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Po-Cheng Chu,1,2 Man-Hua Liao,3 Mao-Gu Liu,1 Cun-Zhao Li,2 Ping-Shan Lai1 1Department of Chemistry, National Chung Hsing University, Taichung, Taiwan; 2Basic Research and Development Department, Powin Biomedical Co. Ltd., Taichung, Taiwan; 3Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, TaiwanCorrespondence: Ping-Shan Lai, Department of Chemistry, National Chung Hsing University, No. 145, Xingda Road, Taichung, 402, Taiwan, Tel +886-4-22840411 Ext 428, Fax +886-4-22862547, Email pslai@email.nchu.edu.twPurpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes.Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications.Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application.Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form. Keywords: cannabidiol, pharmacokinetics, transdermal, nano emulsion, drug patch, nanocarrier

Pei-Chi Lee,1,* Cun-Zhao Li,2,* Chun-Te Lu,3,4,* Min-Han Zhao,2 Syu-Ming Lai,2 Man-Hua Liao,5 Cheng-Liang Peng,6 Hsin-Tung Liu,1 Ping-Shan Lai2 1xTrans Corporate Research and Innovation Center, Taipei City, Taiwan; 2Department of Chemistry, National Chung Hsing University, Taichung, Taiwan; 3Division of Plastic and Reconstructive Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan; 4Institute of Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 5Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan; 6Isotope Application Division, National Atomic Research Institute, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Ping-Shan Lai, Department of Chemistry, National Chung Hsing University, No. 145, Xingda Road, Taichung, 402, Taiwan, Tel +886-4-22840411 ext. 428, Fax +886-4-22862547, Email pslai@email.nchu.edu.twPurpose: Larger nanoparticles of bioactive compounds deposit high concentrations in follicular ducts after skin penetration. In this study, we investigated the effects of microcurrent cloth on the skin penetration and translocation of large nanoparticle applied for wound repair applications.Methods: A self-assembly of curcumin-loaded micelles (CMs) was prepared to improve the water solubility and transdermal efficiency of curcumin. Microcurrent cloth (M) was produced by Zn/Ag electrofabric printing to facilitate iontophoretic transdermal delivery. The transdermal performance of CMs combined with M was evaluated by a transdermal system and confocal microscopy. The CMs/iontophoretic combination effects on nitric oxide (NO) production and inflammatory cytokines were evaluated in Raw 264.7 cells. The wound-healing property of the combined treatment was assessed in a surgically created full-thickness circular wound mouse model.Results: Energy-dispersive X-ray spectroscopy confirmed the presence of Zn/Ag on the microcurrent cloth. The average potential of M was measured to be +214.6 mV in PBS. Large particle CMs (CM-L) prepared using surfactant/cosurfactant present a particle size of 142.9 nm with a polydispersity index of 0.319. The solubility of curcumin in CM-L was 2143.67 μg/mL, indicating 250-fold higher than native curcumin (8.68 μg/mL). The combined treatment (CM-L+M) demonstrated a significant ability to inhibit NO production and increase IL-6 and IL-10 secretion. Surprisingly, microcurrent application significantly improved 20.01-fold transdermal performance of curcumin in CM-L with an obvious escape of CM-L from follicular ducts to surrounding observed by confocal microscopy. The CM-L+M group also exhibited a better wound-closure rate (77.94% on day 4) and the regenerated collagen intensity was approximately 2.66-fold higher than the control group, with a closure rate greater than 90% on day 8 in vivo.Conclusion: Microcurrent cloth play as a promising iontophoretic transdermal drug delivery accelerator that enhances skin penetration and assists CMs to escape from follicular ducts for wound repair applications.Keywords: Zn/Ag electrofabrics, iontophoretic, self-assembly, anti-inflammatory agent, skin penetration, drug delivery

You-Sin Jian,1 Ching-Wen Chen,1 Chih-An Lin,2 Hsiu-Ping Yu,1 Hua-Yang Lin,3 Ming-Yuan Liao,1 Shu-Huan Wu,1 Yan-Fu Lin,1 Ping-Shan Lai1,2,4,5 1Department of Chemistry, 2PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, 3Preclinical Development Research Department, Holy Stone Healthcare Co., Ltd., Taipei, 4Research Center for Sustainable Energy and Nanotechnology, 5Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan Abstract: Carrier-mediated drug delivery systems are promising therapeutics for targeted delivery and improved efficacy and safety of potent cytotoxic drugs. Nimesulide is a multifactorial cyclooxygenase 2 nonsteroidal anti-inflammatory drug with analgesic, antipyretic and potent anticancer properties; however, the low solubility of nimesulide limits its applications. Drugs conjugated with hyaluronic acid (HA) are innovative carrier-mediated drug delivery systems characterized by CD44-mediated endocytosis of HA and intracellular drug release. In this study, hydrophobic nimesulide was conjugated to HA of two different molecular weights (360 kDa as HA with high molecular weight [HAH] and 43kDa as HA with low molecular weight [HAL]) to improve its tumor-targeting ability and hydrophilicity. Our results showed that hydrogenated nimesulide (N-[4-amino-2-phenoxyphenyl]methanesulfonamide) was successfully conjugated with both HA types by carbodiimide coupling and the degree of substitution of nimesulide was 1%, which was characterized by 1H nuclear magnetic resonance 400 MHz and total correlation spectroscopy. Both Alexa Fluor® 647 labeled HAH and HAL could selectively accumulate in CD44-overexpressing HT-29 colorectal tumor area in vivo, as observed by in vivo imaging system. In the in vitro cytotoxic test, HA–nimesulide conjugate displayed >46% cell killing ability at a nimesulide concentration of 400 µM in HT-29 cells, whereas exiguous cytotoxic effects were observed on HCT-15 cells, indicating that HA–nimesulide causes cell death in CD44-overexpressing HT-29 cells. Regarding in vivo antitumor study, both HAL–nimesulide and HAH–nimesulide caused rapid tumor shrinkage within 3 days and successfully inhibited tumor growth, which reached 82.3% and 76.4% at day 24 through apoptotic mechanism in HT-29 xenografted mice, without noticeable morphologic differences in the liver or kidney, respectively. These results indicated that HA–nimesulide with improved selectivity through HA/CD44 receptor interactions has the potential to enhance the therapeutic efficacy and safety of nimesulide for cancer treatment. Keywords: COX-2 inhibitor, nimesulide, hyaluronic acid, CD44, colorectal cancer

Shu-Her Chiao,1* Siou-Hong Lin,1* Ching-I Shen,2* Jiunn-Wang Liao,3 I-Jiuan Bau,1 Jiun-Chiou Wei,4 Li-Ping Tseng,1 Shan-hui Hsu,4 Ping-Shan Lai,2 Shinn-Zong Lin,5–7 Jiang-Jen Lin,4 Hong-Lin Su,1,8 1Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, 2Department of Chemistry, Agricultural Biotechnology Center, National Chung Hsing University, 3Graduate Institute of Veterinary Pathobiology, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan; 4Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan; 5Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan; 6Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan; 7Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; 8Department of Physical Therapy, China Medical University, Taichung, Taiwan*These three authors contributed equallyAbstract: Developing effective and safe drugs is imperative for replacing antibiotics and controlling multidrug-resistant microbes. Nanoscale silicate platelet (NSP) and its nanohybrid, silver nanoparticle/NSP (AgNP/NSP), have been developed, and the nanohybrids show a strong and general antibacterial activity in vitro. Here, their efficacy for protecting Salmonella-infected chicks from fatality and septicemia was evaluated. Both orally administrated NSP and AgNP/NSP, but not AgNPs alone, effectively reduced the systemic Salmonella infection and mortality. In addition, quantitative Ag analyses demonstrated that Ag deposition from AgNP/NSP in the intestines was less than that from conventional AgNPs, indicating that the presence of NSP for immobilizing AgNPs reduced Ag accumulation in tissue and improved the safety of AgNPs. These in vivo results illustrated that both NSP and AgNP/NSP nanohybrid represent potential agents for controlling enteric bacterial infections.Keywords: silver, nanoparticle, biocompatibility, infection, cytotoxicity

BACKGROUND: Indoor and ambient air pollution exposure is a major risk to respiratory health worldwide, particularly in low- and middle-income countries (LMICs). Interventional trials have mainly focused on alternatives to cooking stoves, with mixed results. Beyond cooking, additional sources of particulate matter also contribute to the burden of air pollution exposure. This review explores evidence from current randomised controlled trials (RCTs) on the clinical effectiveness of interventions to reduce particulate matter in LMICs.METHODS: Twelve databases and the grey literature (e.g., Government reports and policy papers) were searched. Eligible studies were RCTs conducted in LMICs aiming to reduce particulate exposure from any source and reporting on at least one clinical respiratory outcome (respiratory symptoms, lung function or clinical diagnoses). Data from relevant studies were systematically extracted, the risk of bias assessed and narrative synthesis provided.RESULTS: Of the 14 included studies, 12 tested 'improved' cookstoves, most using biomass, but solar and bioethanol cookers were also included. One trial used solar lamps and another was an integrated intervention incorporating behavioural and environmental components for the treatment and prevention of chronic obstructive pulmonary disease. Of the six studies reporting child pneumonia outcomes, none demonstrated significant benefit in intention-to-treat analysis. Ten studies reported respiratory symptom outcomes with some improvements seen, but self-reporting made these outcomes highly vulnerable to bias. Substantial inter-study clinical and methodological heterogeneity precluded calculation of pooled effect estimates.CONCLUSION: Evidence from the RCTs performed to date suggests that individual household-level interventions for air pollution exposure reduction have limited benefits for respiratory health. More comprehensive approaches to air pollution exposure reduction must be developed so their potential health benefits can be assessed.

Abstract Objective: Generic medicines are often used in public hospitals. However, data on the quality of generic alendronate, its efficacy, side-effects and medication adherence in clinical practice is scarce. Therefore, this study aimed to compare the side-effects and medication adherence of generic (apo-alendronate * ) and proprietary alendronate (Fosamax t ). *Apotex Inc, Toronto, Ontario, Canada. tMerck Sharp & Dohme Corp., Pavia, Italy. Research design and methods: This prospective study involved two groups of patients: (1) postmenopausal osteoporotic women prescribed once-weekly Fosamax (proprietary group) but were switched to apo-alendronate after 2 years ('switched over' group); and (2) patients initiated with once-weekly apo-alendronate (generic group). Participants were recruited from the Osteoporosis Clinic of a tertiary hospital. Data were collected through interviews. Main outcome measures: Side-effects and medication adherence. Results: A total of 131 participants were recruited: proprietary group = 64 and generic group = 67. An intergroup and a within-group comparison were made. Side-effects were reported by 6 (9.4%), 30 (44.8%) and 12 (18.8%) participants in the proprietary, generic and 'switched over' groups, respectively. Participants who were on generic alendronate were at a significantly higher risk of experiencing side-effects compared to those who were taking proprietary alendronate [odds ratio (OR):7.84 (95% CI: 2.98-20.65), p < 0.001]. However, no significant statistical difference was found between the 'switched over' and the proprietary group [OR: 2.23 (95% CI: 0.78-6.37), p = 0.127]. Four out of 12 (33.3%) patients who experienced side-effects immediately after switching to generic alendronate discontinued generic alendronate due to intolerable gastrointestinal side-effects. There was no difference in medication adherence to generic or proprietary alendronate. Conclusions: Medication adherence to both generic and proprietary alendronate appeared similar although patients who were taking generic alendronate* were significantly more likely to experience side-effects than those on proprietary alendronate. Therefore, the switch from proprietary alendronate to the generic forms should not only consider the cost of the products but must also ensure that the generic and proprietary alendronate are equivalent in all aspects of efficacy and safety. [ABSTRACT FROM AUTHOR]

Adina Abdullah,1 Su May Liew,1 Nik Sherina Hanafi,1 Chirk Jenn Ng,1 Pauline Siew Mei Lai,1 Yook Chin Chia,1 Chu Kiong Loo2 1Department of Primary Care Medicine, Faculty of Medicine, University Malaya Primary Care Research Group, University of Malaya, Kuala Lumpur, Malaysia; 2Department of Artificial Intelligence, Faculty of Computer Science and Information Technology, University of Malaya, Kuala Lumpur, Malaysia Background: Telemonitoring of home blood pressure (BP) is found to have a positive effect on BP control. Delivering a BP telemonitoring service in primary care offers primary care physicians an innovative approach toward management of their patients with hypertension. However, little is known about patients’ acceptance of such service in routine clinical care.Objective: This study aimed to explore patients’ acceptance of a BP telemonitoring service delivered in primary care based on the technology acceptance model (TAM).Methods: A qualitative study design was used. Primary care patients with uncontrolled office BP who fulfilled the inclusion criteria were enrolled into a BP telemonitoring service offered between the period August 2012 and September 2012. This service was delivered at an urban primary care clinic in Kuala Lumpur, Malaysia. Twenty patients used the BP telemonitoring service. Of these, 17 patients consented to share their views and experiences through five in-depth interviews and two focus group discussions. An interview guide was developed based on the TAM. The interviews were audio-recorded and transcribed verbatim. Thematic analysis was used for analysis.Results: Patients found the BP telemonitoring service easy to use but struggled with the perceived usefulness of doing so. They expressed confusion in making sense of the monitored home BP readings. They often thought about the implications of these readings to their hypertension management and overall health. Patients wanted more feedback from their doctors and suggested improvement to the BP telemonitoring functionalities to improve interactions. Patients cited being involved in research as the main reason for their intention to use the service. They felt that patients with limited experience with the internet and information technology, who worked out of town, or who had an outdoor hobby would not be able to benefit from such a service.Conclusion: Patients found BP telemonitoring service in primary care easy to use but needed help to interpret the meanings of monitored BP readings. Implementations of BP telemonitoring service must tackle these issues to maximize the patients’ acceptance of a BP telemonitoring service. Keywords: primary health care, qualitative research, home blood pressure monitoring, telemedicine

Wen Wei Chung,1,2 Siew Siang Chua,1 Pauline Siew Mei Lai,3 Siew Pheng Chan4 1Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Pharmacy Department, University Malaya Medical Centre, Kuala Lumpur, Malaysia; 3Department of Primary Care Medicine, University Malaya Primary Care Research Group, 4Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Background: Diabetes mellitus is a lifelong chronic condition that requires self-management. Lifestyle modification and adherence to antidiabetes medications are the major determinants of therapeutic success in the management of diabetes.Purpose: To assess the effects of a pharmaceutical care (PC) model on medication adherence and glycemic levels of people with type 2 diabetes mellitus. Patients and methods: A total of 241 people with type 2 diabetes were recruited from a major teaching hospital in Malaysia and allocated at random to the control (n=121) or intervention (n=120) groups. Participants in the intervention group received PC from an experienced pharmacist, whereas those in the control group were provided the standard pharmacy service. Medication adherence was assessed using the Malaysian Medication Adherence Scale, and glycemic levels (glycated hemoglobin values and fasting blood glucose [FBG]) of participants were obtained at baseline and after 4, 8, and 12 months. Results: At baseline, there were no significant differences in demographic data, medication adherence, and glycemic levels between participants in the control and intervention groups. However, statistically significant differences in FBG and glycated hemoglobin values were observed between the control and intervention groups at months 4, 8, and 12 after the provision of PC (median FBG, 9.0 versus 7.2 mmol/L [P

Li Shean Toh,1 Pauline Siew Mei Lai,2 David Bin-Chia Wu,3 Kok Thong Wong,1 Bee Yean Low,1 Alexander Tong Boon Tan,4 Claire Anderson5 1School of Pharmacy, University of Nottingham, Semenyih, Malaysia; 2Department of Primary Care Medicine, University of Malaya Primary Care Research Group, University of Malaya, Kuala Lumpur, Malaysia; 3School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia; 4Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 5Division of Social Research in Medicine and Health, School of Pharmacy, University of Nottingham, Nottingham, UK Purpose: To develop and validate the English version of the Satisfaction Questionnaire for Osteoporosis Prevention (SQOP) in Malaysia.Methods: The SQOP was modified from the Osteoporosis Patient Satisfaction Questionnaire and developed based on literature review and patient interviews. Face and content validity were established via an expert panel. The SQOP consists of two sections: clinical services and types of counseling. There were 23 items in total, each with a five-point Likert-type response. Satisfaction score was calculated by converting the total score to a percentage. A higher score indicates higher satisfaction. English speaking, non-osteoporotic, postmenopausal women aged ≥50 years were included in the study. Participants were randomized to either the control or intervention group. Intervention participants were provided counseling, whereas control participants received none. Participants answered the SQOP at baseline and 2 weeks later.Results: A total of 140 participants were recruited (control group: n=70; intervention group: n=70). No significant differences were found in any demographic aspects. Exploratory factor analysis extracted seven domains. Cronbach’s a for the domains ranged from 0.531–0.812. All 23 items were highly correlated using Spearman’s correlation coefficient 0.469–0.996 (P

Bisphosphonates are pyrophosphate analogues, with a strong affinity for bones. They inhibit bone resorption and are currently the first choice of treatment for osteoporosis. Bisphosphonates should be taken in a specific manner and for at least one year to be effective in the maintenance and improvement of bone mineral density (BMD), as well as for protection against fractures. We report a case of a postmenospausal osteoporotic woman who lost BMD despite being on bisphosphonate therapy for eight years, highlighting issues that a primary care doctor needs to address before deciding on the next best option.

In this April issue of the Malaysian Family Physician, there are two manuscripts on the validation of instruments. The first manuscript is the validation of the Malay version of the Berlin Questionnaire to identify Malaysian patients at risk for obstructive sleep apnea,1whilst the second manuscript is on the validation of the Malay version of the Diabetes Quality of Life for Youth Questionnaire.2All instruments assessing patient reported outcomes have to be evaluated for its reliability and validity in the country prior to its use. The purpose of this is to ensure that the instrument used is measuring what it is supposed to measure. This is applicable to instruments that have been developed in English by other authors, and validated elsewhere; as well as self-developed instruments or those that have been modified (e.g. translated into another language or otherwise).

Forensic practitioners need contemporary anthropological data for the identification of human remains. The clavicle possesses a high degree of variability in its anatomical, biomechanical, and morphological features that are sex-dependent albeit population specific. The aim of this study was to develop sex estimation models for Malaysian individuals using post-mortem computed tomographic images of the clavicle. Sample comprised scans of 2.0 mm resolution of 405 individuals (209 male; 196 female) aged between 19 to 88 years. These scans were reconstructed and visualized using Infinitt. Six clavicular measurements (i.e. maximum length, C1; midshaft circumference, C2; midshaft maximum diameter, C3; midshaft minimum diameter, C4; maximum breadth of the sternal end, C5; and maximum breadth of the acromial articular surface, C6) were obtained from these images. Data were analyzed using descriptive statistics and discriminant function analysis. Measurements taken from the images were highly precise (ICC = 0.770-0.999). There is a significant difference between all parameters and sex (p < 0.001), however none for age and ethnic group. A multivariate sex estimation model was developed: Sex = (C1*0.86) + (C2*0.236) + (C3*-0.145) + (C5*- 0.074) - 17.618; with an accuracy rate of 89.1 % and sex bias of -3.2 %. Lower accuracy rates were obtained for single variable models (61.5-83.2 %). The resultant sex discriminant models can be used for estimating sex based on the clavicle in our local forensic practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear., Methods: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome., Results: Stratifying patients based on %Notch4 + Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4 + Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection., Conclusions: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4 + Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Spinal muscular atrophy (SMA) is a genetic disease characterized by loss of motor neurons in the spinal cord and lower brainstem. The term "SMA" usually refers to the most common form, 5q-SMA, which is caused by biallelic mutations in SMN1 (located on chromosome 5q13). However, long before the discovery of SMN1 , it was known that other forms of SMA existed. Therefore, SMA is currently divided into two groups: 5q-SMA and non-5q-SMA. This is a simple and practical classification, and therapeutic drugs have only been developed for 5q-SMA (nusinersen, onasemnogene abeparvovec, risdiplam) and not for non-5q-SMA disease., Methods: We conducted a non-systematic critical review to identify the characteristics of each SMA disease., Results: Many of the non-5q-SMA diseases have similar symptoms, making DNA analysis of patients essential for accurate diagnosis. Currently, genetic analysis technology using next-generation sequencers is rapidly advancing, opening up the possibility of elucidating the pathology and treating non-5q-SMA., Conclusion: Based on accurate diagnosis and a deeper understanding of the pathology of each disease, treatments for non-5q-SMA diseases may be developed in the near future.

Acute lung injury (ALI), a critical complication of COVID-19, is characterized by widespread inflammation and severe pulmonary damage, necessitating intensive care for those affected. Although glucocorticoids (GCs), such as dexamethasone (Dex), have been employed clinically to lower mortality, their nonspecific systemic distribution has led to significant side effects, limiting their use in ALI treatment. In this study, we explored the conjugation of Dex to hyaluronic acid (HA) to achieve targeted delivery to inflamed lung tissues. We achieved a conjugation efficiency exceeding 98 % using a cosolvent system, with subsequent ester bond cleavage releasing the active Dex, as verified by liquid chromatography. Biodistribution and cellular uptake studies indicated the potential of the HA conjugate for cluster of differentiation 44 (CD44)-mediated targeting and accumulation. In a lipopolysaccharide-induced ALI mouse model, intravenous (IV) HA-Dex administration showed superior anti-inflammatory effects compared to free Dex administration. Flow cytometry analysis suggested that the HA conjugate preferentially accumulated in lung macrophages, suggesting the possibility of reducing clinical Dex dosages through this targeted delivery approach., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. T.-Y.C. is from Holy Stone Healthcare Co., Ltd., The company and funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2024. Published by Elsevier B.V.)

Managing mass fatality incidents or disasters involving multiple deaths are not uncommon among forensic practitioners. In fact, management of unidentified or unknown bodies is also a vital component of the day-to-day mortuary work practice. The unidentified and subsequently unclaimed bodies have always been a "silent mass disaster," a problem that needs to be tackled within the forensic community and raises the global issue of ethics, law, and human rights. Unidentified bodies' in Malaysia make up an average of 4.02% of all death cases where a total postmortem examination was performed which is comparable with other developing countries within 4-10% which can go up to 25%. Moreover, unstandardized procedures in all mortuaries in different states and districts in Malaysia have worsened the scenario even with guidelines in place. This study aims to address the issues surrounding unidentified and unclaimed bodies including body disposal from a social and legal perspective using case study methodology by comparing four different countries in the Asia Pacific Region through document analysis and interview methods. One of the major findings is evident in 3 out of the 4 models, whereby there is a considerable gap in consolidating the missing person report and information to match with the unidentified bodies received in forensic institutions in an attempt to enhance the identification process which ultimately intends as a closure for the family members. It is also timely to think out of the box beyond dental records and DNA profiling to improve the identification rate for skeletonized remains through means of anthropology biometrics comparison. With the limited literature published surrounding this domain, it is hoped that the suggestions and recommendations to standardize the management of unidentified and unclaimed bodies can benefit many forensic institutions and public mortuaries in this region., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: An estimated 3 billion people, largely in low- and middle-income countries, rely on unclean fuels for cooking, heating, and lighting to meet household energy needs. The resulting exposure to household air pollution (HAP) is a leading cause of pneumonia, chronic lung disease, and other adverse health effects. In the last decade, randomized controlled trials of clean cooking interventions to reduce HAP have been conducted. We aim to provide guidance on how to interpret the findings of these trials and how they should inform policy makers and practitioners. Methods: We assembled a multidisciplinary working group of international researchers, public health practitioners, and policymakers with expertise in household air pollution from within academia, the American Thoracic Society, funders, nongovernmental organizations, and global organizations, including the World Bank and the World Health Organization. We performed a literature search, convened four sessions via web conference, and developed consensus conclusions and recommendations via the Delphi method. Results: The committee reached consensus on 14 conclusions and recommendations. Although some trials using cleaner-burning biomass stoves or cleaner-cooking fuels have reduced HAP exposure, the committee was divided (with 55% saying no and 45% saying yes) on whether the studied interventions improved measured health outcomes. Conclusions: HAP is associated with adverse health effects in observational studies. However, it remains unclear which household energy interventions reduce exposure, improve health, can be scaled, and are sustainable. Researchers should engage with policy makers and practitioners working to scale cleaner energy solutions to understand and address their information needs.

Gene modification therapies (GMTs) are slowly but steadily making progress toward clinical application. As the majority of rare diseases have an identified genetic cause, and as rare diseases collectively affect 5% of the global population, it is increasingly important to devise gene correction strategies to address the root causes of the most devastating of these diseases and to provide access to these novel therapies to the most affected populations. The main barriers to providing greater access to GMTs continue to be the prohibitive cost of developing these novel drugs at clinically relevant doses, subtherapeutic effects, and toxicity related to the specific agents or high doses required. In vivo strategy and treating younger patients at an earlier course of their disease could lower these barriers. Although currently regarded as niche specialties, prenatal and preconception GMTs offer a robust solution to some of these barriers. Indeed, treating either the fetus or embryo benefits from economy of scale, targeting pre-pathological tissues in the fetus prior to full pathogenesis, or increasing the likelihood of complete tissue targeting by correcting pluripotent embryonic cells. Here, we review advances in embryo and fetal GMTs and discuss requirements for clinical application., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders., Competing Interests: Declaration of competing interest H.L.C. is a shareholder in Alamya Health. The other co-authors do not have any conflicts of interests to declare in relation to this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. Objectives: The primary outcome was the change in arterial oxygenation (Pa O 2 /Fi O 2 ) at 48 hours. The secondary outcomes included: time to reach a Pa O 2 /Fi O 2 .300mmHg for at least 24 hours, the proportion of participants with a Pa O 2 /Fi O 2 .300mmHg at 28 days, and survival at 28 and at 90 days. Methods: Mechanically ventilated adults with COVID-19 pneumonia were enrolled in a phase II, multicenter, single-blind, randomized controlled parallel-arm trial. Participants in the intervention arm received inhaled nitric oxide at 80 ppm for 48 hours, compared with the control group receiving usual care (without placebo). Measurements and Main Results: A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in Pa O 2 /Fi O 2 ratio at 48 hours was 28.3mmHg in the intervention group and 21.4mmHg in the control group (mean difference, 39.1mmHg; 95% credible interval [CrI], 18.1 to 60.3). The mean time to reach a Pa O 2 /Fi O 2 .300mmHg in the interventional group was 8.7 days, compared with 8.4 days for the control group (mean difference, 0.44; 95% CrI, 23.63 to 4.53). At 28 days, the proportion of participants attaining a Pa O 2 /Fi O 2 .300mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the control subjects (risk ratio, 2.03; 95% CrI, 1.11 to 3.86). Duration of ventilation and mortality at 28 and 90 days did not differ. No serious adverse events were reported. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of Pa O 2 /Fi O 2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.

Ischemic stroke is a heterogeneous condition influenced by a combination of genetic and environmental factors. Recent advancements have explored genetics in relation to various aspects of ischemic stroke, including the alteration of individual stroke occurrence risk, modulation of treatment response, and effectiveness of post-stroke functional recovery. This article aims to review the recent findings from genetic studies related to various clinical and molecular aspects of ischemic stroke. The potential clinical applications of these genetic insights in stratifying stroke risk, guiding personalized therapy, and identifying new therapeutic targets are discussed herein.

Background: Acute appendicitis is one of the most common abdominal emergencies, with management approaches that vary depending on the available resources and setting. However, there is a lack of studies on the differences of surgical outcomes and quality of care between tertiary care hospitals and regional hospitals., Methods: This multicenter retrospective study included 2158 consecutive adult patients between January 2014 and June 2018 at three hospitals. The patient cohort was divided into regional hospital group (N = 1223) and tertiary care hospital group (N = 935). Baseline characteristics and perioperative outcomes were compared, and factors associated with surgical delay and postoperative complication were investigated., Results: Patients in tertiary care hospital group had longer surgical waiting time (17.3 vs. 12.0 h, p < 0.001), higher risks of surgical delay exceeding 24 h (OR = 2.94, 95% CI 2.17-4.01, p < 0.001), longer operation time (64 vs. 50 min, p < 0.001), more appendix perforation (22.4 vs. 13.3%, p < 0.001), and higher hospital cost compared with regional hospital group. In multivariate analysis, factors associated with surgical delay were tertiary care hospital (OR = 2.94, 95% CI 2.18-4.01, p < 0.001) and delay diagnosis (OR = 18.7, 95% CI 11.7-30.1, p < 0.001), while those associated with postoperative complications were older age (OR = 1.02, 95% CI 1.00-1.04, p = 0.013), male sex (OR = 2.38, 95% CI 1.11-5.52, p = 0.031), surgical delay (OR = 2.99, 95% CI 1.30-6.47, p = 0.007), and appendix perforation (OR = 5.61, 95% CI 2.72-11.85, p < 0.001)., Conclusions: Patients at tertiary care hospitals had longer waiting time, more surgical delays, and appendix perforations, and these were risk factors of postoperative complications. Establishing an effective referral system to redirect appendicitis patients with less complex medical histories from tertiary care hospitals to regional hospitals may enhance the quality of patient care and outcomes, while also reducing medical costs., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the DMD gene. The full mutation spectrum of the DMD gene in Indonesian patients is currently unknown. Mutation-specific therapies are currently being developed, such as exon skipping or stop codon read-through therapy. This study was conducted with the aim of identifying the mutation spectrum of the DMD gene in Indonesia to guide future development and application of feasible therapeutic strategies., Methods: This study is a cross sectional study that enrolled 43 male patients with a clinical suspicion of DMD or BMD. Multiplex ligation-dependent probe amplification (MLPA) reaction was performed to screen for the common mutations in the DMD gene., Results: Out of 43 subjects, deletions accounted for 69.77% (n=30) cases, while duplications were found in 11.63% (n=5) cases. One novel duplication spanning exons 2 to 62 was identified. Deletion mutations clustered around the distal (66.67%) and proximal (26.67%) hot spot regions of the DMD gene while duplication mutations were observed solely at the proximal region. Two false positive cases of single exon deletion detected through MLPA were attributed to sequence mutations affecting primer ligation sites, confirming the need to validate all single exon deletions when using this screening method. Analysis of available maternal DNA samples showed that the rate of de novo mutations (48.15%) appears higher than expected in this population. Out of 31 patients who were classified as DMD based on clinical and genotype characterizations, 60.47% (n=26) of cases were suitable for exon skipping therapy., Conclusion: This is the first comprehensive study showing the feasibility of implementing the MLPA method for routine screening of DMD patients in Indonesia. This is also the first study showing the potential applicability of exon skipping therapy in the majority of DMD cases in the country., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Dwianingsih EK et al.)

Aims: Despite the availability of newer antiseizure medications, carbamazepine (CBZ) remains the gold standard. However, patients of Asian ancestry are susceptible to CBZ-related severe cutaneous adverse reactions. Universal HLA-B*15:02 screening is a promising intervention to address this. With the increasing recognition of integrating real-world evidence in economic evaluations, the cost-effectiveness of universal HLA-B*15:02 screening was assessed using available real-world data in Malaysia., Methods: A hybrid model of a decision tree and Markov model was developed to evaluate 3 strategies for treating newly diagnosed epilepsy among adults: (i) CBZ initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to CBZ initiation; and (iii) alternative prescribing without HLA-B*15:02 screening. The model was populated with real-world inputs derived from the Malaysian population. From a societal perspective, base-case analysis and sensitivity analyses estimated the costs and outcomes over a lifetime. Incremental cost-effectiveness ratios were calculated., Results: In the base-cases analysis, universal HLA-B*15:02 screening yielded the lowest total costs and the highest total quality-adjusted life years (QALYs) gained. Compared with current practice, universal screening was less costly by USD100 and more effective by QALYs increase of 0.1306, while alternative prescribing resulted in 0.1383 QALYs loss at additional costs of USD332. The highest seizure remission rate (56%) was estimated for universal HLA-B*15:02 screening vs. current practice (54%) and alternative prescribing (48%)., Conclusion: Our study suggests that universal HLA-B*15:02 screening is a cost-effective intervention in Malaysia. With the demonstrated value of real-world evidence in economic evaluations, more relevant standardization efforts should be emphasized to better inform decision-making., (© 2023 British Pharmacological Society.)

Severe injuries to the peripheral nervous system (PNS) require Schwann cells to aid in neuronal regeneration. Low-frequency electrical stimulation is known to induce the cogrowth of neurons and Schwann cells in an injured PNS. However, the correlations between electrical stimulation and Schwann cell viability are complex and not well understood. In this work, we develop a machine learning (ML)-integrated workflow that uses conductive hydrogel biointerfaces to evaluate the impacts of fabrication parameters and electrical stimulation on the Schwann cell viability. First, a hydrogel array with varying MXene and peptide loadings is fabricated, which serves as conductive biointerfaces to incubate Schwann cells and introduce various electrical stimulation (at different voltages and frequencies). Upon specific fabrication parameters and stimulation, the cell viability is evaluated and input into an artificial neural network model to train the model. Additionally, a data augmentation method is applied to synthesize 1000-fold virtual data points, enabling the construction of a high-accuracy prediction model (with a testing mean absolute error ≤11%). By harnessing the model's predictive power, we can accurately predict Schwann cell viability based on a given set of fabrication/stimulation parameters. Finally, the SHapley Additive exPlanations model interpretation provides several data-scientific insights that are validated by microscopic cellular observations. Our hybrid approach, involving conductive biointerface fabrication, ML algorithms, and data analysis, offers an unconventional platform to construct a preclinical prediction model at the cellular level.

End stage renal disease (ESRD) patients on renal replacement therapy (RRT) have an increased risk of morbidity and mortality due to healthcare associated infections (HCAIs). The aim of this study is to determine the prevalence, microbial etiology, and risk factors associated with HCAIs among ESRD patients on RRT. A multicenter, retrospective study was conducted from June to December 2019. ESRD patients with minimum of 6 months on RRT were included, while pregnant patients and patients <18 years were excluded. To reduce the risk of selection bias, all patients were randomly selected using a simple random sampling technique. The prevalence showing the proportion of patients that acquired HCAI since the initiation of dialysis until 2019 was calculated using the European patients' academy (EUPATI) formula. Risk factors were assessed using univariate and multivariate regression analysis. The prevalence of HCAI among ESRD patients was 174/400 (43.5%). Catheter related bloodstream infection (CRBSI) was the most common infection [64(36.8%)], followed by peritonitis [45(25.8%)] and pneumonia [37(21.2%)]. Out of 382 total pathogens identified, 204 (53.4%) were Gram positive and 162 (42.4%) were Gram negative. Both methicillin sensitive staphylococcus aureus (MSSA) and methicillin resistant staphylococcus aureus (MRSA) showed statistically significant associations (p<0.05) with CRBSI. Use of multiple accesses, increased blood sugar levels, low serum sodium levels and higher CRP concentration increased the occurrence of HCAIs. The burden of HCAIs among the patients undergoing RRT is high. Preventive strategies and optimum empirical therapy of antibiotics should be used to reduce the risk of these infections among ESRD patients.

Background: The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure., Methods: We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites., Results: Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or "long COVID," suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease., Conclusions: Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention., (© 2023. The Author(s).)

Which social factors explain racial and ethnic disparities in COVID-19 access to care and outcomes remain unclear., Objectives: We hypothesized that preferred language mediates the association between race, ethnicity and delays to care., Design Setting and Participants: Multicenter, retrospective cohort study of adults with COVID-19 consecutively admitted to the ICU in three Massachusetts hospitals in 2020., Main Outcome and Measures: Causal mediation analysis was performed to evaluate potential mediators including preferred language, insurance status, and neighborhood characteristics., Results: Non-Hispanic White (NHW) patients (157/442, 36%) were more likely to speak English as their preferred language (78% vs. 13%), were less likely to be un- or under-insured (1% vs. 28%), lived in neighborhoods with lower social vulnerability index (SVI) than patients from racial and ethnic minority groups (SVI percentile 59 [28] vs. 74 [21]) but had more comorbidities (Charlson comorbidity index 4.6 [2.5] vs. 3.0 [2.5]), and were older (70 [13.2] vs. 58 [15.1] years). From symptom onset, NHW patients were admitted 1.67 [0.71-2.63] days earlier than patients from racial and ethnic minority groups ( p < 0.01). Non-English preferred language was associated with delay to admission of 1.29 [0.40-2.18] days ( p < 0.01). Preferred language mediated 63% of the total effect ( p = 0.02) between race, ethnicity and days from symptom onset to hospital admission. Insurance status, social vulnerability, and distance to the hospital were not on the causal pathway between race, ethnicity and delay to admission., Conclusions and Relevance: Preferred language mediates the association between race, ethnicity and delays to presentation for critically ill patients with COVID-19, although our results are limited by possible collider stratification bias. Effective COVID-19 treatments require early diagnosis, and delays are associated with increased mortality. Further research on the role preferred language plays in racial and ethnic disparities may identify effective solutions for equitable care., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a serious public health threat with the World Health Organisation (WHO) reporting 5.8 million cases and 1.3 million deaths in the year 2020 due to TB. TB can be diagnosed by imaging, histopathological and bacteriological methods with culture remaining the gold standard. This study was performed to look at the sensitivity and specificity of post-mortem computed tomography (PMCT) imaging when compared to culture in diagnosing pulmonary tuberculosis. This was a retrospective comparative study looking at post mortem cases where lung tissue samples sent for TB culture at Hospital Kuala Lumpur were compared against PMCT imaging. Exclusion criteria included contaminated samples, decomposed cases, immunocompromised subjects and those below 18 years of age. Subjects included 80 medico-legal autopsy cases at the National Institute of Forensic Medicine, Hospital Kuala Lumpur, Malaysia who had whole body PMCT done in accordance with the Institute's protocol and tissue samples sent for bacteriology culture for tuberculosis. PMCT findings were positively associated with acid-fast organisms in 23.5 out of 33 cases (71.2%). Our study also showed that PMCT had a sensitivity of 71.3% and specificity of 54.3% (95% CI: 39.5-68.4) in diagnosing TB based on the protocol set in this study. This study showed that there was relatively good agreement between radiological PMCT findings and bacterial culture, suggesting that radiological examination is a relatively reliable tool for preliminary screening and possible diagnosis of TB prior to a postmortem examination which would be beneficial in reducing the risk of transmission of TB to health workers during autopsy.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease in developed countries. In clinical treatment, steroids have been used as bridging and adjunctive therapy after disease-modifying anti-rheumatic drug administration. However, the severe side effects caused by the nonspecific targeting of organs followed by long-term administration have limited their usage in RA. In this study, poorly water-soluble triamcinolone acetonide (TA), a highly potent corticosteroid for intra-articular injection, is conjugated on hyaluronic acid (HA) for intravenous purposes with increased specific drug accumulation in inflamed parts for RA. Our results demonstrate that the designed HA/TA coupling reaction reveals >98 % conjugation efficiency in the dimethyl sulfoxide/water system, and the resulting HA-TA conjugates show lower osteoblastic apoptosis compared with that in free TA-treated osteoblast-like NIH3T3 cells. Furthermore, in a collagen-antibody-induced arthritis animal study, HA-TA conjugates enhanced the initiative targeting ability to inflame tissue and reduce the histopathological arthritic changes (score = 0). Additionally, the level of bone formation marker P1NP in HA-TA-treated ovariectomized mice (303.6 ± 40.6 pg/mL) is significantly higher than that in the free TA-treated group (143.1 ± 3.9 pg/mL), indicating the potential for osteoporotic reduction using an efficient HA conjugation strategy for the long-term administration of steroids against RA., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. T.-Y.C. is from Holy Stone Healthcare Co., Ltd., The company and funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023. Published by Elsevier B.V.)

The clinical features and outcomes of tuberculosis (TB) and COVID-19 coinfection are not well established. This short report describes 11 people with TB/COVID-19 coinfection in Uganda. The mean age was 46.9 ± 14.5 years; eight (72.7%) were male and two (18.2%) were coinfected with HIV. All patients presented with cough whose median duration was 71.1 (interquartile range, 33.1, 109) days. Eight (72.7%) had mild COVID-19 whereas two (18.2%) died, including one with advanced HIV disease. All patients were treated with first-line anti-TB drugs and adjunct therapy for COVID-19 using national treatment guidelines. This report presents the possibility of the coexistence of the two diseases and calls for more vigilance, screening, and collective prevention measures for both COVID-19 and TB.

Background: Expanding electrification and access to other clean and affordable energy, such as solar energy, is a critical component of the Sustainable Development Goals, particularly in sub-Saharan Africa where 70% of people are energy insecure. Intervention trials related to access or less polluting household energy alternatives have typically focused on air quality and biological outcomes rather than on how an intervention affects the end user's lived experiences, a key determinant of uptake and adoption outside of a research setting. We explored perceptions of and experiences with a household solar lighting intervention in rural Uganda., Methods: In 2019, we completed a one-year parallel group, randomized wait-list controlled trial of indoor solar lighting systems (ClinicalTrials.gov NCT03351504) in rural Uganda where participants are largely relying on kerosene and other fuel-based lighting received household indoor solar lighting systems. In this qualitative sub-study, we conducted one-on-one, in-depth qualitative interviews with all 80 female participants enrolled in the trial. Interviews explored how solar lighting and illumination impacted participants' lives. We applied a theoretical model linking social integration and health to analyse dynamic interactions across aspects of study participants' lived experiences. Sensors were used to measure daily lighting use before and after receipt of the intervention solar lighting system., Results: Introduction of the solar lighting system increased daily household lighting use by 6.02 (95% confidence intervals (CI) = 4.05-8.00) hours a day. The solar lighting intervention had far-reaching social implications with improved social integration and, consequently, social health. Participants felt that lighting improved their social status, mitigated the stigma of poverty, and increased the duration and frequency of social interactions. Household relationships improved with access to lighting because of reduced conflicts over light rationing. Participants also described a communal benefit of lighting due to improved feelings of safety. At the individual-level, many reported improved self-esteem, sense of well-being, and reduced stress., Conclusion: Improved access to lighting and illumination had far reaching implications for participants, including improved social integration. More empirical research, particularly in the light and household energy field, is needed that emphasizes the impacts of interventions on social health., Registration: ClinicalTrials.gov No. NCT03351504., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated C-fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A-gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non-SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date---SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health-care providers., (© 2022 Wiley Periodicals LLC.)

Objective: The School Inner-City Asthma Intervention Study 2 (SICAS 2) tested interventions to reduce exposures in classrooms of students with asthma. The objective of this post-hoc analysis was limited to evaluating the effect of high-efficiency particulate (HEPA) filtration interventions on mold levels as quantified using the Environmental Relative Moldiness Index (ERMI) and the possible improvement in the students' asthma, as quantified by spirometry testing., Methods: Pre-intervention dust samples were collected at the beginning of the school year from classrooms and corresponding homes of students with asthma ( n  = 150). Follow-up dust samples were collected in the classrooms at the end of the HEPA or Sham intervention. For each dust sample, ERMI values and the Group 1 and Group 2 mold levels (components of the ERMI metric) were quantified. In addition, each student's lung function was evaluated by spirometry testing, specifically the percentage predicted forced expiratory volume at 1 sec (FEV1%), before and at the end of the intervention., Results: For those students with a higher Group 1 mold level in their pre-intervention classroom than home ( n  = 94), the FEV1% results for those students was significantly ( p  < 0.05) inversely correlated with the Group 1 level in their classrooms. After the HEPA intervention, the average Group 1 and ERMI values were significantly lowered, and the average FEV1% test results significantly increased by an average of 4.22% for students in HEPA compared to Sham classrooms., Conclusions: HEPA intervention in classrooms reduced Group 1 and ERMI values, which corresponded to improvements in the students' FEV1% test results.

Background: Prone position ventilation (PPV) is resource-intensive, yet the optimal strategy for PPV in intubated patients with COVID-19 is unclear., Research Question: Does a prolonged (24 or more h) PPV strategy improve mortality in intubated COVID-19 patients compared with intermittent (∼16 h with daily supination) PPV?, Study Design and Methods: Multicenter, retrospective cohort study of consecutively admitted intubated COVID-19 patients treated with PPV between March 11 and May 31, 2020. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 90-day all-cause mortality and prone-related complications. Inverse probability treatment weights (IPTW) were used to control for potential treatment selection bias., Results: Of the COVID-19 patients who received PPV, 157 underwent prolonged and 110 underwent intermittent PPV. Patients undergoing prolonged PPV had reduced 30-day (adjusted hazard ratio [aHR], 0.475; 95% CI, 0.336-0.670; P < .001) and 90-day (aHR, 0.638; 95% CI, 0.461-0.883; P = .006) mortality compared with intermittent PPV. In patients with Pao 2 /Fio 2  ≤ 150 at the time of pronation, prolonged PPV was associated with reduced 30-day (aHR, 0.357; 95% CI, 0.213-0.597; P < .001) and 90-day mortality (aHR, 0.562; 95% CI, 0.357-0.884; P = .008). Patients treated with prolonged PPV underwent fewer pronation and supination events (median, 1; 95% CI, 1-2 vs 3; 95% CI, 1-4; P < .001). PPV strategy was not associated with overall PPV-related complications, although patients receiving prolonged PPV had increased rates of facial edema and lower rates of peri-proning hypotension., Interpretation: Among intubated COVID-19 patients who received PPV, prolonged PPV was associated with reduced mortality. Prolonged PPV was associated with fewer pronation and supination events and a small increase in rates of facial edema. These findings suggest that prolonged PPV is a safe, effective strategy for mortality reduction in intubated COVID-19 patients., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.