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Purpose: Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis., Experimental Design: In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted., Results: Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood-brain barrier-permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis., Conclusions: Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis., (©2025 American Association for Cancer Research.)

Background: Little is known about the mechanisms of exercise intolerance and exertional symptoms in children with long COVID. Through utilization of cardiopulmonary exercise testing (CPET), this study is the first of its kind to evaluate exertional symptoms and attempt to identify potential mechanism of long COVID-19 in children., Objective: To determine if CPET will uncover potential reasons for persistent symptoms of long COVID when there is no indication of cardiopulmonary or upper airway disease., Methods: We performed a retrospective chart review study involving children 6-17 years of age with symptoms of long COVID at Phoenix Children''s Hospital from January 1, 2021, to June 1, 2022. Symptoms included but were not limited to exercise intolerance, fatigue, shortness of breath, dyspnea on exertion, and chest pain. We recorded any measurable abnormalities present on CPET after comparing it to established normal reference ranges. Range, median, and SD of data points were calculated and p values were determined using the Mann-Whitney U and Fisher's exact test., Results: Twenty-three children with exertional symptoms consistent with long COVID were identified. The most frequent symptoms reported during exercise include dyspnea on exertion (35%), followed by chest pain (30%) and dizziness (13%). Nearly half of the children (47%) demonstrated decreased exercise capacity with 30% displaying limitations due to deconditioning, 22% limited by body habitus, and 13% due to bronchospasm. Other contributing factors include ventilation to perfusion mismatch and volitional hyperventilation., Conclusion: Decreased aerobic activity due to multiple factors was found in 47% of children with a history of COVID-19. This study illustrates the importance of ongoing research into this phenomenon to elucidate its mechanism and assist physicians in making decisions regarding referral to specialists for further testing., (© 2024 American Academy of Physical Medicine and Rehabilitation.)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor overall survival rate. Cellular stress response pathways promoting cancer cell fitness in harsh tumor microenvironment (TME) play a critical role in cancer growth and survival. The influence of oncogenic Kras, multi-functional heterogeneous cancer-associated fibroblasts (CAFs), and immunosuppressive TME on cancer cells makes the disease more complex and difficult to treat. The desmoplastic reaction by CAFs comprises approximately 90 % of the tumor, with only 10 % of cancer cells making things even more complicated, resulting in therapy resistance. Consistently increasing fibrosis creates a hypoxic environment and elevated interstitial fluid pressure inside the tumor constraining vascular supply. Stress conditions in TME alter translation efficiency and metabolism to fulfill the energy requirements of rapidly growing cancer cells. Extensive research has been conducted on multiple molecular and metabolic regulators in PDAC TME. However, the role of TME in influencing translation programs, a prerequisite for cell cycle progression and functional/growth requirements for cancer cells, remains elusive. This review highlights the recent advancements in understanding altered translational programs in PDAC TME. We emphasize the role of ribosome biogenesis, ribosome-induced stress response, and the concept of specialized ribosomes and their probable role in mutationally rewiring the pancreatic TME., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2025. Published by Elsevier B.V.)

Abstract: Natural killer (NK) cells play an integral role in immunosurveillance against myeloid malignancies, with their mature phenotype and abundance linked to prolonged treatment-free remission in chronic myeloid leukemia (CML). However, NK cell function is suppressed during the disease, and the orchestrators of this impairment are not fully understood. Using a chimeric BCR::ABL1+ CML mouse model, we characterized the impact of the leukemic microenvironment on NK cell function. We showed that NK cells have reduced counts, immature phenotype, poor cytotoxicity, and altered expression of activating and inhibitory receptors in CML mice, which revert to a steady state upon BCR::ABL1 inhibition. Single-cell RNA sequencing revealed an inflammatory cytokine response in CML-exposed NK cells, highlighted by the tumor necrosis factor α (TNFα)-induced gene signature, upregulation of TNFα receptor 2, and enrichment of suppressor of cytokine signaling family genes such as Cish, the critical NK cell checkpoint. Ex vivo exposure of healthy NK cells to leukemic soluble factors compromised target-specific NK cell degranulation, which was partially rescued by targeting Cish or TNFα. In alignment with these findings, NK cells from healthy donors displayed suppressed cytotoxicity when exposed to plasma from untreated patients with CML, with a partial restoration upon Cish or TNFα inhibition. Furthermore, NK cells from newly diagnosed patients with CML predestined for blast crisis showed an enrichment of the TNFα-induced proinflammatory gene signature identified in CML mice. These results suggest that targeting inflammatory signaling could enhance NK cell-based immunotherapies for CML., (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Although often clinically silent, myocardial bridges are challenging to functionally characterize and subsequently manage. Here we describe a patient with asymptomatic, transient ST-segment elevations in the emergency room, found to have mid to distal left anterior descending artery bridging raising concern for silent ischemia., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Colony stimulating factor 1 receptor-related leukoencephalopathy (CSF1R-L) is a rare, adult onset leukoencephalopathy. Descriptions from the Indian subcontinent remain limited., Objective: To report four patients with genetically confirmed CSF1R-L from four Asian Indian families, describing clinical, molecular and radiological features., Methods: All patients underwent clinical examination, MRI brain, and whole exome sequencing to identify causative variants in CSF1R gene. We also reviewed published Indian cases with CSF1R-L., Results: Age at enrolment ranged from 34-40 years. Duration of symptoms ranged from 11 months to 2 years. The chief clinical phenotype in three patients was a rapidly evolving cognitive-behavioural syndrome combined with atypical parkinsonism, and asymmetrical spastic tetraparesis in one patient. We identified four different variants (three missense, one inframe deletion). Radiological findings demonstrated white matter involvement, and diffusion restriction involving subcortical white matter and pyramidal tracts., Conclusions: We expand the literature from India with four new cases of CSF1R-L.

Despite water intrusion in microporous materials being extensively investigated, obtaining a detailed overview of the intrusion mechanism in materials with more complex morphology, topology, and physical-chemical characteristics, such as metal-organic frameworks (MOFs), is far from trivial. In this work, we present a qualitative study on the mechanism of water intrusion in a crystallite of hydrophobic Cu2(tebpz) (tebpz = 3,3',5,5'-tetraethyl-4,4'-bipyrazolate) MOF. This MOF is characterized by a complex morphology; it consists of primary (main channels) and secondary (lateral apertures) porosities. This is similar to some zeolites, such as the so-called ITT-type zeolite framework, but it presents the additional characteristics of high flexibility of the material and non-uniform hydrophobicity. Interestingly, in Cu2(tebpz), water intrusion occurs first for some of the channels lying tangent to the surface of the MOF's crystallite. This is due to hydrogen bonding bridging with bulk water across the (thin) lateral apertures of these channels. In macroscopic terms, this can be understood as a local reduction of hydrophobicity favoring intrusion. Temperature and pressure influence the average number of hydrogen bonds and the number of intruded water molecules, explaining the effect of these thermodynamic parameters on the intrusion/extrusion characteristics of this porous material. Molecular dynamics simulations allowed us to glimpse liquid intrusion in this complex hydrophobic material, highlighting how the classical models valid for mesoporous systems, namely, Young-Laplace's law, are not quite appropriate to describe intrusion in such materials., (© 2025 Author(s). Published under an exclusive license by AIP Publishing.)

Background and Objectives: Intracerebral hemorrhage (ICH) is associated with high mortality and morbidity. Uncertainty still exists regarding the benefit of surgery in the management of supratentorial spontaneous ICH (sICH), especially of the basal ganglia and thalamus. Studies have not shown the clinical benefit of early surgical management compared to best medical management plus delayed surgery, when necessary. Our aim was to compare the efficacy of different neurosurgical interventions with best medical management and best medical management alone., Methods: We conducted a single-center, retrospective study at a tertiary care center in India in sICH patients between January 2015 and December 2022. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS) at 3, 6, and 12 months. Time-to-event outcomes were compared using the Kaplan-Meier curve., Results: Among 2600 stroke patients screened, 661 had sICH. Median age was 55 years, and 250 patients (37.8%) underwent neurosurgical intervention. The most common intervention was craniotomy and hematoma evacuation. The median mRS at discharge and follow-up at 3, 6, and 12 months was lower in the conservatively managed group (4, 3, 3, and 3, respectively) compared to the surgical intervention group (5, 5, 5, 4, respectively). However, the ICH score at admission was lower in the conservatively managed group and after adjustment for ICH score, there was no statistically significant difference between the two. Among the interventions, patients undergoing decompression craniectomy had the best functional outcome., Conclusions: Neurosurgical intervention was not associated with better functional outcome when compared to conservative management., (Copyright © 2025 Annals of Indian Academy of Neurology.)

Helminthiasis, affecting billions globally, poses a significant health concern, especially in impoverished regions with inadequate sanitation. The intricate anatomical complexity of helminths requires specialized treatment approaches. There is currently no effective vaccine against helminth infections. Anthelmintics, crucial for combating these infections, target neuromuscular functions in parasites without harming the host. However, the emergence of resistance to existing anthelmintics, notably benzimidazoles, presents a growing global challenge. This review delves into the structure-activity relationship of previously synthesized core anthelmintic scaffolds-Benzimidazole, coumarin, pyrazoline, triazole, and others-to elucidate their promising anthelmintic activities. Understanding the structure-activity relationship of these novel benzimidazole derivatives, Coumarin derivatives, and others is crucial in designing potent anthelmintics, overcoming resistance, and optimizing efficacy to combat the escalating global burden of helminth infections. In the present review, we cover recently studied compounds (from the year 2019 to till date) which have promising anthelmintic activity. This review will be useful for the pharmacology and medicinal chemistry researchers working in the area anthelmintics with various scaffolds like aminobenzothiazole, benzimidazole, benzothiazole, coumarin, chromene, spiroketal, pyrazoline, triazole, etc. to design novel potent anthelmintic compound., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Human papillomavirus (HPV) is associated with an increased risk for a variety of squamous cell carcinomas (SCCs) in the general population. The risk for subsequent SCCs in BMT survivors that are potentially related to HPV (cervical, oropharyngeal, vulvar, vaginal, anal, and penile cancer; HPV-related SCCs) remains unknown., Methods: We determined the risk of HPV-related SCCs in 7,936 2 y-survivors of autologous or allogeneic BMT performed between 1974 and 2014 and identified the role of demographic and clinical factors associated with HPV-related SCCs using proportional subdistribution hazards model for competing risks. Standardized incidence ratio (SIR) was used to compare the risk of HPV-related SCC with age-, sex-, and calendar-specific incidence in the general population., Results: The median age at transplantation was 46 y (range, 0-78 y); 58.5% (n = 4,642) were males, and 72.2% (n = 5,727) were non-Hispanic White. Half of the patients (50.3%, n = 3,991) had received an allogeneic BMT. The SIR for oropharyngeal SCC (n = 53) was 1.8 (95%CI = 1.3-2.3) and for cervical SCC among female BMT recipients (n = 26) was 9.4 (95%CI = 6.3-13.6), compared to the general US population. The hazard of an HPV-related SCC was higher among allogeneic BMT recipients with chronic graft vs host disease (cGvHD) (any HPV-related SCC: HR = 6.24, 95%CI = 3.11-12.50; oropharyngeal: HR = 4.85, 95%CI = 2.11-11.15; cervical: HR = 4.98, 95%CI = 1.65-15.00; reference=autologous BMT). Pre-BMT radiation increased the risk of oropharyngeal SCC (HR = 2.98, 95%CI = 1.57-5.65)., Conclusion: These findings underscore the importance of risk-based HPV vaccination and surveillance after BMT., (© The Author(s) 2025. Published by Oxford University Press.)

Exercise offers a plethora of health benefits. However, certain genetic and acquired diseases such as cardiomyopathies and channelopathies are associated with sudden cardiac death during exercise. Several factors complicate exercise prescription in individuals living with these conditions. The lack of high-quality evidence supporting exercise recommendations, variation in the clinical phenotypes within the same condition and sparse physician education around exercise prescription all leads to a reluctance to provide specific guidance on how to engage in physical activity.This article aims to summarise the latest evidence underpinning risk stratification and current guideline recommendations for physical activity in individuals with cardiomyopathies and channelopathies wishing to engage in exercise. It also aims to provide a basic practical approach to exercise prescription for health professionals involved in the care of these patients. This approach may then serve as a foundation that can be easily personalised. Since risk can never be completely eliminated, all decisions regarding exercise participation should be taken following shared dialogue between the physician, patient and wider stake holders where appropriate., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

A diabetic wound (DW) is an alteration in the highly orchestrated physiological sequence of wound healing especially, the inflammatory phase. These alterations result in the generation of oxidative stress and inflammation at the injury site. This further leads to the impairment in the angiogenesis, extracellular matrix, collagen deposition, and re-epithelialization. Additionally, in DW there is the presence of microbial load which makes the wound worse and impedes the wound healing cycle. There are several treatment strategies which have been employed by the researchers to mitigate the aforementioned challenges. However, they failed to address the multifactorial pathogenic nature of the disease. Looking at the severity of the disease researchers have explored snail mucus and its components such as achacin, allantoin, elastin, collagen, and glycosaminoglycan due to its multiple therapeutic potentials; however, glycosaminoglycan (GAGs) is very important among all because they accelerate the wound-healing process by promoting reepithelialization, vascularization, granulation, and angiogenesis at the site of injury. Despite its varied applications, the field of snail mucus in wound healing is still underexplored. The present review aims to highlight the role of snail mucus in diabetic wound healing, the advantages of snail mucus over conventional treatments, the therapeutic potential of snail mucus, and the application of snail mucus in DW. Additionally, clinical trials, patents, structural variations, and advancements in snail mucus characterization have been covered in the article., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hematoma expansion (HE) occurs in one-fourth to one-third of patients with acute intracerebral hemorrhage (ICH) and is associated with worse outcomes. The co-localization of non-contrast computed tomography (NCCT) hypodensity and computed tomography angiography (CTA) spot sign, the so-called Black-&-White (B&W) sign, has been shown to have high predictive accuracy for HE in a single-center cohort. In this analysis, we aimed to validate the predictive accuracy of the B&W sign for HE in a multicenter cohort., Methods: Acute ICH patients from the multicenter, observational PREDICT study (Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT) were included. Outcomes included HE (⩾6 mL or ⩾33%) and severe HE (⩾12.5 mL or >66%). The association between B&W sign and outcomes was assessed with multivariable regression analyses adjusted for baseline factors., Results: Three hundred four patients were included, with 106 (34.9%) showing HE. The spot sign was present in 76 (25%) patients, the hypodensity sign in 119 (39.1%), and the B&W sign in 29 (9.5%). In the stratum with positive spot signs, patients with B&W signs experienced more frequent HE (79.3% vs 46.8%, p = 0.008), hematoma absolute growth (19.1 mL (interquartile range (IQR) = 6.4-40) vs 3.2 mL (IQR= 0-23.3), p = 0.018), and hematoma relative growth (92% (IQR = 16-151%) vs 24% (IQR= 0-69%), p = 0.038). There was a strong association between B&W sign and HE (adjusted odds ratio (OR) = 7.83 (95% confidence interval (CI) = 2.93-20.91)) and severe HE (adjusted OR = 5.67 (95% CI = 2.41-13.36)). The B&W sign yielded a positive predictive value of 79.3% (IQR = 61.7-90.1) for HE. Inter-rater agreement was moderate (k = 0.54)., Conclusion: The B&W sign is associated with an increased likelihood of HE and severe HE by approximately eightfold and fivefold, respectively., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Paediatric Systemic lupus erythematosus (SLE) constitutes 10 to 20% of cases of SLE with more severe disease and higher mortality. We report a case of an adolescent girl with SLE with multisystem involvement who was started on hydroxychloroquine and oral prednisolone. However, due to persistent worsening of skin lesions and falling cell counts, pulsed dexamethasone was initiated which showed improvement in the skin lesions, cell counts, proteinuria and pleural effusion but there was a persistent fall in the haemoglobin. The patient was diagnosed with refractory autoimmune hemolytic anemia (AIHA) and treated with Rituximab which showed marked improvement in AIHA. Therefore, Rituximab can be considered in managing childhood SLE with refractory AIHA., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Genomic variations associated with dystonia in Asian Indians remain largely unknown., Objectives: To identify genomic alterations associated with dystonia in the Asian Indian population using next generation sequencing approaches., Methods: From September 2018 to December 2023, we enrolled 745 individuals including probands with dystonia and family members, in the Indian Movement Disorder Registry and Biobank. Clinical and demographic data were captured on a REDCap platform. We performed whole exome sequencing (WES) on DNA specimens obtained from 267 individuals with isolated, combined or complex dystonia. Variants were classified according to joint guidelines of American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP)., Results: The mean age of the WES cohort was 33.8 ± 16.2 years, and mean age at onset (AAO) of dystonia was 25.6 ± 17.7 years. 62.2% had isolated dystonia, 7.9% combined and 29.2% had complex phenotypes. WES identified pathogenic/ likely pathogenic variants in 54 patients (20.2%) including 14 novel variants in known dystonia genes. Variants in THAP1 were most common followed by PANK2, GLB1, PLA2G6, TOR1A, ANO3, VPS16, SGCE, SPG7, FTL and other genes. Multifocal/generalized distribution of dystonia [OR: 4.1; 95% CI 1.4-12.2, P = 0.011] and family history [OR: 4.3; 95% CI 2.1-8.9, P < 0.001] were associated with positive yield on WES., Conclusion: THAP1 was the most frequent dystonia associated gene in this cohort. Singleton WES identifiedpotentially pathogenic variants in approximately one out of five patients tested, and contributed to management decisions in 4%., (© 2025 International Parkinson and Movement Disorder Society.)

Rationale: Early mortality in intracerebral hemorrhage (ICH) is due to hematoma volume (HV) expansion, and there are no effective treatments available other than reduction in blood pressure. Tranexamic acid (TXA) a hemostatic drug that is widely available and safe can be a cost-effective treatment for ICH, if proven efficacious., Hypothesis: Administration of TXA in ICH patients when given within 4.5 h of symptom onset will reduce early mortality at 30 days., Design: Indian Trial of Tranexamic acid in Spontaneous Intracerebral Haemorrhage (INTRINSIC trial) is a multicenter, randomized, open-label, trial enrolling patients aged more than 18 years presenting with non-traumatic ICH within 4.5 h of symptom onset or when last seen well. Study participants received 2 g of TXA administered within 45 min while control group received standard of care. Intensive blood pressure reduction as per INTERACT 2 protocol is followed is done in both groups. Study plans to recruit 3400 patients. Primary outcome is mortality at day 30. Secondary outcomes are radiological reduction in HV at 24 h from baseline, neurological impairment at day 7 or earlier (if discharged), and assessments of dependency and quality of life at day 90., Summary: If proven to be beneficial, TXA will have a major impact on medical management of ICH., Trial Registration: Clinical Trial Registry India (CTRI/2023/03/050224) and Clinical Trials.gov (NCT05836831)., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The prevalence of suboptimal self-rated health (SRH) and its association with subsequent all-cause and cause-specific mortality after blood or marrow transplantation (BMT) were examined., Methods: Study participants were drawn from the multicenter Blood or Marrow Transplant Survivor Study, and included patients who were transplanted between 1974 and 2014 and had survived ≥2 years after BMT. Participants (aged ≥18 years) completed a survey at a median of 9 years from BMT, and were followed for a median of 5.6 years after survey completion. Survivors provided information on sociodemographic factors, chronic health conditions, health behaviors, and SRH (a single-item measure rated as excellent, very good, good, fair, or poor; excellent, very good, and good SRH were classified as good SRH, and fair and poor were classified as suboptimal SRH). The National Death Index Plus and Accurint databases and medical records provided vital status through December 2021., Results: Of 3739 participants, 784 died after survey completion (21%). Overall, 879 BMT survivors (23.5%) reported suboptimal SRH. Pain, low socioeconomic status, psychological distress, lack of exercise, severe/life-threatening chronic health conditions, post-BMT relapse, obesity, smoking, and male sex were associated with suboptimal SRH. BMT survivors who reported suboptimal SRH had a 1.9-fold increased risk of all-cause mortality (95% confidence interval [CI], 1.6-2.3), 1.8-fold increased risk of recurrence-related mortality (95% CI, 1.4-2.5), and 1.9-fold increased risk of non-recurrence-related mortality (95% CI, 1.4-2.4) compared to those who reported good SRH., Conclusions: This single-item measure could help identify vulnerable subpopulations who could benefit from interventions to mitigate the risk for subsequent mortality., (© 2024 American Cancer Society.)

Background: Traditionally, sternotomy has been the gold standard approach for the treatment of thymomas. However, interest in minimally invasive techniques such as video-assisted and robot-assisted thymectomy is gaining momentum. Concerns have been raised over the possibility of en-bloc resection using minimal access techniques due to limited working space and increased tumour manipulation leading to tumour breach and recurrence., Methods: An observational cohort study was conducted at a tertiary referral centre from 1 April 2012 to 31 December 2020 and followed up until 31 March 2023. Consecutive patients of thymoma were evaluated for demography, symptoms and imaging preoperatively and included for the study. Post minimally invasive thymectomy, surgical, neurological and oncological outcomes were evaluated through out-patient and telephonic follow-up., Results: Fifty-two patients underwent minimally invasive thymectomy. Video-assisted thoracoscopic surgery for thymectomy was used in 49 patients (94.2%) with 3 (5.8%) patients undergoing robot-assisted thoracoscopic surgery. Median tumour size was 4 cm (interquartile range (IQR) 3-5) with a median operative duration of 150 min (IQR 120-180), blood loss of 135 ml (IQR 42.5-250), post-operative stay of 3 days (IQR 2-4) and no 30-day surgery related morbidity and mortality. Annual contrast-enhanced computed tomography imaging, available in 46 (88.5%) patients, showed no recurrence at a median follow-up of 43 (IQR, 21-75) months. No symptoms suggesting recurrence was noted at a median clinical follow-up of 57 (IQR 44-95.5) months and 88.5% patients were expected to survive a period of 10 years., Conclusion: Minimally invasive thymectomy is technically feasible with minimal morbidity and acceptable intermediate-term oncological outcomes in patients suffering with thymoma., Trial Registration: Institute ethical committee approval: Ref no. IECPG-551/14.11.2018.Clinical Trial Registry of India: Ref no. CTRI/2019/04/018784., Competing Interests: Conflict of interestThe authors declare no competing interests., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: An ex-27-week gestation female infant developed bilateral forearm nodules at 4 weeks of life during treatment for methicillin-sensitive Staphylococcus aureus bacteremia. A pure growth of Candida albicans was isolated on culture of both sterile aspiration of the forearm abscess and urine without evidence of methicillin-sensitive Staphylococcus aureus . The patient went on to develop bilateral obstructive renal fungal bezoars at 11 weeks of life., Results: Bilateral nephrostomies were required to alleviate obstruction with the addition of local irrigation with amphotericin B deoxycholate. Two weeks later, urokinase via the nephrostomy tubes was added due to an unchanged appearance on ultrasound (US) and ongoing candiduria. A significant reduction in the size of bezoars was seen on US after 3 days. Sterilization of urine culture was achieved 7 weeks into treatment, and resolution of bezoars on US was seen 9 weeks after treatment began. No adverse events occurred from the use of local urokinase., Conclusions: Urokinase irrigation via nephrostomy is an effective and safe adjunctive treatment in refractory obstructive renal candidiasis in neonates., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: The alpha-2 agonist xylazine is increasingly detected as an adulterant in illicitly manufactured fentanyl. There is concern that xylazine may be responsible for an emerging pattern of necrotizing wounds among people who use drugs, but the clinical features of wounds associated with xylazine remain poorly characterized., Objective: To systematically characterize the location, wound bed surface, and chronicity of wounds among persons with confirmed xylazine exposure., Design, Setting, and Participants: This case series at 3 academic medical hospitals in Philadelphia, Pennsylvania, included patients with emergency department or inpatient encounters from April 2022 to February 2023 who had a wound-related chief complaint and xylazine detected with urine gas chromatography-mass spectroscopy., Exposure: Xylazine., Main Outcomes and Measures: The location, size, wound bed, and chronicity of wounds associated with xylazine using electronic medical record abstraction and Fisher exact tests., Results: Of 59 wounds from 29 unique patients with confirmed xylazine exposure (mean [SD] age, 39.4 [8.8] years; 15 [52%] male; all using fentanyl, and 23 [79%] routinely injecting opioids), 53 wounds (90%) were located on extremities, and 41 (69%) involved extensor surfaces. Five wounds (9%) involved exposed deep structures such as bone or tendon. Of 57 wounds with photographs, 34 (60%) had wound beds of predominantly devitalized tissue (eschar or slough). Based on patient report, 28 wounds (48%) were acute (<1 month old), 12 (20%) were subacute (present for 1-3 months), and 17 (29%) were chronic (developed ≥3 months prior). Subacute and chronic wounds were more often medium or large in size (odds ratio, 48.5; 95% CI, 8.2-1274.8; P < .001) and more frequently had devitalized wound beds (odds ratio, 9.5; 95% CI, 2.9-37.0; P < .001)., Conclusions and Relevance: In this case series of hospitalized patients with confirmed xylazine exposure, wounds were commonly located on extensor surfaces of the extremities, frequently had devitalized tissue or exposed deep structures, and were more likely to have larger and necrotic wound beds the longer they had persisted. This systematic characterization of xylazine-associated wounds may inform identification, management, and research to address this emerging public health threat.

Purpose: This systematic review aimed to identify and compare tools used to evaluate quality of life (QoL) after pelvic radiation for cervical cancer and to describe variations in results within commonly used instruments. This review hypothesized regional preferences in the selection of these tools and an absence of uniformity in their application globally., Methods and Materials: A comprehensive search of 6 databases was conducted between the inception of each included database and June 14, 2023, focusing on studies evaluating the QoL of patients with cervical cancer during and after radiation. Excluded were studies involving cancers originating outside the cervix, those not exclusively undergoing radiation or chemoradiation therapy, such as patients who have undergone surgery, and non-English studies., Results: Ultimately, 229 studies covering 25,693 patients and 51 countries were identified. Most studies were conducted in Asia (35.6%) and Europe (32.9%). Ninety-nine QoL instruments were identified, not including those that were specific to a single study. The European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (20.5%) and the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire cervical cancer module (16.0%) were the most commonly used; however, US-based studies primarily used the Functional Assessment of Cancer Therapy-General surveys. Furthermore, there was significant variability in the timelines of survey usage in relation to when treatment was completed, further limiting the comparisons that can be made. Of the 127 studies that reported data on the time points after completion of treatment at which QoL was measured, 72.4% measured QoL within 1 year of treatment completion, and 48.8% measured QoL >1 year after treatment completion, with some studies using multiple time points for their research., Conclusions: This study revealed a fragmented landscape with significant variability in QoL survey use, limiting the generalizability and usefulness of these results to drive meaningful change. There is a need for a global standardized method to evaluate QoL after treatment of cervical cancer with radiation therapy for comparison across regions. Simplified tools may assist with the broader collection of data, which may lead to advancements for improvement of the QoL of these patients., (© 2024 The Authors.)

Background: Long-acting injectable antiretrovirals (LAI-ARVs) for HIV prevention and treatment have been demonstrated in clinical trials to be non-inferior to daily oral medications, providing an additional option to help users overcome the challenges of daily adherence. Approval and implementation of these regimens in low- and middle-income settings have been limited., Method: This study describes the anticipated barriers and facilitators to implementing LAI-ARVs in Vietnam to inform future roll-out. From July to August 2022, we conducted 27 in-depth interviews with healthcare workers and public health stakeholders involved in HIV programs at national, provincial, and clinic levels across four provinces in Vietnam. The interviews followed a semi-structured questionnaire and were audio recorded. Data were analyzed using a rapid thematic analysis approach to identify facilitators and barriers to the adoption of LAI-ARVs., Results: In total, 27 participants from 4 provinces were interviewed including 14 (52%) men and 13 (48%) women. Participants median age was 48 years and they had 11.5 years of experience with HIV services and programs. Perceived user-level facilitators included the greater convenience of injectables in comparison to oral regimens, while barriers included the increased frequency of visits, fear of pain and side effects, and cost. Clinic-level facilitators included existing technical capacity to administer injections and physical storage availability in district health centers, while barriers included lack of space and equipment for administering injections for HIV-related services, concerns about cold chain maintenance for LAI-ART, and workload for healthcare workers. Health system-level facilitators included existing mechanisms for medication distribution, while barriers included regulatory approval processes and concerns about supply chain continuity., Conclusion: Overall, participants were optimistic about the potential impact of LAI-ARVs but highlighted important considerations at multiple levels needed to ensure successful implementation in Vietnam., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in full compliance with the ethical principles outlined in the Declaration of Helsinki and adhered to relevant national guidelines and regulations. The study was reviewed and approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (#2022P000341) in Boston, USA and Hanoi University of Public Health (#022–116/DD-YTCC) in Hanoi, Vietnam. All participants provided informed consent prior to participation. Consent for publication: Not applicable. Competing interests: Todd M. Pollack receives funding from Gilead Sciences through a grant to Beth Israel Deaconess Medical Center (Boston, MA, USA) and has received travel support from Gilead Sciences. All other authors have no financial or non-financial interests to disclose., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is a World Health Organisation (WHO) grade IV glioma originating from astrocytes. It is the most common malignant primary tumour of the brain and central nervous system (CNS) and is associated with fast progression and violent local spread, with a median overall survival of approximately 15 months after diagnosis. Due to its late and varied presentation, it is often diagnosed only after it has grown considerably. The symptomatology can vary from the individual being completely asymptomatic to mild sensory or sensorimotor symptoms. The symptoms usually arise due to compression of the fibres rather than pressure on vital structures.  We discuss a case of a 72-year-old male who presented with complaints of tingling in the left upper limb for one day, improving spontaneously. A noncontrast CT head was nondiagnostic, and an MRI reported a likely metastatic lesion, and further imaging was advised. A detailed history was taken from an oncology point of view but the patient denied any weight loss, fever, recent travel, and family history of cancers. The scans were discussed at a neuroradiology multidisciplinary team (MDT) discussion an MRI with contrast was planned. After a thorough discussion and further review by neuroradiology consultants, the patient was diagnosed with a grade IV glioblastoma - a primary tumour of the brain - which was confirmed by a biopsy and immunohistochemistry. He was treated with two cycles of radiotherapy initially, followed by chemotherapy. Unfortunately, he died eight months after the start of the treatment due to a massive pulmonary embolism, complicated by nosocomial infection. This report highlights the importance of early diagnosis and treatment for patients with glioma. It also sheds light on the symptomatology and difficulties faced in the diagnosis of gliomas. Treating physicians should adopt an MDT approach in such cases and discuss the various possibilities and differentials., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bhatia et al.)

Over the past years, many significant advances have been made in the field of gene therapy and shown promising results in clinical trials conducted. Gene therapy aims at modifying or replacing a defective, inefficient, or nonfunctional gene with a healthy, functional gene by administration of genome material into the cell to cure genetic diseases. Various methods have been devised to do this by using several viral and non-viral vectors which are either administered by in vivo or ex vivo technique. Viral vectors are best suitable for this therapy due to their potential to invade cells and deliver their genetic material whereas non-viral vectors are less efficient than viral vectors but possess some advantages such as less immunogenic response and large gene carrying capacity. Recent advances in biotechnology such as CRISPR-Cas9 mediated genome engineering and Cancer treatment with Chimeric antigen receptor (CAR) T-cell therapy are addressed in this review. This review article also delves into some recent research studies, gene therapy trials, and its applications, laying out future hopes for gene therapy in the treatment of various diseases namely haemophilia, Muscular dystrophy, SCID, Sickle cell disease, Familial Hypercholesterolemia, Cystic Fibrosis. Additionally, it also includes various nanoformulations and clinical trial data related to gene therapy., Competing Interests: Declarations. Conflict of Interest: None., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Importance: Cutaneous malignant neoplasms are the most common subsequent neoplasm after blood or marrow transplant (BMT), but a full assessment among survivors is lacking., Objective: To identify risk factors for subsequent cutaneous malignant neoplasms using the BMT Survivor Study (BMTSS)., Design, Setting, and Participants: This retrospective cohort study included patients who underwent transplant from 1974 to 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and survived 2 years or longer, as well as a comparison cohort of siblings. Both groups completed the BMTSS survey. Data analysis took place from October 2022 to October 2024., Exposures: Demographics, pre-BMT and BMT-related therapeutic exposures, chronic graft-vs-host disease (cGVHD), and posttransplant immunosuppression., Main Outcomes and Measures: Incident cutaneous malignant neoplasms (basal cell carcinoma [BCC], squamous cell carcinoma [SCC], and melanoma) after BMT. Exposures were evaluated for association with subsequent neoplasms using proportional subdistribution hazards models (reported as subdistribution hazard ratio [SHR] and 95% CI)., Results: Among the 3880 BMT survivors (median [range] age at BMT, 44.0 [0-78.0] years; 2165 [55.8%] male; 190 [4.9%] Black, 468 [12.1%] Hispanic, 2897 [74.7%] non-Hispanic White, and 325 [8.4%] of other race [including Asian and Pacific Islander] and multiracial) who were followed up for a median (range) of 9.5 (2.0-46.0) years, 605 developed 778 distinct cutaneous neoplasms (BCC, 321; SCC, 231; melanoma, 78; and unknown type, 148). The 30-year cumulative incidence of any cutaneous malignant neoplasm was 27.4% (BCC, 18.0%; SCC, 9.8%; and melanoma, 3.7%). Seventy-year cumulative probabilities of BCC, SCC, and melanoma were considerably higher in BMT survivors than siblings (18.1% vs 8.2%, 14.7% vs 4.2%, and 4.2% vs 2.4%, respectively). Among BMT survivors, risk factors for subsequent cutaneous malignant neoplasms included age of 50 years and older at BMT (BCC: SHR, 1.76; 95% CI, 1.36-2.29; SCC: SHR, 3.37; 95% CI, 2.41-4.72), male sex (BCC: SHR, 1.39; 95% CI, 1.10-1.75; SCC: SHR, 1.85; 95% CI, 1.39-2.45), pre-BMT monoclonal antibody exposure (BCC: SHR, 1.71; 95% CI, 1.27-2.31), allogeneic BMT with cGVHD (BCC: SHR, 1.48; 95% CI, 1.06-2.08; SCC: SHR, 2.61; 95% CI, 1.68-4.04 [reference: autologous BMT]), post-BMT immunosuppression (BCC: SHR, 1.63; 95% CI, 1.24-2.14; SCC: SHR, 1.48; 95% CI, 1.09-2.02; melanoma: SHR, 1.90; 95% CI, 1.16-3.12), and transplant at City of Hope (BCC: SHR, 3.55; 95% CI, 2.58-4.89; SCC: SHR, 3.57; 95% CI, 2.34-5.47 [reference: University of Minnesota]) or University of Alabama at Birmingham (BCC: SHR, 2.35; 95% CI, 1.35-4.23; SCC: SHR, 2.63; 95% CI, 1.36-5.08 [reference: University of Minnesota]). Race and ethnicity other than non-Hispanic White were protective for BCC (Black: no cases; Hispanic: SHR, 0.27; 95% CI, 0.16-0.44; other race and multiracial: SHR, 0.26; 95% CI, 0.14-0.50 [reference: non-Hispanic White]) and SCC (Black: SHR, 0.17; 95% CI, 0.04-0.67; Hispanic: SHR, 0.28; 95% CI, 0.16-0.50; other race and multiracial: SHR, 0.13; 95% CI, 0.05-0.37 [reference: non-Hispanic White]). Total body irradiation was associated with BCC risk among those younger than 50 years at BMT (SHR, 1.92; 95% CI, 1.27-2.92)., Conclusions and Relevance: In this cohort study, the high risk of cutaneous malignant neoplasms and malignant-specific risk factors suggest a need for personalized patient counseling and posttransplant dermatologic surveillance.

Background and Objectives: Tau PET is being increasingly appraised as a novel diagnostic modality for dementia work up. Given limited data among South Asians, we assessed the frequency, patterns, phenotypic associations and incremental value of positive Tau PET scans in clinically diagnosed neurodegenerative dementia., Methods: This cross-sectional study recruited consecutive patients of Alzheimer's disease (AD) and non-AD syndromes (September 2021 to October 2022, India). Participants underwent clinical interview, cognitive assessment, MRI brain and tau PET scan ([F-18]ML-104). Visual read in a priori regions of interest was used to identify patterns of tau deposition in the brain., Results: We recruited 54 participants (mean age: 63.2 ± 9.2 years, 64.8 % men, 77.8 % dementia, 70.4 % early onset cases, 37.8 % APOE4+). The analysis identified abnormal tau uptake in 40/54 (74.1 %) participants; with uptake in AD signature areas in 27/40 (67.5 %) cases [cortical subtype (74.1 %), limbic (14.8 %), combined cortical/limbic (11.1 %)], and patterns not conforming to AD in 13/40 (32.5 %) cases. Tau PET substantiated the diagnosis of AD among 17/19 (89.5 %) cases with clinically diagnosed AD dementia, 8/23 (34.8 %) cases with suspected non-AD cause, and 2/12 (16.7 %) cases with mild cognitive impairment. A trend for increasing proportion of early onset cases, and worsening cognition, behavior and functional ability was seen, from 'limbic' to 'combined cortical/limbic' to 'cortical' subgroups., Conclusion: Tau PET is a useful modality to differentiate AD dementia from other neurodegenerative causes in the Indian setting where amyloid biomarkers are not widely available. Biological subtypes of AD map well onto clinical phenotypes and need study in larger cohorts., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Reactive oxygen species (ROS) play a dual role in cancer, acting as both signaling molecules that promote tumour growth and as agents that can inhibit tumour progression through cytotoxic effects. In cancer therapy, ROS-responsive drug delivery systems take advantage of the elevated ROS levels found in tumors compared to healthy tissues. These systems are engineered to release drugs precisely in response to increased ROS levels in tumour cells, allowing targeted and controlled treatment, minimizing side effects, and enhancing therapeutic outcomes. ROS generation in cancer cells is linked to metabolic changes, mitochondrial dysfunction, and oncogenic signaling, leading to increased oxidative stress. Tumour cells manage this by upregulating antioxidant defenses to prevent ROS from reaching harmful levels. This balance between ROS production and neutralization is critical for cancer cell survival, making ROS both a challenge and an opportunity for targeted therapies. ROS also connect inflammation and cancer. Chronic inflammation leads to elevated ROS, which can damage DNA and proteins, promoting mutations and cancer development. Additionally, ROS contribute to protein degradation, affecting essential cellular functions. Therapeutic strategies targeting ROS aim to either increase ROS beyond tolerable levels for cancer cells or inhibit their antioxidant defenses. Nanocarriers responsive to ROS show great potential in improving the precision of cancer treatments by releasing drugs specifically in high ROS environments, like tumors. This review discusses the mechanisms of ROS in cancer, its role in inflammation and protein degradation, and the advances in ROS-targeted nanocarrier therapies across different cancer types., Competing Interests: Declarations. Conflict of interest: The authors report no conflicts of interest., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background and Aim: Unplanned extubation (UE) is an adverse event that can occur for neonates that are intubated and mechanically ventilated. UE is recognised as an important quality measure in the neonatal intensive care unit (NICU) due to the negative impact these events may have on the neonate. We aimed to use quality improvement (QI) methodology to reduce the rate of UE to the global standard of <1/100 ventilation days., Methods: A 12-month retrospective audit on mechanically ventilated neonates in our NICU identified a mean UE rate of 1.78/100 ventilation days. A clinical guideline focusing on best practice was introduced with key interventions identified by a review of the literature as those which were thought to reduce UE rates. The key interventions in the clinical guideline were introduced sequentially. UE rates were analysed monthly using control charts and the reported cause of each UE event was analysed. Three 12-month periods were included: preintroduction of QI interventions (period 1), during introduction of QI interventions (period 2), and after introduction of QI interventions (period 3)., Results: The introduced interventions reduced the mean rate of UE from 1.78/100 ventilation days in period 1 to 0.8/100 ventilation days in period 3 of the QI project., Conclusions: The key interventions introduced in this QI project were successful in reducing rates of UE by 55%, allowing achievement of the global standard of <1/100 ventilation days., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Importance: Bronchopulmonary dysplasia (BPD) is a common adverse outcome in extremely preterm infants born at less than 28 weeks' gestation. Systemic corticosteroids are effective against BPD but may be associated with adverse outcomes. Corticosteroids given directly into the lungs may be effective and safer., Objective: To investigate the effectiveness of early intratracheal corticosteroid administration on survival free of BPD in extremely preterm infants., Design, Setting, and Participants: Double-blind randomized clinical trial conducted in 21 neonatal units in 4 countries (Australia, New Zealand, Canada, and Singapore), enrolling infants born at less than 28 weeks' gestation and less than 48 hours old who were mechanically ventilated (regardless of ventilator settings or oxygen requirements) or who were receiving noninvasive respiratory support and had a clinical decision to treat with surfactant. Recruitment occurred from January 2018 to March 2023. The last participant was discharged from the hospital in August 2023., Interventions: Infants were randomly allocated (1:1) to receive budesonide, 0.25 mg/kg, mixed with surfactant (poractant alfa), administered via an endotracheal tube or thin catheter, or surfactant only., Main Outcomes and Measures: The primary outcome was survival free of BPD at 36 weeks' postmenstrual age. There were 15 secondary outcomes, including the 2 components of the primary outcome (survival at 36 weeks and BPD among survivors), and 9 predefined safety outcomes (adverse events)., Results: The primary analysis included 1059 infants, 524 in the budesonide and surfactant group and 535 in the surfactant-only group. Overall, infants had a mean gestational age of 25.6 weeks (SD, 1.3 weeks) and a mean birth weight of 775 g (SD, 197 g); 586 (55.3%) were male. Survival free of BPD occurred in 134 infants (25.6%) in the budesonide and surfactant group and 121 infants (22.6%) in the surfactant-only group (adjusted risk difference, 2.7% [95% CI, -2.1% to 7.4%]). At 36 weeks' postmenstrual age, 83.2% of infants were alive in the budesonide and surfactant group and 80.6% in the surfactant-only group. Of these, 69.3% and 71.9% were diagnosed with BPD, respectively., Conclusions and Relevance: In extremely preterm infants receiving surfactant for respiratory distress syndrome, early intratracheal budesonide may have little to no effect on survival free of BPD., Trial Registration: anzctr.org.au Identifier: ACTRN12617000322336.

A 50-year-old male patient presented with a 10-year history of progressive cerebellar ataxia, multifocal dystonia with dystonic tremors, and oculomotor abnormalities including bilateral ptosis, slow saccades, and reduced range of ocular movements. There were no signs of cognitive impairment, parkinsonism, autonomic dysfunction, or muscle weakness, and the family history was unremarkable. This case presents the diagnostic approach to adult-onset cerebellar ataxia with dystonia and abnormal eye movements. In this era of genomic testing, our case highlights the role of clinical phenotyping and the utility of whole-exome sequencing in ataxias.

Background: A healthier diet is associated with lower chronic disease burden, but the impact of neighbourhood food environments on disability and death in older adults is not known., Methods: In the Cardiovascular Health Study, a cohort study of adults aged 65+, we calculated study years until death (years of life (YOL)), study years without activities of daily living (ADL) difficulty (years of able life; YoAL) and percent of study years without ADL difficulty (compression of disability). Linear regression quantified associations of food establishments within 5 km of baseline home address (as a z-score) with each outcome, adjusted for sociodemographic characteristics. Sensitivity analyses considered adjustment for risk factors and comorbidities, multiple imputation, alternate neighbourhood definitions (1-km radial buffer, census tract) and restriction on residential stability., Results: We included 4298 participants followed for up to 26 years. All food retail establishments were associated with 6 months higher YoAL per SD in the main model (beta, 0.50 years; 95% CI 0.01, 0.98; p=0.046), with similar findings across sensitivity analyses except when restricting on residential stability. Supermarkets and produce markets were associated with compression of disability (beta, 2.31; 95% CI, 0.04, 4.57) and when using 1-km buffers with YOL (beta, 0.23 years; 95% CI 0.03, 0.43) and YoAL (beta, 0.21 years; 95% CI 0.01, 0.41). Non-supermarket food stores were associated with YoAL (beta, 0.67 years; 95% CI, 0.07, 1.27) and compression of disability (beta, 3.03; 95% CI 0.44, 5.62), but significance was not consistent across sensitivity analyses. Fast-food restaurants did not reach statistical significance in any model., Conclusion: All food retail was associated with YOL without impairment. Neighbourhood food retail access and type may both have roles in extending YOL and years of able life among older adults, but the findings were sensitive to decisions made during measurement and modelling., Competing Interests: All authors have completed the Unified Competing Interest form (attached to cover letter) and declare: RB, JP and ABN report no support from any organisation for the submitted work; DSS and GSL report governmental grants from the National Institutes of Health during the conduct of the study. KJM reports grants from United States Highbush Blueberry Council during the conduct of the study. GSL reports royalties from Oxford University Press. All authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: HPV self sampling can act as a tool to engage women in cervical screening and population based studies can inform optimal implementation of this approach., Methods: Self sampling kits were mailed to women who had defaulted from routine screening resident in an entire territorial health board in Scotland. Kit return rates and compliance to colposcopy follow up in those who were HPV mRNA positive were assessed. Concordance of the self-sample with samples taken later at colposcopy was measured alongside PPV of an mRNA positive result for CIN2+., Results: Of 4173 women invited to participate, 20.5 %, returned their kit and a greater return rate with increasing age was observed. HPV mRNA positivity was 12.0 %, and invalidity rate was approximately 3 %. Compliance to colposcopy follow up was 88.3 % and the PPV for an mRNA test for CIN2+ on a self sample was 25.6 %. hr-HPV concordance on the initial swab and the follow up swab and liquid based cytology (LBC) sample taken at colposcopy was 67.1 % and 30 % respectively., Conclusions: HPV self sampling using a "mail to all" approach is feasible in Scotland although only 1 in 5 actively responded to the offer. Future work to monitor screening behaviours in those who were invited but did not engage initially will help quantify any additional benefit(s) incurred., Competing Interests: Declaration of competing interest Hologic provided gratis assays and consumables required for the project and resource to support laboratory work, however all analysis was performed independently. RB, KC, HE and LCs institution has received research funding or gratis consumables to support research from the following commercial entities in the last 3 years: Euroimmun, GeneFirst, SelfScreen, Hiantis, Seegene, Roche, Hologic, Abbott, Barinthus Biotherapeutics PLC & Daye. KC has attended advisory board meetings for Hologic and Barinthus Biotherapeutics PLC; no personal renumeration occurred but UK travel covered., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Purpose: Brain imaging is needed when investigating epilepsy. Imaging options available include MRI and CT scan which may be non-contrast (NCCT) or contrast-enhanced (CECT). The specific clinical question and probable epilepsy substrate in the epidemiological context and socioeconomic milieu are important in determining the choice of imaging. In patients with well-controlled focal or unknown epilepsy who are unlikely to be surgical candidates, is CECT essential or can NCCT be an acceptable choice?, Methods: A prospective observational study was conducted at a tertiary care centre in India. Consecutive patients with focal or unknown epilepsy who were relatively well-controlled on medical treatment underwent NCCT followed by CECT brain. Three neuroradiologists independently reported the images. Proportion of abnormalities missed on NCCT and picked only on CECT were determined. How often abnormalities picked on CECT changed patient management was also analysed., Results: Two hundred and nineteen patients with focal (87 %) or unknown (13 %) epilepsy underwent NCCT followed by CECT brain. Most had epilepsy for >3 months and an annual seizure frequency of 2-10 seizures. There was a nearly perfect inter-observer agreement between 3 neuroradiologists in reporting the NCCT and CECT as 'normal' or 'abnormal' with kappa (κ) values of 0.9 and 1.0 respectively. The sensitivity of NCCT compared to CECT in detecting an abnormality was 97 % (CI 92.6 - 99.5 %) and the specificity was 99 % (CI 94.9 - 99.9 %). There was no significant difference in the proportion of NCCTs and CECTs found abnormal (50.22 % vs 51.14 %, p = 0.91). A solitary calcified granuloma was the most common abnormality reported on NCCT as well as CECT, 21.0 % and 19.1 % respectively. New findings picked on CECT alone, did not change management in any patient., Conclusion: When imaging focal or unknown epilepsy, an NCCT performs as well as a CECT, especially in regions where calcified lesions contribute a significant etiological burden. The role of imaging in epilepsy varies between patients and a universal recommendation of an MRI or a CECT in all patients is neither cost-efficient nor evidence-based. In drug responsive focal or unknown epilepsy of longstanding duration, CT scans are either normal or have calcified lesions that are easily picked on NCCT., Competing Interests: Declaration of competing interest None of the following authors declare any conflict of interest., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Paclitaxel, a potent chemotherapeutic agent derived from the bark of the Pacific yew tree, has demonstrated significant efficacy in the treatment of various cancers, including colon cancer. This comprehensive review delves into the conventional treatments for colon cancer, emphasizing the crucial role of paclitaxel in contemporary management strategies. It explores the intricate process of sourcing and synthesizing paclitaxel, highlighting the importance of its structural properties in its anticancer activity. The review further elucidates the mechanism of action of paclitaxel, its pharmacological effects, and its integration into chemotherapy regimens for colon cancer. Additionally, novel drug delivery systems, such as nanocarriers, liposomes, nanoparticles, microspheres, micelles, microemulsions, and niosomes, are examined for their potential to enhance the therapeutic efficacy of paclitaxel. The discussion extends to recent clinical trials and patents, showcasing advancements in paclitaxel formulations aimed at improving treatment outcomes. The review concludes with prospects in the field underscoring the ongoing innovation and potential breakthroughs in colon cancer therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oral pre-exposure prophylaxis (PrEP) reduces HIV acquisition risk from sex by 99% and from injection drug use by ≥74% when used as recommended. The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a goal of 21.2 million persons using (initiating or continuing) PrEP globally in 2025. In 2016, CDC, with the U.S. President's Emergency Plan for AIDS Relief, joined ministries of health to implement PrEP globally. PrEP is beneficial for persons at substantial risk for acquiring HIV, including but not limited to key populations, which include female sex workers, men who have sex with men, persons in prisons and other enclosed settings, persons who inject drugs, and transgender persons. Annual country targets were used to guide scale-up. In 2023, CDC supported 856,816 PrEP initiations, which represents nearly one quarter of the 3.5 million persons globally who either initiated or continued PrEP that year. During 2017-2023, CDC supported PrEP initiations for 2,278,743 persons, 96.0% of whom were in sub-Saharan Africa. More than one half (64.0%) were female and 44.9% were aged 15-24 years. Overall, CDC achieved 118.7% of its PrEP initiation targets for the 7-year period. Among PrEP initiations for key populations, the majority in sub-Saharan Africa were female sex workers, whereas in Southeast Asia, Eurasia, and the Americas, the majority were men who have sex with men. Continued rapid scale-up is needed to meet the UNAIDS goal to end HIV as a public health threat., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Cardiopulmonary exercise testing (CPET) is a noninvasive test that provides a comprehensive assessment of the integrative exercise responses by measuring parameters calculated on a breath-by-breath basis. It can provide insight into the fitness level, cause of exercise limitation, and safe parameters for exercise prescription in children 6 years and older. Common indications for CPET include undiagnosed exercise-induced dyspnea, exercise intolerance in pediatric chronic conditions and for monitoring response after therapy/intervention. It can be utilized to assess the overall fitness, pre-operative risk, and prognosis in chronic conditions. CPET is accessible and dependable in pediatrics, yet challenges like a lack of standardized protocols are noted. With continued development and technological advancements in CPET, there is potential for revolutionizing pediatric diagnostic health care.

The dairy industry is grappling with significant challenges in managing effluent due to environmental concerns and stringent regulatory demands, necessitating innovative solutions. The paper investigates how microbial engineering is transforming the treatment of dairy wastewater, offering advanced methods to minimize environmental impact and enhance sustainability. It delves into the current challenges faced by the dairy industry, such as regulatory compliance and the limitations of traditional treatment technologies, and introduces microbial engineering as a promising solution for effluent management. Microbial engineering leverages genetic engineering techniques and microorganisms to enhance the efficiency of treatment processes like bioaugmentation and bioremediation. The environmental and economic benefits of microbial engineering, highlighting its potential to reduce pollution and lower operational costs for the dairy industry. The specific figures can vary based on factors like farm size and location, studies suggest that microbial engineering can reduce wastewater pollution by up to 50% and nutrient runoff by 30%. It also identifies key challenges and there are still areas including strains for specific pollutants (drugs, hormones), enhance degradation pathways, and increase microbes' stability (stress tolerance, long-term viability) that require further innovation to maximize its benefits. Through case studies and success stories, the paper demonstrates practical applications of microbial engineering in managing dairy effluent, illustrating how it can revolutionize industrial practices for a more sustainable future., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Accurate target delineation is essential when using intensity modulated radiation therapy for intact cervical cancer. In 2011, the Radiation Therapy Oncology Group published a consensus guideline using magnetic resonance imaging (MRI). The current project expands on the previous atlas by including computed tomography (CT)-based contours, contours with MRI and positron emission tomography (PET) registrations, the addition of common and complex scenarios, and incorporating information on simulation and treatment planning techniques., Methods and Materials: Twenty-eight experts in gynecologic radiation oncology contoured 3 cases, first on a noncontrast CT simulation scan and then with registered diagnostic scans. The cases included (1) International Federation of Gynecology and Obstetrics (FIGO) IIIC1 with a bulky tumor and vaginal metastasis, (2) FIGO IIB with calcified uterine fibromas, and (3) FIGO IIIC2 with large lymph nodes. The contours on all 6 data sets (3 CT simulations without diagnostic images and 3 with registered images) were analyzed for consistency of delineation using an expectation-maximization algorithm for simultaneous truth and performance level estimation with kappa statistics as a measure of agreement. The contours were reviewed, discussed, and edited in a group meeting prior to finalizing., Results: Contours showed considerable agreement among experts in each of the cases, with kappa statistics from 0.67 to 0.72. For each case, diagnostic PET ± MRI was associated with an increase in volume. The largest increase was the clinical target volume (CTV) primary for case 2, with a 20% increase in volume and a 54% increase in simultaneous truth and performance level estimation volume, which may be due to variance in registration priorities. For the third case, 92.9% increased their CTVs based on the addition of the diagnostic PET scan. The main areas of variance were in determining the superior extent of CTV coverage, coverage of the mesorectum, and simulation and planning protocols., Conclusions: This study shows the value and the challenges of using coregistered diagnostic imaging, with an average increase in volumes when incorporating MRI and PET., Competing Interests: Disclosures Walter R. Bosch, PhD, has funding from the US NCI, Grant U24 CA 189893., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Abstract: Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Musculocontractural Ehlers-Danlos syndrome (MC-EDS) is a rare entity worldwide with underlying pathogenic variant in the carbohydrate sulfotransferase 14 (CHST14) gene. Previous reports of the same entity from India were of two unrelated cases. Ours is the first report of two siblings in an Indian family with craniofacial dysmorphism and distal arthrogryposis with a clinical diagnosis of EDS, where an underlying pathogenic variant in CHST14 was detected by exome sequencing., (© 2024 Wiley Periodicals LLC.)

Purpose: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Previous studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific subpopulations., Methods: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 patients with NHL (median age at transplant, 57 years; range, 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated the association between CH and t-MN among males and females., Results: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after a median follow-up of 5 years. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR], 2.10; 95% CI [1.08 to 4.11]; P = .029). CH was associated with increased t-MN risk among males (aHR, 1.83 [95% CI, 1.01 to 3.31]) but not females (aHR, 0.56 [95% CI, 0.15 to 2.09]). Although the prevalence and type of CH mutations in PBSC were comparable, the 8-year cumulative incidence of t-MN was higher among males vs. females with CH (12.4% v 3.6%) but was similar between males and females without CH (4.9% v 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males., Conclusion: presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.

An optical biosensor is a specialized analytical device that utilizes the principles of optics and light in bimolecular processes. Localized surface plasmon resonance (LSPR) is a phenomenon in the realm of nanophotonics that occurs when metallic nanoparticles (NPs) or nanostructures interact with incident light. Conversely, surface-enhanced Raman spectroscopy (SERS) is an influential analytical technique based on Raman scattering, wherein it amplifies the Raman signals of molecules when they are situated near specific and specially designed nanostructures. A detailed exploration of the recent ground-breaking developments in optical biosensors employing LSPR and SERS technologies has been thoroughly discussed along with their underlying principles and the working mechanisms. A biosensor chip has been created, featuring a high-density deposition of gold nanoparticles (AuNPs) under varying ligand concentration and reaction duration on the substrate. An ordinary description, along with a visual illustration, has been thoroughly provided for concepts such as a sensogram, refractive index shift, surface plasmon resonance (SPR), and the evanescent field, Rayleigh scattering, Raman scattering, as well as the electromagnetic enhancement and chemical enhancement. LSPR and SERS both have advantages and disadvantages, but widely used SERS has some advantages over LSPR, like chemical specificity, high sensitivity, multiplexing, and versatility in different fields. This review confirms and elucidates the significance of different disease biomarker identification. LSPR and SERS both play a vital role in the detection of various types of cancer, such as cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, colorectal cancer, and brain tumors. This proposed optical biosensor offers potential applications for early diagnosis and monitoring of viral disease, bacterial infectious diseases, fungal diseases, diabetes, and cardiac disease biosensing. LSPR and SERS provide a new direction for environmental monitoring, food safety, refining impurities from water samples, and lead detection. The understanding of these biosensors is still limited and challenging., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Authors.)

Complete androgen insensitivity syndrome (CAIS) presents significant challenges in the accurate diagnosis and personalized management of individuals with a 46, XY karyotype who exhibit a female phenotype due to complete insensitivity to androgens. This retrospective case report analyzes the clinical data, genetic testing, hormonal profiling, and imaging studies of a patient who was initially misdiagnosed during hernioplasty and later misidentified as having Mayer-Rokitansky-Küster-Hauser syndrome. The report details the establishment of the correct diagnosis and implementation of a personalized management strategy that postponed gonadectomy until post-puberty. This approach included continuous monitoring and tailored estrogen replacement therapy, which facilitated informed patient decisions and comprehensive feminization while preventing the long-term consequences of estrogen deficiency. Supported by a literature review, this case report emphasizes the necessity of a multidisciplinary approach to managing CAIS, highlighting the importance of heightened awareness, accurate diagnostics, and personalized therapeutic plans to ensure holistic, patient-centered care., Competing Interests: Declaration of conflicting interestThe Authors declare that there are no conflicts of interest.

Context: The varying interactions contributing to the development of juvenile idiopathic arthritis (JIA) drive the struggle to understand its etiology. Among the environmental risk factors, vitamin D has been posited to have a component in disease progression, acting as an inflammatory mediator., Objective: To investigate the correlation between serum 25-hydroxyvitamin D [25(OH)D] levels, indicative of vitamin D, among patients diagnosed with JIA compared with control participants. The aim was to elucidate potential therapeutic implications of vitamin D in the management of JIA., Data Sources: A systematic search of 6 electronic databases (MEDLINE, Embase, Scopus, CINAHL, Web of Science, and Cochrane Library) was performed until February 2023. Inclusion criteria required participants to be <16 years old (either clinically diagnosed with JIA or a matched control participant), with vitamin D levels measured through serum laboratory methods. Exclusion criteria omitted studies in which participants used vitamin D supplementation or medications affecting vitamin D levels without corresponding statistical analyses on their association with vitamin D levels., Data Extraction: Each article was reviewed by at least 2 independent reviewers to assess eligibility for analysis., Data Analysis: Data were qualitatively analyzed to compare means of serum 25(OH)D levels (ng/mL) between patients with JIA and control participants, followed by a meta-analysis to obtain effect size., Results: Ten eligible studies were included qualitatively, and eight were included in the meta-analysis. Seven studies found a statistically significant difference in vitamin D levels between control participants and patients with JIA, with five of these reporting a lower mean vitamin D level in patients with JIA. A random-effects model using standardized mean difference found a statistically significant difference in vitamin D levels between control participants and patients with JIA (-0.49; 95% CI, -0.92 to -0.06)., Conclusions: The findings from the analysis indicate vitamin D levels were lower in patients with JIA as compared with healthy control participants at baseline. It is recommended that research into vitamin D supplementation and JIA should be conducted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Objective . MRI is the standard imaging modality for high-dose-rate brachytherapy of cervical cancer. Precise contouring of organs at risk (OARs) and high-risk clinical target volume (HR-CTV) from MRI is a crucial step for radiotherapy planning and treatment. However, conventional manual contouring has limitations in terms of accuracy as well as procedural time. To overcome these, we propose a deep learning approach to automatically segment OARs (bladder, rectum, and sigmoid colon) and HR-CTV from female pelvic MRI. Approach . In the proposed pipeline, a coarse multi-organ segmentation model first segments all structures, from which a region of interest is computed for each structure. Then, each organ is segmented using an organ-specific fine segmentation model separately trained for each organ. To account for variable sizes of HR-CTV, a size-adaptive multi-model approach was employed. For coarse and fine segmentations, we designed a dual convolution-transformer UNet (DCT-UNet) which uses dual-path encoder consisting of convolution and transformer blocks. To evaluate our model, OAR segmentations were compared to the clinical contours drawn by the attending radiation oncologist. For HR-CTV, four sets of contours (clinical + three additional sets) were obtained to produce a consensus ground truth as well as for inter/intra-observer variability analysis. Main results . DCT-UNet achieved dice similarity coefficient (mean ± SD) of 0.932 ± 0.032 (bladder), 0.786 ± 0.090 (rectum), 0.663 ± 0.180 (sigmoid colon), and 0.741 ± 0.076 (HR-CTV), outperforming other state-of-the-art models. Notably, the size-adaptive multi-model significantly improved HR-CTV segmentation compared to a single-model. Furthermore, significant inter/intra-observer variability was observed, and our model showed comparable performance to all observers. Computation time for the entire pipeline per subject was 12.59 ± 0.79 s, which is significantly shorter than the typical manual contouring time of >15 min. Significance . These experimental results demonstrate that our model has great utility in cervical cancer brachytherapy by enabling fast and accurate automatic segmentation, and has potential in improving consistency in contouring. DCT-UNet source code is available athttps://github.com/JHU-MICA/DCT-UNet., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)