with and without adverse childhood experiences and psychiatric diagnoses, beyond just panic disorder. Our findings reveal that changes in Oura Ring-derived measures are associated with next-day PAs, with distinct associations observed across different mental health diagnoses. For individuals with panic disorder, the likelihood of PA increases with time spent inactive. For those with depression, the likelihood of PA increases with decreased variation in nightly respiratory rate, decreased rapid eye movement sleep, and increased time spent in high-intensity activity. For those without a mental health diagnosis, the likelihood of PA increases with decreased heart rate variability. Data aggregation window sizes that capture the associations with PA risk vary by diagnosis and the type of feature, suggesting that cumulative physiological patterns from windows up to 7 days before a PA contribute to onset. These findings point to the possibility that continuous monitoring of panic attack risk could one day support preventive mental health intervention.

Human trafficking is a priority concern in the U.S, but few research studies have investigated the nature and extent of its occurrence on U.S. college campuses nor strategies to stop it. The objective of this research was to identify its occurrence (force/coercion/fraud into sex exchanges for something of monetary or other value) among college students in San Diego County and Imperial Valley, California, where some of the highest documented rates of human trafficking occur nationally, and its implications for policy. College students (n = 971) from 12 campuses in Southern California responded to fliers posted on their campuses by completing online self-administered surveys. Nearly one in five students (18%) surveyed reported experiencing human trafficking in college. In bivariate analyses, trafficked students were more likely to be BIPOC, LGBTQ, foster youth, fraternity/sorority members, use illicit substances, experience abuse (physical, emotional, sexual, or being told to recruit others), transport/sell drugs, perform labor, and exchange sex for grades/schoolwork. Multiple logistic regression analyses (adjusting for age, sexual orientation, race) revealed those trafficked were more likely as college students to exchange sex across the U.S.-Mexico border (OR = 4.02; CI: 2.52-6.17), be inhibited to seek academic counseling (OR = 2.58; CI = 1.63-4.10), acquire a sexually transmitted infection (OR:1.63; CI: 1.04-2.57), wonder how they would afford their next meal (OR:1.20; CI: 1.03-1.40), and feel pressure from others (i.e., instructors, peers) to engage in sex (OR:2.69; CI:11.75-4.12). Strategies may need to: 1) expand Title IX implementation to encompass human trafficking/sexual exploitation information at all universities, and 2) amend or introduce state laws mandating human trafficking prevention awareness training at schools to include colleges/universities.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting adverse effect of oxaliplatin-based chemotherapy that markedly impairs treatment adherence and long-term quality of life. Despite extensive investigation, effective preventive and therapeutic strategies remain limited, reflecting the complex and multifactorial nature of its pathogenesis. In this review, we revisit the mechanisms underlying OIPN and propose an integrated, stage-dependent mechanistic perspective. Current evidence indicates that OIPN arises from dynamic interactions among multiple pathological processes operating across temporal and anatomical scales. Early oxaliplatin-induced neurotoxicity is primarily expressed as functional and electrophysiological disturbances, which manifest clinically as acute sensory symptoms such as cold hypersensitivity. With sustained exposure, these alterations progressively engage downstream neuroinflammatory and metabolic cascades, ultimately contributing to structural pathology, including axonal degeneration, and to chronic, often persistent, peripheral neuropathy. Importantly, these mechanisms form self-amplifying loops that facilitate the transition from reversible acute symptoms to irreversible structural damage, providing a mechanistic explanation for the limited success of single-target neuroprotective strategies. Emerging complementary mechanisms are briefly discussed to outline future research directions. By reorganizing current evidence into a hierarchical, stage-linked framework that connects upstream neuronal vulnerability, early functional dysfunction, and downstream inflammatory-structural persistence, this review aims to clarify not only the pathophysiological complexity of OIPN but also its implications for stage-specific and combination-based intervention strategies.

Takotsubo syndrome (TS) is characterized by transient left ventricular dysfunction accompanied by dynamic changes in myocardial tissue; however, differences in cardiac magnetic resonance (CMR) findings across disease phases remain incompletely characterized, particularly in large multicenter cohorts. This retrospective analysis from the multicenter EVOLUTION registry included 439 consecutive patients with TS (400 females; mean age 70.01 ± 11.59 years), stratified according to the time from symptom onset to CMR into acute (1-72 hours), subacute (4-21 days), and late (≥22 days) acquisition groups. Among these, 146 (33%) were classified as acute, 266 (60%) as subacute, and 27 (6%) as late. Biventricular systolic function was higher in patients imaged at later time points (both p = 0.001). Myocardial edema and late gadolinium enhancement (LGE) were more prevalent and extensive in patients imaged earlier and less evident in those imaged later. In multivariable analysis, T2-mapping Z-score and LGE extent were independently associated with earlier timing of CMR. T2-mapping Z-score decreased by approximately 0.22 units per day, corresponding to an average relative decline of 3-4% per day. In conclusion, cross-sectional CMR assessment in TS demonstrates that patients imaged at later time points exhibit more preserved systolic function and lower prevalence of myocardial edema and LGE, supporting the dynamic and reversible nature of myocardial injury in this condition; however, longitudinal studies with serial imaging are needed to confirm these findings.

Skeletal homeostasis depends on tightly coordinated communication between osteoclasts and osteoblasts, yet the molecular logic governing this coupling remains incompletely understood. This review reframes the osteoclast-osteoblast relationship by integrating developmental biology, molecular signaling, and translational perspectives into a unified analytical framework. We first trace the developmental origins of osteoclasts across embryonic hematopoietic waves, presenting evidence that ontogenetic heterogeneity-rather than being a developmental relic-actively shapes the coupling capacity of osteoclast populations throughout life. We then examine the hierarchical differentiation cascade of the osteoblast lineage, emphasizing how the adipo-osteo switch and hormonal regulation at each differentiation stage create multiple points of vulnerability and therapeutic opportunity. A central argument of this review is that pre-osteoclasts function as major, and potentially dominant, coupling effectors in bone remodeling. Operating through a secretome that includes sphingosine-1-phosphate, PDGF-BB, and afamin, these mononuclear precursors coordinate osteoblast recruitment and vascularization independently of bone resorption. However, the relative contribution of pre-osteoclast-derived signals versus other coupling mechanisms likely varies by skeletal site, age, and pathological context. We systematically dissect three core signaling cascades-BMP, sphingolipid/sclerostin, and WNT-and argue that their functional convergence creates a robust yet tunable communication network. We further evaluate recently identified coupling factors including cardiotrophin-1, SLIT3, C3a, and CTHRC1, alongside surface-mediated and vesicle-based communication systems. Finally, we critically assess current therapeutic strategies through the lens of coupling biology, proposing that the persistent failure to develop truly disease-modifying skeletal therapies stems from an incomplete appreciation of the multi-layered nature of osteoclast-osteoblast communication. Collectively, this review establishes that the anabolic and resorptive functions of the osteoclast lineage are mechanistically separable and proposes that therapeutic strategies aimed at expanding the coupling-competent pre-osteoclast pool-rather than broadly suppressing or stimulating remodeling-represent a paradigm shift toward next-generation skeletal therapies that preserve, rather than disrupt, the endogenous coupling network.

Surgery remains the primary treatment modality for high-grade glioma; yet, Q10 median overall survival has seen only modest improvement over the past few decades. Lack of reliable preclinical models that recapitulate the volumes and infiltrative nature of human tumors is a persistent challenge for development and evaluation of new surgical techniques. In this context, the Oncopig model has been shown to produce realistic tumors in other organs. It is a transgenic model that encodes for the oncogenic P53 and KRAS mutations which can be switched on through delivery of Cre-recombinase, usually using a viral vector, driving endogenous tumor induction. The objective of this study was to explore the potential of Oncopigs as preclinical high-grade glioma model. A cocktail of adeno-associated viruses (AAV) encoding Cre-recombinase was implanted in the brains of ten Oncopigs. Animals were then monitored for tumor growth using MRI. Once tumors were detected, an additional MRI was acquired several days later to track growth and animals then either underwent surgical resection or tissue harvest. Tumor specimens were collected for histopathological analysis. Tumors were observed on MRI scans for six of the ten pigs. The median time to observed tumor onset was 24 days and ranged from 13 to 104 days. Tumor volumes prior to euthanasia in these animals ranged from 250 to 2000 mm3. Pathological analysis of tumor specimens revealed infiltrative tumors in six subjects, with features consistent with high-grade glioma. Fluorescence-guided surgical resection with ALA-PpIX in one animal revealed high levels of PpIX fluorescence, also consistent with high-grade gliomas in humans. These results indicate that the Oncopig can be used to induce brain tumors that exhibit pathological features consistent with high-grade glioma in humans. A realistic high-grade glioma model such as this should support better preclinical development and evaluation of new surgical and other treatment strategies.

Drug repurposing is the strategy of identifying novel therapeutic uses for existing, unapproved, or failed drugs distinct from their original indications. Given the unique nature of repurposing, clinical trials for repurposed agents warrant specific design considerations. This article covers specific factors to consider when designing clinical trials for repurposed agents. The specific factors identified are the drug's characteristics, its clinical context, the design and methodology of the repurposing trial, the quality and management of supporting data, and other ethical and organizational concerns specific to repurposing. Drug repurposing is a natural approach to reduce costs and increase the efficiency of drug development, and such trials may offer ethical advantages in terms of participant risk and social value. In the modern landscape of clinical trials, numerous barriers to initiating repurposing efforts exist. Notably, these include challenges related to intellectual property, data availability, and the unexpected and widespread consequences of off-label use and drug access. Other barriers to safe and effective repurposing will continue to challenge trialists and stakeholders, especially regarding the reuse of data, communication, documentation, and other potential confounding factors not experienced in standard trials. Thus, careful ethical assessment of trial characteristics is necessary.

While improvements have been made across the HIV care continuum in South Africa, gaps remain. Relationship-focused couples-based approaches may be one avenue to improve HIV-related outcomes for men and women. Prior couples-based studies have been found to improve several HIV care and treatment outcomes in this context, but few have considered viral suppression as the primary outcome. We aimed to compare a couples-based motivational-interviewing intervention delivered to couples to similar content delivered to men and women in couples separately. We will test the efficacy of this approach in a randomised controlled trial. Our goal is to enrol 270 heterosexual couples for this trial, with at least one partner living with HIV. Couples will be randomised into one of two arms, stratified by couples' HIV status. The intervention arm, Simunye ('We are one' in isiZulu), will provide two sessions of motivational information and skills regarding HIV-related behaviours to couples together, along with relationship-focused content and skills. The content is based on Partner Steps (P-steps), a couples-focused adaptation of Life Steps, an evidence-based programme shown to improve adherence and viral suppression. The control group will receive two sessions as individuals, with similar HIV-related information but without relationship-focused content. Participants will be followed up at 6, 12 and 18 months postrandomisation. The baseline questionnaire will include measures of relationship domains such as satisfaction and communication, and measures pertaining to HIV and reproductive health (eg, fertility intentions, HIV knowledge and risk perception, and sexual behaviour), and mental health (eg, depression symptoms). The primary outcome is viral suppression, based on dried blood spots. Secondary outcomes will include other aspects of treatment engagement. We will also examine hypothesised mediators of intervention participation, for example, relationship dynamics. Primary analyses will use a multilevel modelling approach, which will feature planned time-averaged comparisons of postbaseline measurements across the intervention and control groups to test the primary hypothesis. The analysis will account for the dyadic nature of the data, for example, participants nested within couples. This trial was approved by the Institutional Review Board (IRB) at the Human Sciences Research Council in South Africa, protocol number 2/27/01/21, and the IRB at the University of Michigan (HUM 00203672). Human subjects' concerns or adverse events will be reported to both IRBs and the Data Safety and Monitoring Board. We will disseminate findings to community members and stakeholders via community meetings, as well as by conference presentations and publications in peer-reviewed journals. Clinicaltrials.gov Protocol Registration NCT05231707 registered on 8 February 2022. Protocol version 2.0, 31 October 2025.

To report the outcomes of patients with heel pad degloving injuries, and to identify patient, injury, or treatment factors associated with successful repair. Retrospective cohort study. Single level 1 academic trauma center. All patients admitted with an acute heel pad degloving injury between 2005-2024 were included. The primary outcome was successful repair of a heel pad degloving injury. Univariate analysis was performed to examine risk factors for primary repair failure. Fifty-eight patients with acute heel pad degloving injuries were included, of whom fifty were male with average age of 35 years (range 6-69, SD 17). Forty patients were treated with an attempt at primary repair, three were treated primarily with a flap, and 15 were treated with primary amputation. Primary repair was successful in 15 patients (38%). Repair method (suture alone, augmentation with k-wires, incisional wound vac) was not associated with repair success (p>0.05 for all). Of the patients with failed primary repair, 6 underwent secondary amputation, while 19 underwent attempted salvage with a flap (13), skin graft (5), or dermal substitute (1). Of the 19 with attempted salvage, 10 (53%) had complications including persistent ulceration, infection, and/or wound breakdown. Two of this cohort underwent secondary amputation. No patients in the successful primary repair group underwent later amputation. The rate of success after attempted primary repair of heel pad degloving injuries was 38% in this series. The rate of secondary amputation was 20%. Augmenting primary repair with suture anchors or k-wires, or addition of a wound vac, was not significantly associated with improved success rates in univariate analysis, although these findings are limited by the retrospective nature of the study. Skin and soft tissue necrosis was the reason for failure of primary repair in all cases. Future studies may consider using techniques such as indocyanine green angiography to assess heel pad perfusion and identify patients at risk for failure of primary repair. Finally, although complication rates after failed primary repair were high, ultimately most limbs that underwent secondary flap reconstruction were able to be salvaged. III.

The treatment of central nervous system tumors remains challenging owing to their highly proliferative nature, aggressiveness, and poor prognosis. Additionally, existing treatment methods have several problems, including high risk of complications, systemic side effects, and impact on patients' quality of life. Recently, cannabidiol (CBD), a non-psychoactive cannabinoid found in Cannabis sativa, has emerged as an alternative therapeutic medication because of its potential antitumor activity with fewer side effects. We evaluated the cell viability, clonogenicity, migration, apoptotic nuclear morphology, and cell cycle phases of C6 rat glioma, SH-SY5Y human neuroblastoma, and HT22 immortalized mouse hippocampus neuronal cultures treated with CBD ranged between 0 and 10 μg/mL. CBD concentrations exceeding 5 μg/mL induced significant reductions in cell viability in C6 glioma and SH-SY5Y neuroblastoma cultures, accompanied by decreased clonogenicity in both cultures at 10 μg/mL. A scratch assay for cell migration revealed that 5 μg/mL CBD suppressed C6 glioma cell migration. Additionally, late apoptotic nuclear morphology was observed in C6 glioma cultures treated with 10 μg/mL cannabidiol. Similarly, HT22 hippocampal neuronal cultures exhibited decreased cell viability and clonogenicity, with apparent nuclear signs of apoptosis at CBD concentrations over 5 μg/mL. Notably, CBD disrupted HT22 cell migration at concentrations of 2.5 and 5 μg/mL. Proteomic profiling of C6 glioma revealed upregulation of ribosomal proteins, molecular chaperones, and modulators of cytoskeletal dynamics upon treatment with 1 μg/mL CBD. In comparison, treatment with 2.5 μg/mL CBD led to marked downregulation of endoplasmic reticulum chaperones, mitochondrial ATP synthase, and cytoskeletal regulators. Our findings confirm the sensitivity of glioma, neuroblastoma, and hippocampal neuronal cultures to CBD, providing valuable insights for further research into its therapeutic potential against glioma, neuroblastoma, and neuronal disorders.