The emergence of aggregation-induced emission (AIE) luminogens has revolutionized biomedical theranostics, yet the exploration of natural AIE-active therapeutics remains nascent. Herein, we propose a novel "AIE-Pharmacology" paradigm, employing the natural flavonoid acacetin as an intrinsic AIEgen with pharmacological activity for self-monitored therapy of asthenozoospermia. Overcoming traditional aggregation-caused quenching (ACQ), acacetin utilizes its aggregation-enhanced emission and excited-state intramolecular proton transfer (ESIPT) properties to enable simultaneous treatment, high-contrast imaging, and tracking. We developed an extracellular vesicles (EVs)-based co-delivery system loaded with acacetin and β-Nicotinamide mononucleotide (NMN). This nanoplatform (EVs@N + A) exhibits inherent affinity for the testicular microenvironment. Upon targeted accumulation, released acacetin triggers a potent anti-ferroptotic response by upregulating GPX4 and SLC7A11 and suppressing lipid peroxidation. In parallel, NMN elevates intracellular NAD+ levels, reprogramming cellular metabolism and restoring ATP production. This dual strategy-inhibiting ferroptosis and rejuvenating metabolism-effectively rescues sperm function, enhancing sperm count, motility, and progressive movement in vivo. Our work reports acacetin as a multifunctional AIEgen in reproductive medicine and establishes a traceable theranostic platform, introducing the "AIE-Pharmacology" paradigm as a promising approach for treating male infertility and other diseases.
Drug-induced obsessive-compulsive (OC) symptoms have been described for clozapine and several second-generation antipsychotics, whereas reports involving cariprazine remain scarce. The present report describes the case of a 28-year-old Thai female patient with bipolar II disorder who had premorbid, subclinical counting compulsion, which had remained stable since its onset in adolescence. After 3 days of cariprazine treatment during a regimen switch for bipolar disorder, the pre-existing counting compulsion worsened and additional patterns of OC symptoms emerged. At seven days after discontinuation of cariprazine, the newly emerged symptoms were fully resolved, while the counting compulsion returned to its baseline subclinical severity. The present report highlights the need for clinical vigilance regarding OC symptom exacerbation with cariprazine treatment as a part of comprehensive follow-up of the mental health and wellbeing of psychiatric patients. Potential mechanistic considerations involving serotonergic and dopaminergic systems are discussed. The literature review of drug-induced OC symptomatology in the present study also identified limited documentation of premorbid OC symptomatology and age-at-onset phenotypes. Future reports incorporating detailed phenotypic characterization may improve the identification of patients at risk of symptom exacerbation.
Bicruciate-retaining (BCR) total knee arthroplasty (TKA) was developed to better replicate native knee biomechanics by preserving both cruciate ligaments. First-generation BCR implants were notorious for technical challenges and suboptimal survivorship. However, advancements in implant design and surgical techniques have renewed interest in second-generation BCR TKA systems. This study aimed to evaluate the overall survivorship of contemporary (second-generation) BCR primary TKA implants. A systematic review of PubMed, Scopus, Embase, Web of Science, and Cochrane databases was conducted from inception to January 3, 2025. Inclusion criteria were studies that reported the number of revisions following second-generation BCR TKA. We excluded case reports, review articles, and studies that evaluated first-generation BCR TKA. A total of 1046 articles were retrieved; ultimately, 13 were included. Events per person-years pooled analysis was performed to estimate the incidence of all-cause revision, adjusting for duration of follow-up. Heterogeneity was measured using I2 test. A p-value < 0.05 was considered statistically significant. A total of 1,087 BCR TKA implants among 13 studies were analyzed. The mean follow-up was 2.6 years. A total of 62 (5.7%) knees were revised. The overall pooled rate of all-cause revision was 1.6 per 100 person-years (95% confidence interval [CI] 0.009-0.023) Heterogeneity among the analyzed studies was significant (I2 = 75.5%, p < 0.001). Contemporary BCR TKA implants showed improved survivorship compared to historical reports, with a low pooled all-cause revision rate of 1.6 per 100 person-years, corresponding to a 1.6% chance of revision per year of follow-up. Despite the associated heterogeneity, these findings suggest that modern BCR designs offer durable outcomes and support their continued use. Further long-term comparative data are needed to better define their role relative to modern knee implants.
Genomics is transforming health care but its implementation raises challenges. This paper reports a 2025 workshop on justice in the implementation of genomics for rare disorders. The workshop goals were to develop a consensus understanding of the problems faced by rare disease patients and families where justice is at stake, to achieve a shared perspective on support for rare disease patients, and to consider the implications for justice in several areas of rare disease genomics, in both research and healthcare. We heard about the diverse experiences and needs of patients. Inequity between different rare diseases is marked. The need for coordination of care for rare disease patients is under-recognized but good models of rare disease care exist. The value of conscientious professionalism to nurture a rare disease mindset needs to be emphasized in the training of each new generation of healthcare students//trainees. The circumstances of different population groups differ systematically. The needs of indigenous and other historically marginalised groups must also be addressed. However, the subordination of individuals to the benefit of the population (i.e. eugenics) must be resisted. Those engaged in genomics projects or diagnostics may need protection from hype and misuse of their personal data, There are different perspectives on the fair allocation of resources to healthcare and research for rare conditions. Health economics and health technology assessment can be practised equitably, so as to meet the challenges of rare disease clinical trials and address the needs of patients and communities.
WHO-designated critical-priority Enterobacterales are increasingly detected beyond healthcare settings, with reports in marine wildlife suggesting broader environmental dissemination and raising potential concerns about wildlife health. Procellariiformes are highly migratory pelagic seabirds and key sentinels of ocean health, yet colonisation by these bacteria remains understudied. To address this gap, we evaluated critical Enterobacterales in samples from Procellariiformes admitted to a rehabilitation centre on the southern coast of Brazil. Thirty-one Enterobacterales isolates, pre-selected based on β-lactam resistance from the CePRAM/R3 Animal culture collection, were retrospectively analysed and characterised phenotypically and genotypically. Among these, 17 (54.8%) met WHO critical-priority criteria. Fifteen were resistant to third-generation cephalosporins, with frequent detection of blaCTX-M-1 and co-resistance to quinolones, aminoglycosides, and tetracyclines. Two isolates (Enterobacter roggenkampii and Escherichia coli) produced NDM-1 and underwent whole-genome sequencing; both carried blaNDM-1 on an IncA/C2 plasmid and had extensive resistomes. The E. coli co-produced NDM and CTX-M-8 and encoded a broad virulence repertoire consistent with an APEC-associated genotype. In silico analyses revealed determinants associated with heavy-metal, biocide tolerance, osmotic and ionic stress responses, suggesting genomic potential for persistence in saline and contaminated environments. Three host species carrying critical-priority Enterobacterales are currently listed as threatened, underscoring conservation and One Health concerns. The detection of critical-priority, virulent Enterobacterales among pre-selected resistant isolates from Procellariiformes supports their relevance in One Health surveillance, while also highlighting potential risks to threatened hosts. These findings support integrated One Health surveillance and mitigation efforts spanning wildlife, marine environments, and human activities.
Uterine cancers include endometrial cancer (EC), cervical cancer (CC), and uterine sarcomas, with leiomyosarcoma being the most common subtype. Each tumour type has distinct biological behaviour, imaging features, and treatment approaches. Radiologists must be familiar with normal uterine anatomy and its variations, as well as key imaging characteristics and common patterns of tumour spread to ensure accurate staging and optimal treatment selection. MRI is the imaging modality of choice for evaluating uterine malignancies due to its excellent soft tissue contrast and multiplanar capabilities. Accurate assessment requires dedicated multiparametric protocols, as recommended by the European Society of Urogenital Radiology (ESUR), including high-resolution T2-weighted imaging, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) sequences when appropriate. 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) complements MRI in patients with CC by providing the highest accuracy for detecting lymph-node and distant metastases. CT is mainly used for systemic evaluation. This article presents a practical guide for radiologists, describing the main clinical indications, patient preparation, and tailored MRI protocols. It also highlights key imaging findings that should be evaluated and reported. KEY POINTS: MRI is the preferred imaging modality for evaluating uterine malignancies due to its superior soft tissue contrast and multiplanar capabilities. Common clinical indications include MRI staging of endometrial and cervical cancers, assessment of eligibility for fertility preservation, and characterisation of indeterminate myometrial lesions. Adherence to established imaging guidelines is strongly recommended to ensure high-quality images as well as complete and clinically relevant radiology reports.
The rapid integration of artificial intelligence (AI) technologies in healthcare, ranging from diagnostic tools to clinical decision support systems, is transforming medical practice and education. However, without deliberate integration of ethics, there is a risk that medical education will reproduce a technosolutionist orientation by privileging efficiency and data-driven outputs over patient autonomy, justice and professional integrity. While AI-related courses are increasingly being introduced into medical curricula, ethical considerations often remain peripheral, with most frameworks emphasising technical skills over moral reasoning. As future clinicians will face complex ethical challenges related to autonomy, safety, bias, transparency and accountability in AI-integrated clinical settings, there is an urgent need to evaluate how ethics is incorporated into AI education. With AI curricula still in their formative stages, this moment presents a critical opportunity to proactively design ethical components, rather than introducing them after harms have emerged. This scoping review aims to systematically map the ethical-technical balance in AI-related medical education curricula, identifying current practices, gaps and opportunities for curriculum development. This scoping review will follow the Joanna Briggs Institute methodology and be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. The review will address how ethical considerations are integrated into AI-related curricula in medical education and examine the balance between ethical and technical content. A comprehensive search strategy will be employed across multiple databases, including MEDLINE, Web of Science, Google Scholar, EBSCO, the Virtual Health Library, the Bioethics Literature Database and PhilPapers, as well as grey literature sources such as institutional reports, curricula and policy documents. Publications from January 2020 to December 2025 will be included. Data will be charted and analysed using descriptive qualitative content analysis, followed by a theory-informed interpretive analysis drawing on the hidden curriculum theory of medical education. This review does not require ethics approval, as it involves analysis of publicly available data. Findings will be disseminated through a peer-reviewed publication and presented at relevant conferences and workshops focused on medical education or bioethics.
Hidradenitis suppurativa (HS) is a painful inflammatory skin disease within the pilosebaceous unit associated with numerous comorbidities, including obesity type-2-diabetes (T2DM), and a general meta-inflammatory state. This narrative review explores the therapeutic potential of GLP-1-receptor-agonists (GLP-1RAs) in treating HS by analyzing mechanisms of action and clinical outcomes. Based on a literature search, encompassing 12 cohorts and 4 case-based reports, current evidence demonstrates significant improvements in both clinical and patient-reported outcomes in patients with HS treated with GLP-1RAs. Treatment consistently resulted in reduced body mass index (BMI) and disease activity, measured by Hurley-staging and the number of nodules and abscesses. Patients across studies experienced fewer flares and less pain, supporting improvements in dermatology quality of life (DLQI) scores. Studies observed reductions in systemic inflammatory markers and improved glycemic control. The beneficial effects of GLP-1RAs in HS are attributed to the reduction in mechanical friction and metabolic improvements from weight loss. Suggestively, concurrent and direct anti-inflammatory mechanisms, including inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and modulation of cytokines, occur independently of weight-reduction. Results from cohorts and cases supported this theory, showing significant improvements in HS and metabolic markers independent of weight-related outcomes. Four supplementary cohorts found GLP-1RAs beneficial for cardiovascular comorbidities in patients with HS. Additionally, studies suggest that GLP-1RAs enhance the efficacy of biologic therapies used for HS and reduce the need for adjunctive treatment. In conclusion, GLP-1RAs represent a promising pleiotropic treatment within a multimodal therapy strategy for HS and comorbidities.
Piper regnellii ("Pariparoba"), is a shrub widely employed in traditional medicine, particularly in the form of leaf infusions or decoctions. These preparations are traditionally used for the treatment of wounds, infections, edema, skin lesions, pain, and other inflammatory conditions. Building upon traditional reports of P. regnellii associated with inflammatory conditions, this study combined chemical profiling and bioactivity assays to evaluate its inhibitory effects on key inflammatory mediators (PGE2 and LTB4), alongside its effects on the reduction of calcium oxalate (CaOx) crystals. The anti-urolithiatic activity of P. regnellii infusion was evaluated using urine containing calcium oxalate (CaOx) crystals at concentrations of 0.5, 1.0, and 1.5 mg/mL. The results were compared to negative and positive controls (sodium citrate and Cystone®). Anti-inflammatory activity was assessed using an ex vivo human whole blood assay, evaluating key inflammation mediators, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). The infusion's chemical profile was determined by UHPLC-ESI-HRMS in positive ion mode, using a gradient chromatographic method. Data were processed using MZmine software, and chemical annotation was performed utilizing in-house and online databases. In the ex vivo anti-inflammatory assay, infusion samples significantly reduced LTB4 and PGE2 levels with significant statistical differences compared to the negative control (p≤0.05). The infusion demonstrated inhibition percentages of 57.4% and 75.1% for the release of LTB4 and PGE2, respectively. In the in vitro anti-urolithiatic evaluation, all tested concentrations of P. regnellii showed statistically significant differences compared to the negative control (p≤0.05), with the highest concentration (1.5 mg/mL) demonstrating the strongest crystal reduction capacity (90.4%) and a calculated IC50 value of 0.21 mg/mL for anti-urolithiatic activity. Metabolic profiling of the aqueous extract revealed the presence of multiple bioactive compounds. The predominant classes of annotated compounds found on P. regnellii infusion were flavonoids, and other classes of compounds were also found. From all detected metabolites, 12 could be annotated at level 2 of confidence. This study provides scientific evidence supporting the traditional use of P. regnellii infusion related to inflammatory conditions. Additionally, the evaluation of its anti-urolithiatic effects expands the preliminary pharmacological insights into this species. Collectively, these findings suggest that P. regnellii may represent a promising source of bioactive compounds for the development of multitarget strategies addressing both inflammatory processes and urolithiasis-associated mechanisms.
Heart failure (HF), a major global health challenge, affects millions worldwide and poses substantial healthcare and economic burdens. It is estimated that a large proportion of those with early systolic dysfunction remain asymptomatic at a stage when guideline-directed medical therapies have been shown to prevent disease progression. To develop an artificial intelligence (AI) model capable of predicting abnormal left ventricular ejection fraction (EF) directly from static, non-gated, non-contrast chest computed tomography (CT) scans as a form of opportunistic screening. Using a multi-institutional dataset of 34 058 paired non- contrast CT images and echocardiogram reports from two academic centres, we trained our model of classification for predicting left-ventricle ejection fraction (LVEF) categories: abnormal EF (EF < 50%) vs. normal on 25 948 studies. We validated the model on 8110 paired chest CT and echocardiogram results from a separate institution. The model achieved an area under the receiver operating characteristic (AUROC) curve of 0.786 on the hold-out test set and 0.762 on external validation to detect an abnormal EF (<50%). Beyond strong predictive performance, the AI model surpassed expert radiologists in both accuracy and efficiency and provided interpretable visualizations highlighting imaging features linked to reduced LVEF. In this study, we developed and validated an AI model capable of predicting abnormal LVEF directly from static, non-gated, non-contrast chest CT scans, a novel application for an imaging modality typically used for unrelated indications as a form of opportunistic screening. This technology holds significant promise for early detection of systolic HF, reducing the diagnostic gap, and improving outcomes in asymptomatic HF patients.
Qualitative research offers key insights into enablers and obstacles of healthcare-seeking behavior, and the credibility of findings depends on methodological quality. This study aims to critically appraise the methodological quality of existing qualitative studies on delayed medical consultation in obstructive sleep apnea (OSA) patients, thereby identifying common limitations and offering recommendations for future improvements. A systematic search was conducted in EMBASE, MEDLINE, and CENTRAL databases, covering literature from inception to February 2026. Inclusion criteria were qualitative studies (e.g., phenomenological, ethnographic, or grounded theory paradigms) on medical consultation delays in adult OSA patients, excluding single-case studies or narrative reports with very small samples. Two reviewers independently assessed studies against five dimensions, with disagreements resolved by discussion. Three studies were included, from which eight methodological issues were identified: (1) potential "survivorship bias" from including only diagnosed patients; (2) recall bias in retrospective designs; (3) insufficient consideration of the role of comorbidities in the healthcare-seeking process; (4) unclear directionality between cognitive factors and delayed behavior; (5) lack of in-depth analysis of deviant cases; (6) oversimplified view of family/friend support; (7) insufficient transparency in reporting interview guides and data saturation; and (8) absence of researcher reflexivity during data collection and analysis. Current qualitative studies on delayed medical consultation in OSA patients have several methodological flaws that may affect their validity. Future research should prioritize prospective, community-based studies targeting high-risk OSA populations not yet seeking medical help, and comprehensively document the entire trajectory of their medical consultation delay. This will enhance research rigor and provide clearer guidance for developing more actionable intervention strategies.
This study reports a congenital heart disease, characterized by ventricular wall thinning and septal defects, caused by a heterozygous missense mutation (R755 W) in the glycolytic gene PFKP (platelet isoform of phosphofructokinase-1). The pathogenic mechanism involves the PFKP mutation impairing enzyme activity, which inhibits cardiomyocyte proliferation and leads to the thinning of the compact myocardium. In the mouse model, we found that administering the downstream metabolite, fructose-1,6-bisphosphate, reversed the myocardial hypoplasia in fetal mice, providing proof-of-concept for in utero intervention. Clinically, we successfully prevented the transmission of the disease using preimplantation genetic testing, resulting in the birth of a healthy infant.
Neuropathic pain is one of the most common and debilitating complications following spinal cord injury (SCI), frequently surpassing motor and sensory deficits as the symptom patients most want treated. Despite advances in understanding the molecular and physiological mechanisms underlying central neuropathic pain, effective treatments remain lacking and show wide variability in efficacy. Previous reports have indicated that early intervention represents the most effective pain management strategy, underscoring the clinical importance of identifying patients at risk during the acute care phase. We utilized the TRACK-SCI prospective clinical research database to assess neuropathic pain outcomes in all enrolled SCI patients and identify acute care variables predictive of chronic neuropathic pain development. Pain status was evaluated at 6 and 12 months post-injury. Candidate predictors were analyzed using multidimensional analytics, and a logistic regression model was constructed and validated using repeated 5-fold cross-validation. Of 61 patients in the study cohort, 36 (59%) reported neuropathic pain in the chronic stages after SCI. Four acute care variables were identified as significant predictors of chronic neuropathic pain development: (1) the total number of systemic injuries sustained, (2) the injury severity score (ISS), (3) the lower limb total motor score, and (4) the sensory pinprick total score. The logistic regression model achieved a balanced accuracy of 74.3%, and repeated 5-fold cross-validation yielded an AUC of 0.708. These findings highlight a crucial role of polytrauma in the development of chronic pain after SCI. The four identified predictors are parameters routinely measured in every trauma center, making the proposed model readily translatable to clinical practice. This predictive tool may enable earlier, targeted intervention for at-risk patients, addressing the clinical need for proactive pain management strategies in the acute post-SCI setting. Future work should validate this model in larger, independent cohorts and explore its utility in guiding early treatment decisions.
Healthcare workers (HCWs) may have a higher risk of developing long COVID due to greater exposure to COVID-19, with symptoms extending beyond the acute phase impacting their daily living activities and job performance. To systematically map the existing literature on the impact of long COVID on HCWs' job performance, focusing on their time to return to work and work ability. A scoping review following PRISMA-ScR guidance included peer-reviewed studies in English or Spanish (January 2020-December 2024). Four databases were searched. Experimental, epidemiological and qualitative studies were eligible. Two reviewers independently screened records. Methodological quality was appraised using the Mixed-Methods Appraisal tool (MMAT). Nineteen studies were included, mainly European and predominantly cross-sectional. Long COVID was most often defined as symptoms lasting ≥ 3 months. Among HCWs with prior infection or whole-staff samples, prevalence ranged from 10% to 74%, with multiple reports above 50%. Thirteen studies evaluated RTW, with 19-63% resumed work within six months, commonly with restrictions, while around one in five remained unable to work in some cohorts. Full-time employment decreased markedly (e.g., 57% pre-infection vs 31% at follow-up). Between 16% and 40% required workplace adjustments such as reduced hours, reassignment, or avoidance of night shifts. Sixteen studies reported diminished work ability compared with pre-infection or unaffected peers. Greater symptom burden, particularly cognitive impairment and fatigue, consistently predicted poorer outcomes. One study estimated a mean of 223 days to reach current work-ability levels. Older age, depression, comorbidity, and acute disease severity were recurrent associated factors while evidence for gender and job category was inconsistent. Long COVID delays RTW and reduces work ability in HCWs. Health services should plan long-term occupational follow-up, flexible reintegration pathways, and targeted accommodations while higher-quality longitudinal research refines risk and prognosis.
The demand for secondary rhytidectomies is increasing. These procedures are technically more demanding than primary surgery due to postsurgical anatomical changes, presenting unique challenges and risks. The objective of this systematic review is to define these challenges, describe common surgical principles, and summarize the reported outcomes and complications of secondary rhytidectomies. A literature search was conducted on PubMed and Scopus using particular keywords. Inclusion criteria included randomized controlled trials, observational studies, comparative studies, case series and case reports that reported the surgical outcomes of secondary rhytidectomies. Fourteen articles were included in this systematic review, encompassing 737 patients. Presentation was approximately 9-12 years after primary surgery. The most consistent intraoperative finding was altered anatomy, including a thinner, more delicate superficial musculoaponeurotic system (SMAS), fibrosis, and scarred tissue planes. Reported complication rates in cohort studies ranged from 2.0 % to 21.1 %. The most common complications were hematoma and temporary facial nerve injury, with rates of the latter reaching as high as 11.9 % in some series. Other reported adverse events included seroma, minor skin slough, and delayed healing. A secondary rhytidectomy presents distinct intraoperative challenges stemming from altered anatomy. Despite this increased complexity, the existing literature suggests that overall complication rates are comparable to those of primary facelifts.
Peripartum cardiomyopathy (PPCM) is a rare disease that causes heart failure during pregnancy or in the early postpartum period, and there were no reports on the trend of clinical condition and treatment in Japan. This explanatory retrospective study aimed to investigate the changes in clinical conditions and treatment in patients with PPCM. Twenty-three patients (aged 22-43 years; mean age, 32 years) with PPCM from four hospitals in Nagasaki Prefecture were included. We compared the heart failure status and treatments of PPCM between the 10 years from January 2002 to December 2011 (first era) (N = 10) and the 11 years from January 2012 to December 2022 (second era) (N = 13). Left ventricular ejection fraction (LVEF) on admission was higher (first era 20% (interquartile range (IQR) 17-34) vs. second era 34% (IQR 25-37), p = 0.0213), and less patients treated with inotropes in patients in second era than those in first era (first era 6/10 (60%) vs. second era 2/13 (15%), p = 0.0393). Hospitalization period was shorter in second era than those in first era (first era 38 days (IQR 22-45) vs. second era 19 days (IQR 16-22), p = 0.0159). In recent years, patients with PPCM have been admitted before progression of LV dysfunction, and that may be related to a decrease in use of inotropes and hospitalization period in Japan.
Natural products are used in the discovery of novel therapeutic agents. Ischemic stroke is a neurological disorder caused by the obstruction of cerebral blood vessels, sometimes leading to paralysis and potentially death. Despite the complexity of this condition, therapeutic options are limited and typically associated with severe side effects, including intracranial hemorrhage. The present study aimed to explore the toxicity and anti-ischemic stroke activity of aqueous extracts from the aerial parts of gotu kola (Centella asiatica; CA), moringa leaves (Moringa oleifera; MO), turmeric rhizomes (Curcuma longa; CL), black pepper seeds (Piper nigrum; PN), and snakehead fish fillets (Channa striata; CS) in zebrafish. Toxicity tests were conducted in zebrafish embryos for 96 h. Ischemic stroke was induced in zebrafish larvae incubated in ponatinib (Pon) solution. In total, three concentrations of each extract, namely ¼ of the 10% lethal concentration (LC10), ½ LC10 and LC10, were derived from toxicity testing and applied in anti-ischemic stroke assays. All extracts were considered non-toxic as their LC50 values were >100 µg/ml. At certain concentrations, the extracts decreased hatching (>625 µg/ml CA and CL, >250 µg/ml MO, and >125 µg/ml CS) and survival rates (>625 µg/ml CA, >250 µg/ml MO, >156.25 µg/ml, >125 µg/ml PN and CS) and resulted in morphological deformity. Moreover, CA, MO, CL and CS, especially at their highest concentrations, significantly decreased the area of cerebral thrombosis compared with the Pon group. CA, MO, PN and CS ameliorated locomotor deficits following ischemia, as evidenced by significant improvements in average speed and total distance traveled. Among all extracts, CS at 29 µg/ml showed the greatest potential for development as an ischemic stroke treatment, exhibiting the strongest effects in preventing blood vessel blockage and restoring locomotor function following ischemia.
Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets. We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors. In 2023, there were an estimated 9·11 million (95% uncertainty interval 8·04-10·3) incident cases of all-form TB, 1·22 million (0·98-1·49) deaths, and 54·6 million (43·8-65·5) DALYs globally. HIV-related TB comprised 781 000 (690 000-879 000) incident cases and 210 000 (142 000-279 000) deaths, contributing 11·0 million (7·56-14·3) DALYs. MDR-TB accounted for 466 000 (198 000-1 080 000) incident cases, 102 000 (31 700-238 000) deaths, and 3·96 million (1·31-9·01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19·2% (17·8-20·5) and deaths declined by 22·6% (4·7-35·7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768 000 (592 000-970 000) and DALYs to 34·9 million (27·8-43·8) in 2023; MDR-TB deaths would decrease to 77 200 (23 400-183 000) and DALYs to 3·12 million (1·03-7·29). Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress. Gates Foundation.
Artificial intelligence (AI) is increasingly being integrated into healthcare, particularly in data-intensive chronic diseases that rely on longitudinal monitoring and shared decision-making. Multiple sclerosis is a prototypical example of such care, but real-world benefit will depend on whether people accept AI support in different clinical roles. We conducted a cross-sectional, web-based survey among 241 people with MS (pwMS) to assess comfort with AI across eight clinical domains and to identify predictors of acceptance. We derived an artificial-intelligence attitudes composite with high internal consistency (Cronbach alpha = 0.90). Overall acceptance was moderate (mean 3.39 ± 0.78). Acceptance differed across domains, demonstrating a responsibility gradient: comfort was highest for supportive applications such as chronic management (54.4%) and symptom screening (50.2%), but lower for treatment selection (38.6%) and diagnosis (35.3%; P < 0.001). In multivariable models, frequent general AI use (at least weekly; 30.7%) was the strongest independent predictor of acceptance (P < 0.001). Acceptance also differed by region (Eastern vs Western Germany, P = 0.025), whereas clinical disability was not significantly associated. Older age was associated with lower acceptance of AI-supported management. Most participants viewed AI as a logistical support tool but, assuming equal diagnostic accuracy, 78.8% preferred joint artificial-intelligence-clinician decision-making with clinician final responsibility. These findings indicate that acceptance may be context-dependent and more strongly associated with prior familiarity than with disease severity. Implementation should move beyond technical validation to transparent, clinician-led 'human-in-the-loop' workflows with explicit accountability and staged adoption beginning with low-risk use cases.
T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCEs are now being investigated for the treatment of autoimmune diseases, with promising initial results. The interest in using TCEs for autoimmune diseases is rapidly growing given their comparable potency with cellular therapies, combined with the advantages of biologics, including ease of manufacturing, off-the-shelf availability, better safety and more convenient delivery. Here we review the history of TCEs, focus on distinct aspects of the mechanism of action of TCEs and explain design principles. We also discuss key challenges for future TCE development in autoimmunity, including enhanced safety, high convenience and complete target cell elimination. Finally, we provide an overview of the preclinical and clinical development landscape and give an outlook on next-generation TCEs that are optimized to treat a wide variety of autoimmune diseases.