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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.)

Purpose: 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., Competing Interests: The authors declare no conflicts of interest., (© 2024 Chu et al.)

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.)

Purpose: 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., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Lee et al.)

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.

Background: Medical students' white coats were found to harbor harmful organisms. This could be due to non-compliance to white coat hygiene measures. Therefore, we aim to develop and validate a questionnaire to assess the of knowledge, attitude, and practice (LAUNDERKAP) of white coat use among medical students in Malaysia., Methods: This study was conducted in 4 local medical schools. LAUNDERKAP was developed via literature review and had 3 domains: attitude, knowledge, practice. An expert panel assessed the content validity and clarity of wording. LAUNDERKAP was then piloted among 32 medical students. To test construct validity and internal consistency, 362 medical students were approached. Construct validity was assessed using exploratory factor analysis. Internal consistency was evaluated using Cronbach alpha for attitude and practice, while Kuder-Richardson 20 (KR-20) was used for knowledge., Results: A total of 319 of 362 students responded. Exploratory factor analysis extracted 1 factor each for attitude and knowledge respectively, and 3 factors for practice. Cronbach alpha for attitude was 0.843 while KR-20 for knowledge was 0.457. Cronbach alpha for practice ranged from 0.375 to 0.689. The final LAUNDERKAP contained 32-items (13 attitude, 9 knowledge, 10 practice)., Conclusions: LAUNDERKAP had adequate psychometric properties and can be used to assess KAP of medical students towards white coat use., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Curcumin, a well-known natural lipophilic phenolic compound, plays a vital role in inhibiting the influenza infection. Currently, many kinds of formulations for the enhancement of a water dispersion of curcumin have been developed; however, the anti-influenza abilities of formulated curcumin have been much less investigated. In this study, the optimized self-assembled micelles of RH 40/Tween 80 loaded with curcumin (Cur-M) in an oil-free-based system were spherical with a hydrodynamic size at 13.55 nm ± 0.208 and polydispersity at 0.144 characterized by atomic force microscopy and dynamic light scattering, respectively. Additionally, Cur-M significantly increased the bioactivity/stability of curcumin and effectively inhibited the influenza A virus infection and its replication after viral entry, indicating the alteration of the inhibition mechanisms of curcumin against virus infection via RH 40/Tween 80 micelle formulation. Furthermore, a solid formulation (Cur-SM) of Cur-M was successfully developed by a one-pot physical adsorption method using a small amount of adsorbent and ~50% of curcumin/Cur-M that could be burst released from Cur-SM in 1 h, facilitating the fast-releasing applications. Ultimately, all of the results show that Cur-SM acts as a good nano-formulation of curcumin with improved solubility/dispersity in aqueous solutions and demonstrate new anti-influenza mechanisms of curcumin for pharmaceutical development., Competing Interests: The authors declare no conflict of interest.

Features of the airway microbiome in persons with cystic fibrosis (pwCF) are correlated with disease progression. Microbes have traditionally been classified for their ability to tolerate oxygen. It is unknown whether supplemental oxygen, a common medical intervention, affects the airway microbiome of pwCF. We hypothesized that hyperoxia significantly impacts the pulmonary microbiome in cystic fibrosis. In this study, we cultured spontaneously expectorated sputum from pwCF in artificial sputum medium under 21%, 50%, and 100% oxygen conditions using a previously validated model system that recapitulates microbial community composition in uncultured sputum. Culture aliquots taken at 24, 48, and 72 h, along with uncultured sputum, underwent shotgun metagenomic sequencing with absolute abundance values obtained with the use of spike-in bacteria. Raw sequencing files were processed using the bioBakery pipeline to determine changes in taxonomy, predicted function, antimicrobial resistance genes, and mobile genetic elements. Hyperoxia reduced absolute microbial load, species richness, and diversity. Hyperoxia reduced absolute abundance of specific microbes, including facultative anaerobes such as Rothia and some Streptococcus species, with minimal impact on canonical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. The effect size of hyperoxia on predicted functional pathways was stronger than that on taxonomy. Large changes in microbial cooccurrence networks were noted. Hyperoxia exposure perturbs airway microbial communities in a manner well tolerated by key pathogens. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting. IMPORTANCE The airway microbiome in persons with cystic fibrosis (pwCF) is correlated with lung function and disease severity. Supplemental oxygen use is common in more advanced CF, yet its role in perturbing airway microbial communities is unknown. By culturing sputum samples from pwCF under normal and elevated oxygen conditions, we found that increased oxygen led to reduced total numbers and diversity of microbes, with relative sparing of common CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting.

Background: Emery-Dreifuss Muscular Dystrophy (EDMD) is an uncommon genetic disease among the group of muscular dystrophies. EDMD is clinically heterogeneous and resembles other muscular dystrophies. Mutation of the lamin A/C (LMNA) gene, which causes EDMD, also causes many other diseases. There is inter and intrafamilial variability in clinical presentations. Precise diagnosis can help in patient surveillance, especially before they present with cardiac problems. Hence, this paper shows how a molecular work-out by next-generation sequencing can help this group of disorders., Case Presentation: A 2-year-10-month-old Javanese boy presented to our clinic with weakness in lower limbs and difficulty climbing stairs. The clinical features of the boy were Gower's sign, waddling gait and high CK level. His father presented with elbow contractures and heels, toe walking and weakness of limbs, pelvic, and peroneus muscles. Exome sequencing on this patient detected a pathogenic variant in the LMNA gene (NM&#95;170707: c.C1357T: NP&#95;733821: p.Arg453Trp) that has been reported to cause Autosomal Dominant Emery-Dreifuss muscular dystrophy. Further examination showed total atrioventricular block and atrial fibrillation in the father., Conclusion: EDMD is a rare disabling muscular disease that poses a diagnostic challenge. Family history work-up and thorough neuromuscular physical examinations are needed. Early diagnosis is essential to recognize orthopaedic and cardiac complications, improving the clinical management and prognosis of the disease. Exome sequencing could successfully determine pathogenic variants to provide a conclusive diagnosis., (© 2022. The Author(s).)

Background: COVID-19 was declared a pandemic by the World Health Organization (WHO). COVID-19 is highly contagious, making it a threat to healthcare workers, including those working in mortuaries. Therefore, it is important to determine if the cause of death (COD) could be identified using limited autopsy, diagnostic tests and post-mortem imaging modalities instead of full autopsy. This study aims to examine the effectiveness of post-mortem imaging, specifically post-mortem computed tomography (PMCT) at determining the COD during a pandemic., Methods: This cross-sectional study included 172 subjects with suspected or unknown COVID-19 status brought in dead to the institute's mortuary during the pandemic in Malaysia. PMCT images reported by forensic radiologists and their agreement with conventional autopsy findings by forensic pathologists regarding COD were analysed to look at the effectiveness of PMCT in determining COD during a pandemic., Results: Analysis showed that 78.7% (133) of cases reported by forensic radiologists concurred with the COD certified by forensic pathologists. Of these cases, 85 (63.9%) had undergone only external examination and real-time reverse transcriptase polymerase chain reaction (rRT-PCR) COVID-19 testing, meaning that imaging was the sole method used to determine the COD besides history from available medical records and the investigating police officer., Conclusion: PMCT can be used as a complement to medicolegal autopsies in pandemic contexts, as it provides significant information on the possible COD without jeopardising the safety of mortuary health care workers., Competing Interests: Conflict of Interest None., (© Penerbit Universiti Sains Malaysia, 2022.)

1-Phenyl-1 H -1,2,3-triazole 1 (ARUK3001185) was prepared on large scale from aniline 4 by application of both (1) a copper catalyzed azide-alkyne cycloaddition (CuAAC) with (trimethylsilyl)acetylene, and (2) a Clark modification of the Sakai reaction. The one-pot Sakai-Clark method with (MeO) 2 CHCH[double bond, length as m-dash]NNHTos (2b) proved to be superior as it was operationally simple, metal-free, and avoided the use of aryl azide 7. The Sakai-Clark method has been reliably performed on large scale to produce >100 g of 1 in good efficiency and high purity., Competing Interests: B. N. A., N. J. W, and P. V. F. are co-inventors of patent application WO 2020043866, which describes inhibitors of Notum. The authors have no other relevant affiliations or financial involvement apart from those disclosed., (This journal is © The Royal Society of Chemistry.)

Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p < 0.05), when comparing the area under the tumor growth curve to that of the saline-treated DNP-immunized mice. Meanwhile, IYIY-DNP at 10 mg/kg had no effect on TrkC-negative 67NR tumor-bearing mice immunized with DNP. Tumor growth suppression activity of IYIY-DNP in DNP-immunized mice was associated with an increase in the anti-DNP IgG (7.3 × 10 6  ± 1.6 U/mL) and IgM (0.9 × 10 6  ± 0.07 U/mL) antibodies after five cycles of DNP treatment, demonstrated potential for hapten-based pre-immunization then treatment with IYIY-DNP to elicit ADCP for improved immunotherapy of TrkC expressing cancers., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The environmental microbiome represents the entirety of the microbes and their metabolites that we encounter in our environments. A growing body of evidence supports the role of the environmental microbiome in risk for and severity of allergic diseases and asthma. The environmental microbiome represents a ubiquitous, lifelong exposure to non-self antigens. During the critical window between birth and 1 year of life, interactions between our early immune system and the environmental microbiome have 2 consequences: our individual microbiome is populated by environmental microbes, and our immune system is trained regarding which antigens to tolerate. During this time, a diversity of exposures appears largely protective, dramatically decreasing the risk of developing allergic diseases and asthma. As we grow older, our interactions with the environmental microbiome change. While it continues to exert influence over the composition of the human microbiome, the environmental microbiome becomes increasingly a source for antigenic stimulation and infection. The same microbial exposure protective against disease development may exacerbate disease severity. Although much has been learned about the importance of the environmental microbiome in allergic disease, much more remains to be understood about these complicated interactions between our environment, our microbiome, our immune system, and disease., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Tuberculosis (TB) is significantly associated with multiple postinfectious, non-communicable diseases after microbiological cure. For example, those with a history of TB disease have a higher risk of developing chronic lung diseases at a younger age. However, the extent and nature of post-TB complications are not well described. Here, we present a protocol for a systematic review and meta-analysis, which aims to synthesise literature on the burden of post-TB lung disease (PTLD) in sub-Saharan Africa, describe phenotypes, long-term outcomes and the health-related quality of life of people with PTLD., Methods and Analysis: A systematic search will be conducted using PubMed, EMBASE, Web of Science, African Journals Online and the Cochrane Library of Systematic Reviews. Papers published in English and French languages that report the prevalence, clinical features, quality of life and long-term outcomes of people with PTLD in sub-Saharan Africa will be considered. We will assess and critically appraise the methodological quality of all studies using the modified covidence. Qualitative and quantitative (network and meta-analysis) synthesis will be performed and STATA V.16 will be used to estimate the burden of PTLD., Ethics and Dissemination: Ethical approval is not required for this systematic review and meta-analysis. Our results will be published in peer-reviewed journals., Prospero Registration Number: CRD42021274018., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests., Objective: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA., Methods: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA 576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity., Results: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01)., Conclusions: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA., (Copyright © 2022. Published by Elsevier Inc.)

Rationale: While studies suggest that the lung microbiome may influence risk of chronic obstructive pulmonary disease (COPD) exacerbations, little is known about the relationship between the nasal biome and clinical characteristics of COPD patients., Methods: We sampled the nasal lining fluid by nasosorption of both nares of 20 people with moderate-to-severe COPD. All 40 samples, plus 4 negative controls, underwent DNA extraction, and 16SV4 ribosomal RNA (rRNA) (bacterial) and ribosomal internal transcribed spacer 2 (ITS2) (fungal) sequencing. We measured the proportion of variance (R 2 ) in beta diversity explained by clinical factors, including age, sex, body mass index (BMI), COPD treatment, disease severity (forced expiratory volume in 1 second [FEV 1 ], symptom/exacerbation frequency), peripheral eosinophil level (≥150 versus <150 cells/µL) and season of sampling, with the PERMANOVA test on the Bray-Curtis dissimilarities, accounting for within-person correlation of samples. We assessed the relative abundance of microbial features in the nasal community and their associations with clinical characteristics using the Microbiome Multivariable Association with Linear Models (MaAsLin2) package., Results: The most abundant nasal fluid bacterial taxa were Corynebacterium , Staphylococcus , Streptococcus , Moraxella , and Dolosigranulum , and fungal taxa were Malassezia , Candida , Malasseziales , Cladosporium and Aspergillus . Bacterial microbiome composition was associated with short-acting muscarinic antagonist use (R 2 11.8%, p =0.002), sex (R 2 8.3%, p =0.044), nasal steroid use (R 2 7.7%, p =0.064), and higher eosinophil level (R 2 7.6%, p =0.084). Mycobiome composition was associated with higher eosinophil level (R 2 14.4%, p =0.004) and low FEV 1 (R 2 7.5%, p =0.071). No specific bacterium or fungus differed significantly in relative abundance by clinical characteristics in the multivariate per-feature analysis., Conclusion: The taxonomical composition of the nasal biome is heterogeneous in COPD patients and may be explained in part by clinical characteristics., (JCOPDF © 2022.)

Background/purpose: The appropriate management of postoperative upper alimentary tract fistula (UATF) remains uncertain. The efficacy of esophagogastroduodenoscopy (EGD) tissue glue repair in the treatment of patients with postoperative UATF was explored. We also conducted a systematic review of the literature regarding the inpatient management of UATF., Methods: Totally 24 patients received EGD tissue glue repair for postoperative UATF at our institute from April 2014 to April 2020. Independent characteristics of size of fistula, location of the UATF, complications, and recurrences were analyzed. PubMed and Cochrane Library databases were reviewed. A pooled analysis was performed, and subgroup analysis was conducted separately for different anatomic locations and techniques., Results: With a mean follow-up of 40 months, the fistula failed to close with EGD tissue glue repair in 2 of 24 patients (8.3%). Eight patients required repeated EGD tissue glue repair, which was more frequent in oral or thoracic UATF (p = 0.053), but all achieved a successful seal in the EGD tissue after glue repair alone (n = 22). The fistula size was correlated with the demand for repeated EGD tissue glue repair (p = 0.017). Besides, a total of 30 studies regarding 2356 cases of postoperative UATF between 2010 and 2021 were retrieved and analyzed. Several non-operative methods were generally accepted as the initial approach, with a non-inferior success rate compared to operative techniques., Conclusion: The results suggest that no single approach toward UATF is superior in terms of success rate and healing time. The potential advantages of EGD tissue glue repair after drainage were more suitable for patients with postoperative UATF and multiple comorbidities., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Psoriasis is a chronic inflammatory skin disease that can significantly impact the quality of human life. Various drug treatments are available; however, due to their long-term severe side effects the usage of these drugs is limited. Photodynamic therapy (PDT) has been clinically approved for skin diseases due to its non-invasive nature. We present novel NNO-tridentate vanadium(IV) complexes used in PDT for anti-inflammatory effects in an imiquimod-induced psoriasis-like skin disease mouse model. The vanadium(IV) complexes (1-4) were synthesized using the NNO-tridentate ligand with a benzo[ i ]dipyrido[3,2- a ;2',3'- c ]phenazine (dppn) moiety, and were characterized by UV/Visible spectroscopy, EPR spectroscopy, NMR ( 1 H, and 13 C) spectroscopy, electrospray ionization mass (ESI-MS) spectrometry and cyclic voltammetry (CV) studies. The photocytotoxicity of vanadium(IV) complexes (1-4) was low under dark conditions and complex (4) showed remarkable photocytotoxicity under blue light (430 nm, 8 W cm -2 , 30 min) irradiation. Moreover, [VO( t -butylL)(dppn)] (4)-mediated PDT down-regulated inflammatory cytokines IL-17A and IL-22 in the psoriasis-like mouse model, which could evidence the significant relieving of the psoriatic-like symptoms in the mouse model. Overall, these results suggested that [VO( t -butylL)(dppn)] (4) could be a potential candidate for the treatment of psoriasis both in vitro and in vivo .

The concept of vulnerability has played an important role in theoretical bioethics as well as in numerous authoritative guidelines on research ethics. The concept helps to identify situations in which research participants and other individuals may be at a heightened risk of experiencing harm. However, existing guidance documents on the ethics of human germline gene editing largely fail to make any reference to considerations of vulnerability. In this article, we discuss this oversight and we highlight the role that vulnerability can play in ethical debates about human heritable genome editing. Future guidance documents on germline gene editing should pay attention to considerations of vulnerability and reference these appropriately.

Purpose: Code status orders impact clinical outcomes as well as patients' and surrogates' experiences. This is the first multicenter cohort examining code status orders of ICU patients with COVID-19 reported to date., Materials and Methods: This is a retrospective cohort study including adult patients who tested positive for SARS-CoV-2 and were admitted to the ICU at three hospitals in Massachusetts from March 11, 2020 - May 31, 2020. We examined differences in code status orders at multiple timepoints and performed multivariable regression analysis to identify variables associated with code status at admission., Results: Among 459 ICU patients with COVID-19, 421 (91.7%) were Full Code at hospital admission. Age and admission from a facility were positively associated with DNR status (adjusted OR 1.10, 95% CI 1.05-1.15, p < 0.001 and adjusted OR 2.68, CI 1.23-5.71, p = 0.011, respectively) while non-English preferred language was negatively associated with DNR status (adjusted OR 0.29, 95% CI 0.10-0.74, p = 0.012). Among 147 patients who died during hospitalization, 95.2% (140) died with DNR code status; most (86.4%) died within two days of final code status change., Conclusions: The association of non-English preferred language with Full Code status in critically ill COVID-19 patients highlights the importance of medical interpreters in the ICU. Patients who died were transitioned to DNR more than in previous studies, possibly reflecting changes in practice during a novel pandemic., (© 2022 The Author(s).)

Manganese-zinc ferrite (MZF) is known as high-performance magnetic material and has been used in many fields and development. In the biomedical applications, the biocompatible MZF formulation attracted much attention. In this study, water-soluble amphiphilic vitamin E (TPGS, d-alpha-tocopheryl poly(ethylene glycol 1000) succinate) formulated MZF nanoparticles were synthesized to serve as both a magnetic resonance imaging (MRI) contrast agent and a vehicle for creating magnetically induced hyperthermia against cancer. The MZF nanoparticles were synthesized from a metallic acetylacetonate in an organic phase and further modified with TPGS using an emulsion and solvent-evaporation method. The resulting TPGS-modified MZF nanoparticles exhibited a dual-contrast ability, with a longitudinal relaxivity (35.22 s -1 mM Fe -1 ) and transverse relaxivity (237.94 s -1 mM Fe -1 ) that were both higher than Resovist ® . Furthermore, the TPGS-assisted MZF formulation can be used for hyperthermia treatment to successfully suppress cell viability and tumor growth after applying an alternating current (AC) electromagnetic field at lower amplitude. Thus, the TPGS-assisted MZF theranostics can not only be applied as a potential contrast agent for MRI but also has potential for use in hyperthermia treatments.

Background: Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II is an autosomal recessive condition encompassing a heterogeneous group of disorders characterized by symmetrical growth retardation leading to dwarfism, microcephaly, and a range of multiple medical complications including neurovascular diseases. Biallelic pathogenic variants in the pericentrin gene (PCNT) have been implicated in its pathogenesis., Case Presentation: We performed whole-exome sequencing to ascertain the diagnosis of a 2 year and 6 months old boy who presented with severe failure to thrive, microcephaly, and facial gestalt suggestive of MOPD Type II which included features such as retrognathia, small ears, prominent nasal root with a large nose, microdontia, sparse scalp hair, bilateral fifth finger clinodactyly. He had a small ostium secundum atrial septal defect and bilaterally small kidneys. Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II was confirmed based on a pathogenic compound heterozygous frameshift variant in the PCNT gene c.5059&#95;5060delAA | p. Asn1687fs (novel variant) and c.9535dup (p. Val3179fs). His parents were found to be heterozygous carriers for the variants., Conclusion: We report a novel frameshift variant in the PCNT gene and a previously unreported phenotype for Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II., (© 2022. The Author(s).)

Ultraviolet-A (UVA) exposure is a major cause of skin aging and can induce oxidative damage and accelerate skin wrinkling. Many natural polysaccharides exhibit a UV protective effect. In research on Pholiota nameko polysaccharides (PNPs), a natural macromolecular polysaccharide (4.4-333.487 kDa), studies have shown that PNPs can significantly decrease elastase activity to protect against UVA-induced aging in Hs68 human dermal fibroblasts. Cellular experiments in the present study indicated that PNPs can protect against UVA-induced oxidative damage in Hs68 cells by inhibiting the production of reactive oxygen species. Furthermore, PNPs significantly attenuated UVA-induced cell aging by decreasing the protein expression of matrix metalloproteinase 1, 3, and 9. Pretreatment of Hs68 cells with PNP-40, PNP-60, and PNP-80 before UVA irradiation increased protein expression of tissue inhibitor metalloproteinase 1 by 41%, 42%, and 56% relative to untreated cells. In conclusion, this study demonstrates that PNPs are a natural resource with potentially beneficial effects in protecting against UVA-induced skin aging.