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Background: Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear., Methods: We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104., Results: Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations ( KRAS , NRAS , WT1 , CDKN2A or CDKN2B , or RUNX1 ), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT., Conclusions: Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.)., (Copyright © 2024 Massachusetts Medical Society.)

This study aims to design and optimize ondansetron (OND) gastro-retentive floating minitablets for better and prolonged control of postoperative nausea and vomiting (PONV) with improved patient compliance. Minitablets were directly compressed and encapsulated in a size 2 capsule shell with an overall dose of 24 mg. Central composite design (CCD) was applied keeping one cellulose ether derivative HPMC K15M and Carbopol 971 as variable and used as swelling and rate retarding agents. The other cellulose derivative i.e. sodium carboxymethyl cellulose, along with mannitol, sodium bicarbonate, and talc, were used in fixed quantities. The floating lag time, total floating time, swelling index, in-vitro drug release, and zero-order (RSQ value), were critical quality parameters. The optimized formulation (F pred ) was evaluated for all critical parameters, along with surface morphology, thermal stability, chemical interaction, and accelerated stability. The in silico PBPK modeling was applied to compare the bioavailability of F pred with reference OND immediate-release tablets. The numerical optimization model predicted >90 % drug release with zero-order at 12 h. In silico PBPK modeling revealed comparable relative bioavailability of F pred with the reference formulation. The gastroretentive floating minitablets of OND were successfully designed for prolonged emesis control in patients receiving chemotherapeutic agents., 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.)

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10 -8 ). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10 -6 ). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10 -3 ). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy., (© 2024. The Author(s).)

Importance: Approximately 15-45% of female patients develop transient postoperative urinary retention (POUR) following pelvic reconstructive surgery. Catheter options for bladder drainage include transurethral indwelling catheter (TIC), intermittent self-catheterization (ISC), and suprapubic tube (SPT). Each strategy has risks and benefits; none have been shown to be clinically superior, and to date, no comprehensive comparative economic analysis has been published., Objective: The objective of this study was to evaluate the cost of these different bladder catheterization strategies after transvaginal pelvic surgery., Study Design: A Canadian universal single-payer (government funded) health system perspective was taken, and a decision tree model was constructed to evaluate the costs associated with each catheterization strategy over a 6-week horizon. Base-cases were set based on recently published clinical data of our institutions, 2 academic tertiary care centers, and based on systematic reviews and meta-analyses. Costs were established in consultation with process stakeholders, in addition to published values., Results: The average cost calculated for management of transient POUR after outpatient pelvic reconstructive surgery was 150.69 CAD (median 154.86; interquartile range [IQR] 131.30-176.33) for TIC, 162.28 CAD (median 164.72; IQR 144.36-189.39) for ISC and 255.67 CAD (median 270.63; IQR 234.32-276.82) for SPT. In costing inpatient surgical data, the average cost calculated was 134.22 CAD (median 123.61; IQR 108.87-151.85) for TIC and 224.61 CAD (median 216.07; IQR 203.86-231.23) for SPT., Conclusion: TIC and ISC were found to be significantly less costly than SPT in managing transient POUR following transvaginal pelvic reconstructive surgery., Competing Interests: Dr. Colleen McDermott is a medical advisor for Szio Inc., COSM Inc., Abbvie, and Lupin Pharma, and a speaker for Pfizer. These corporations were not involved in or influenced any facet of this study, including project development, data collection, and manuscript writing. The authors have declared they have no conflicts of interest., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

Introduction: Patients with traumatic intracranial hemorrhage (tICH) are at increased risk of venous thromboembolism and may require anticoagulation. We evaluated the utility of surveillance computed tomography (CT) in patients with tICH who required therapeutic anticoagulation., Methods: This single institution, retrospective study included adult patients with tICH who required anticoagulation within 4 weeks and had a surveillance head CT within 24 hours of reaching therapeutic anticoagulation levels. The primary outcome was hematoma expansion (HE) detected by the surveillance CT. Secondary outcomes included 1) changes in management in patients with HE on the surveillance head CT, 2) HE in the absence of clinical changes, and 3) mortality due to HE. We also compared mortality between patients who did and did not have a surveillance CT., Results: Of 175 patients, 5 (2.9%) were found to have HE. Most (n = 4, 80%) had changes in management including anticoagulation discontinuation (n = 4), reversal (n = 1), and operative management (n = 1). Two patients developed symptoms or exam changes prior to the head CT. Of the 3 patients (1.7%) without preceding exam changes, each had only very minor HE and did not require operative management. No patient experienced mortality directly attributed to HE. There was no difference in mortality between patients who did and those who did not have a surveillance scan., Conclusions: Our findings suggest that most patients with tICH who are started on anticoagulation could be followed clinically, and providers may reserve CT imaging for patients with changes in exam/symptoms or those who have a poor clinical examination to follow., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures Drs Engelberg, Kross, and Creutzfeldt report funding from the National Institutes of Health.

Objective: We aimed to elucidate associations between geographic location, size, and ranking of medical schools that orthopaedic surgery residents graduate from and the residencies that they match both pre-COVID-19 and post-COVID-19 pandemic by examining the 2017 to 2022 orthopaedic surgery residency cohorts., Methods: Demographics were extracted using Doximity Residency Navigator platform, the 2021 US News and World Report, and program websites. Medical schools were classified as large if they had >613 medical students. Postgraduate year 1 (PGY-1) (2021 match) and PGY-2 (2022 match) residents were classified as the COVID-19 cohort. Location was categorized as Northeast, Midwest, South, and West. Chi-square tests, Cohen's H value, and descriptive statistics were used for analysis with statistical significance set at p <0.05., Results: Four thousand two hundred forty-three residents from 160 accredited US orthopaedic residency programs (78.4%) were included. Northeastern applicants were most likely to match in the same region (p <0.01), and southern applicants were most likely to match at their home program (p <0.001). Applicants affected by the COVID-19 pandemic did not differ from their predecessors with regards to matching to the same region (p = 0.637) or home program (p = 0.489). Applicants from public medical schools were more likely to match in the same region and at their home program (p <0.001), whereas those from private medical schools were more likely to match at top-ranked residencies (p <0.001). Students from both top 25- and top 50-ranked medical schools were more likely to match at their home program (p <0.01) and attend top 20-ranked residency programs (p <0.0001)., Conclusion: These results demonstrate significant associations between matched residencies and attended medical schools' geographic location, school type, and ranking. During the pandemic, geographic trends were overall unchanged, whereas residents from large or lower-ranked schools were more likely to match at home programs, and those from private or top-ranked schools were less likely to attend top residencies., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A584)., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Background: Stroke is a neurological disease and a leading cause of mortality worldwide. Strokes mainly consist of two types: hemorrhage and ischemia. Stroke patients are being administered multiple drug therapy and are at risk of drug-related problems., Aim: To estimate drug-related problems (DRPs) and clinical end outcomes in hospitalized stroke patients., Methods: Current study was a multicenter, cross-sectional prospective observational study including 250 stroke patients admitted to tertiary care hospitals in Karachi, Pakistan. The study included all clinical subtypes of stroke patients i.e. Stroke, Ischemic stroke, Hemorrhagic stroke, CVA, and TIA. Associations among patient-clinical end outcomes and drug therapy-related variables like DRPs, mortality, and morbidity rates were estimated using Pearson's chi-squared test. Statistical analysis was done by using SPSS software, version 25., Results: A total of 250 patients participated in this study suffering from different clinical subtypes of stroke i.e. Ischemic stroke, hemorrhagic stroke, TIA, and CVA, including 46% male and 54% female patients. The majority of patients' stay at the hospital was between 1-10 days. The overall mortality rate in stroke patients was 51%. HAIs were observed in 70% of patients, HAIs faced by patients were SAP, CAP, UTI, sepsis, and VAP. Drugs were assessed according to NEML i.e. access group antibiotics, watch group antibiotics, reserve group antibiotics, statins, antiepileptics, and proton pump inhibitors. Majorly ceftriaxone was administered to 79% of patients, piperacillin-tazobactam to 52%, and cefixime to 48%, whereas meropenem was administered to 42% of patients along with vancomycin to 39% of total patients. A high mortality rate was observed in the case of Klebsiella pneumoniae and Staphylococcus aureus i.e. 78% and in the case of streptococcus pneumoniae 61% mortality rate was observed. Due to the presence of DRPs and various other clinical factors like comorbidities, DDIs, HAIs, administration of potentially nephrotoxic drugs, and administration of antibiotics without having CST, hospitalized stroke patients faced many problems., Conclusion: This study helped determine DRPs along with various clinical factors affecting the clinical end outcomes of patients suffering from any clinical subtype of stroke. Due to the enhancement in the evidence of the incidence of DRPs in tertiary care hospitals, pharmacist-led drug therapy review by interfering with doctors and other medical professionals at the patient bed site is needed and should be done to avoid any negative end outcomes and serious issues related to DRPs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In support of the environmental justice (EJ) movement, researchers, activists, and policymakers often use environmental data to document evidence of the unequal distribution of environmental burdens and benefits along lines of race, class, and other socioeconomic characteristics. Numerous limitations, such as spatial or temporal discontinuities, exist with commonly used data measurement techniques, which include ground monitoring and federal screening tools. Satellite data is well poised to address these gaps in EJ measurement and monitoring; however, little is known about how satellite data has advanced findings in EJ or can help to promote EJ through interventions. Thus, this scoping review aims to (1) explore trends in study design, topics, geographic scope, and satellite datasets used to research EJ, (2) synthesize findings from studies that use satellite data to characterize disparities and inequities across socio-demographic groups for various environmental categories, and (3) capture how satellite data are relevant to policy and real-world impact. Following PRISMA extension guidelines for scoping reviews, we retrieved 81 articles that applied satellite data for EJ research in the United States from 2000 to 2022. The majority of the studies leveraged the technical advantages of satellite data to identify socio-demographic disparities in exposure to environmental risk factors, such as air pollution, and access to environmental benefits, such as green space, at wider coverage and with greater precision than previously possible. These disparities in exposure and access are associated with health outcomes such as increased cardiovascular and respiratory diseases, mental illness, and mortality. Research using satellite data to illuminate EJ concerns can contribute to efforts to mitigate environmental inequalities and reduce health disparities. Satellite data for EJ research can therefore support targeted interventions or influence planning and policy changes, but significant work remains to facilitate the application of satellite data for policy and community impact.

Aim: Insulin therapy require self-administration of subcutaneous injection leading to painful and inconvenient drug therapy. The aim is to fabricate nanoemulsion (NE) based insulin loaded microneedles with improved bioavailability and patient compliance. Materials & methods: Different ratios of polyvinyl alcohol and polyvinylpyrrolidone as polymers were prepared through micro-molding technique for microneedles. Characterization of were performed using scanning electron microscope, differential scanning calorimetry, Fourier-transform infrared spectroscopy and circular dichroism. Mechanical strength, hygroscopicity and pain perception of these microneedles were also evaluated. In vitro release, permeation and in vivo PK/PD study of NE-based microneedles were conducted. Results: NE-based microneedles of insulin have improved bioavailability and quick response. Conclusion: Microneedles loaded with insulin can be effectively delivered insulin transdermally to treat diabetes with increased convenience and patient compliance.

IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a loss of normal IKAROS function, conferring leukemic stem cell properties, including self-renewal and subsequent uncontrolled growth. IKZF1 deletions are associated with treatment resistance and inferior outcomes. Early identification of IKZF1 deletions in B-ALL may inform the intensification of therapy and other potential treatment strategies to improve outcomes in this high-risk leukemia.

In the United States (U.S.), studies on nitrogen dioxide (NO 2 ) trends and pollution-attributable health effects have historically used measurements from in situ monitors, which have limited geographical coverage and leave 66% of urban areas unmonitored. Novel tools, including remotely sensed NO 2 measurements and estimates of NO 2 estimates from land-use regression and photochemical models, can aid in assessing NO 2 exposure gradients, leveraging their complete spatial coverage. Using these data sets, we find that Black, Hispanic, Asian, and multiracial populations experience NO 2 levels 15-50% higher than the national average in 2019, whereas the non-Hispanic White population is consistently exposed to levels that are 5-15% lower than the national average. By contrast, the in situ monitoring network indicates more moderate ethnoracial NO 2 disparities and different rankings of the least- to most-exposed ethnoracial population subgroup. Validating these spatially complete data sets against in situ observations reveals similar performance, indicating that all these data sets can be used to understand spatial variations in NO 2 . Integrating in situ monitoring, satellite data, statistical models, and photochemical models can provide a semiobservational record, complete geospatial coverage, and increasingly high spatial resolution, enhancing future efforts to characterize, map, and track exposure and inequality for highly spatially heterogeneous pollutants like NO 2 .

Background: Recently enacted environmental justice policies in the United States at the state and federal level emphasize addressing place-based inequities, including persistent disparities in air pollution exposure and associated health impacts. Advances in air quality measurement, models, and analytic methods have demonstrated the importance of finer-scale data and analysis in accurately quantifying the extent of inequity in intraurban pollution exposure, although the necessary degree of spatial resolution remains a complex and context-dependent question., Objective: The objectives of this commentary were to a ) discuss ways to maximize and evaluate the effectiveness of efforts to reduce air pollution disparities, and b ) argue that environmental regulators must employ improved methods to project, measure, and track the distributional impacts of new policies at finer geographic and temporal scales., Discussion: The historic federal investments from the Inflation Reduction Act, the Infrastructure Investment and Jobs Act, and the Biden Administration's commitment to Justice40 present an unprecedented opportunity to advance climate and energy policies that deliver real reductions in pollution-related health inequities. In our opinion, scientists, advocates, policymakers, and implementing agencies must work together to harness critical advances in air quality measurements, models, and analytic methods to ensure success. https://doi.org/10.1289/EHP13063.

Purpose: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy., Experimental Design: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia., Results: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL., Conclusions: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making., (©2023 American Association for Cancer Research.)

Objective: The present study aimed to assess the thyroid outcomes six-months after radioactive Iodine-131 therapy (RIT) among hyperthyroid patients and identify the factors associated with them., Methods: This retrospective observational study was conducted at the department of Nuclear Medicine and Molecular Imaging, Northwest General Hospital & Research Centre during 2013 to 2019. For the study purpose, the thyroid outcomes of 153 hyperthyroid patients were studied retrospectively for six months after RIT. The data was obtained from the medical records. Patient baseline characteristics, clinical features, laboratory investigations, results of thyroid imaging, and therapeutic investigations were acquired and recorded in a structured questionnaire., Results: Out of the 153 screened records of hyperthyroid patients, 19.6% became euthyroid, 9.2% remained hyperthyroid, and 25.5% developed hypothyroidism after six months of RIT. The observed remission rate by the end of six months was 80.95%. Three months post-RIT, gender and RAI doses had a significant effect on thyroid function. The frequency of hypothyroidism was higher among those treated with an RAI dose of ≤ 20 mCi (83.0%) than those treated with a higher dose > 20 mCi (17%). Moreover, most patients receiving > 20 mCi radioiodine became euthyroid (64.5%). Similar outcomes were observed after six months of the therapy, except gender was replaced by etiologies of hyperthyroidism (p=0.009)., Conclusion: Radioactive iodine (131-I) therapy is effective for the treatment of hyperthyroidism. However, the appropriate dose is still debatable, as there was a high incidence of hypothyroidism post-therapy., (Copyright: © Pakistan Journal of Medical Sciences.)

This study investigated the ability of natural nanotubular clay mineral (Halloysite) and cellulose ether based biocomposite matrix as a controlled release agent for Verapamil HCl (BCS Class-I). Drug-loaded halloysite was prepared and tablet formulations were designed by varying amount of hydroxy propyl methyl cellulose (HPMC K4M). Physical characterization was carried out using SEM, FTIR, and DSC. Tabletability profiles were evaluated using USP1062 guidelines. Drug release kinetics were studied, and physiologically based pharmacokinetic (PBPK) modeling was performed. Compressed tablets possess satisfactory yield pressure of 625 MPa with adequate hardness and disintegration within 30 min. The initial release of the drug was due to surface drug on tablets, while the prolonged release at later time points (around 80 % drug release at 12 h) were due to halloysite loading. The FTIR spectra exhibited electrostatic attraction between the positively charged drug and the negatively charged Si-O-Si functional group of halloysite, while the thermogram showed Verapamil HCl melting point at ~146 °C with enthalpy change of -126.82 J/g. PBPK modeling exhibited PK parameters of optimized matrix formulation (VER-HNT 3% ) comparable to in vivo data. The study effectively demonstrated the potential of prepared biocomposite matrix as a commercially viable oral release modifying agent for highly soluble drugs., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has transformed the global view of education, including graduate and postgraduate education making the development of an alternative approach in times of social isolation an academic imperative. The present review aims to investigate the challenges experienced among undergraduate and postgraduate education and the strategies adopted to address these challenges during the pandemic., Method: The preferred reporting items for the systematic review and meta-analyses extension for Scoping Reviews (PRISMA-ScR) were followed. The aim was to include journal articles published in the English language that discussed the influence of the pandemic on educational processes and applied innovative approaches as a solution to educational challenges. From January to August 2020, PubMed, EMBASE, and Google Scholar were searched for articles, yielding 10,019 articles. Two groups of authors examined the retrieved articles separately to avoid any risk of bias. The title and abstract of the articles were used for scrutiny, followed by full-text screening based on the established inclusion and exclusion criteria. The facts and findings of the studies were also discussed based on per capita income, literacy rate, and Internet accessibility., Results: Thirty of the obtained articles were included in the study. The selected articles were from North and South/Latin America, Asia & Pacific, South Africa, and Europe regions. Nineteen of the selected articles dealt with undergraduate education, ten with postgraduate, and one with both groups. The affordability of digital devices and the availability of Internet services were the major challenges for low- and middle-income economies. The ZOOM platform has been adopted by more than 90% of the education systems., Conclusion: Means of communication, including visual media, digitized content, and other web-based platforms, have been recognized as efficient learning and training tools, but have not been fully accessible for mass application and use due to the lack of availability of resources, their cost, and insufficient training among the users. In light of this review, it is suggested that harmonized and collaborative efforts should be made to develop cost-effective and user-friendly tools to overcome the current challenges and prevent future educational crises., Systemic Review Registration: The review was not registered., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Meningitis is an important cause of morbidity and mortality in children and adults. Its treatment strategy varies with age and gender. To assess potential drug-related problems (PDRP) and clinical outcomes in bacterial meningitis patients, a multicenter, clinical, descriptive, cross-sectional prospective observational study in 120 patients admitted to different tertiary care hospitals in Karachi was conducted. It includes both males 48% and females 52% belonging from all age groups i.e. peadiatrics (01 to 12 years), adults (18 to 65 years), and geriatrics (66 to 75 years). Out of these 72 patients were admitted in the public sector and 48 patients were admitted in private sector hospitals. Nosocomial infections were developed in 41% of patients during their stay at the hospital. Potentially nephrotoxic drugs were administered to all BM patients, these drugs should be administered carefully. Majorly Ceftriaxone was administered to 86% of patients, Vancomycin 71%, and meropenem 73% whereas 68% of patients were administered piperacillin-tazobactam. Organisms involved as causative agents in the majority of patients are Neisseria meningitides, Pseudomonas aeruginosa and, Streptococcus pneumoniae. DRPs impacted patient clinical outcomes in presence of many other factors like comorbidities, DDIs, Nis, administration of potentially nephrotoxic drugs, and administration of watch group and reserve group antibiotics without having culture sensitivity test, even after having CST no principles of de-escalation for antibiotics were done, which is a very important factor for hospitalized patients having IV antibiotics. The mortality rate among BM patients was 66%. The majority of patients (87%) stay at the hospital was 1-10 days. The present study helped in the identification of DRPs along with some other factors affecting the clinical outcomes in patients suffering from bacterial meningitis. Healthcare professionals should receive awareness and education on the importance of CST before initiating antibiotic therapy. Pharmacist-led medication review is necessary and should be followed to avoid negative outcomes and serious consequences related to DRPs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Antifibrinolytics, such as tranexamic acid (TXA), have been shown to decrease intraoperative blood loss across multiple surgical disciplines. However, they carry the theoretical risk of thromboembolic events secondary to induced hypercoagulability. Therefore, the aim of this study was to systematically review the available literature and perform a meta-analysis on the use of TXA in meningioma resection to assess thromboembolic risks., Methods: The PubMed, Web of Science, and Google Scholar databases were reviewed for all randomized controlled trials presenting primary data on TXA use during resection of intracranial meningiomas. Data were gathered on operative duration, venous thromboembolic complications, deep venous thrombosis, use of allogeneic blood transfusion, estimated blood loss (EBL), and postoperative hemoglobin. Patients who received TXA were compared with controls who did not receive TXA intraoperatively using random-effects models., Results: A total of 508 unique articles were identified, of which 493 underwent full-text review. Ultimately, 6 studies with 381 total patients (190 receiving TXA) were included in the final analysis. All 6 trials were randomized, blinded, and placebo controlled with a TXA administration rate of a 20-mg/kg load followed by a 1-mg/kg/hr infusion. All studies were performed in lower-middle-income countries. There were no reported instances of venous thromboembolism (VTE) in the TXA and non-TXA cohorts. Patients receiving TXA exhibited fewer allogeneic transfusions (21.5% vs 41.6% [OR 0.26, 95% CI 0.09-0.77], p = 0.02) and lower EBL (MD -282.48 mL [95% CI -367.77 to -197.20 mL], p < 0.001) compared with patients who did not receive TXA, and they also had lower rates of perioperative complications (10.7% vs 19.9% [OR 0.47, 95% CI 0.2-0.95], p = 0.04)., Conclusions: Current literature suggests that TXA is not associated with increased risk for VTE when administered during resection of intracranial meningioma. TXA appears to decrease intraoperative blood loss and allogeneic transfusion requirements during meningioma resection and thus may improve the safety of surgical management of this pathology.

Background: As ground-level falls (GLFs) are a significant cause of mortality in elderly patients, field triage plays an essential role in patient outcomes. This research investigates how machine learning algorithms can supplement traditional t-tests to recognize statistically significant patterns in medical data and to aid clinical guidelines., Methods: This is a retrospective study using data from 715 GLF patients over 75 years old. We first calculated P -values for each recorded factor to determine the factor's significance in contributing to a need for surgery ( P < .05 is significant). We then utilized the XGBoost machine learning method to rank contributing factors. We applied SHapley Additive exPlanations (SHAP) values to interpret the feature importance and provide clinical guidance via decision trees., Results: The three most significant P -values when comparing patients with and without surgery are as follows: Glasgow Coma Scale (GCS) ( P < .001), no comorbidities ( P < .001), and transfer-in ( P = .019). The XGBoost algorithm determined that GCS and systolic blood pressure contribute most strongly. The prediction accuracy of these XGBoost results based on the test/train split was 90.3%., Discussion: When compared to P -values, XGBoost provides more robust, detailed results regarding the factors that suggest a need for surgery. This demonstrates the clinical applicability of machine learning algorithms. Paramedics can use resulting decision trees to inform medical decision-making in real time. XGBoost's generalizability power increases with more data and can be tuned to prospectively assist individual hospitals., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A taste-masked chewable tablet of ciprofloxacin using ion exchange resin Kyron T-134 for enhancing compliance for the paediatric population was developed. The drug-to-resin ratio was optimized for maximum taste masking by studying the effects of soaking time (X1) and mixing time (X2) on complexation (%) using Central Composite Rotatable Design (CCRD). The resin complexes were characterized by bitterness score, DSC, FTIR, and PXRD. The complex was further formulated and optimized into chewable tablets through full factorial design, The optimized formulation was subjected to a bioequivalence study, and a virtual approach of PBPK modelling was adapted to predict the pharmacokinetics of the drug in the paediatric group. The drug resin ratio of 1:1.5 yielded an optimum drug loading of 99.05%. The optimized formulation shows minimum disintegration time with more than 99% drug release within 30 min. The formulation F-9 was found to be bioequivalent with a geometric mean ratio of C max , T max , AUC 0-t , and AUC 0-∞ within 90% CI. It was concluded that quality by design approach can successfully be applied to optimize the drug resin ratio and PBPK modeling is a successful predictive tool for estimating the pharmacokinetics of ciprofloxacin HCl in the paediatric population., (© 2023. Springer Nature Limited.)

Background: Per- and polyfluoroalkyl substances (PFAS) may disrupt mammary gland development and function; thereby inhibiting milk supply and breastfeeding duration. However, conclusions on the potential effects of PFAS and breastfeeding duration are limited by prior epidemiologic studies that inconsistently adjusted for past cumulative breastfeeding duration and by a lack of examination of the joint effects of PFAS mixtures., Methods: In Project Viva, a longitudinal cohort that enrolled pregnant participants from 1999 to 2002 in the greater Boston, MA area, we studied 1079 women who ever attempted to lactate. We investigated associations of plasma concentrations of select PFAS in early pregnancy (mean: 10.1 weeks gestation) with breastfeeding termination by 9 months, after which women typically cite self-weaning as the reason for terminating breastfeeding. We used Cox regression for single-PFAS models and quantile g-computation for mixture models, adjusting for sociodemographics, prior breastfeeding duration, and weeks of gestation at the time of blood draw., Results: We detected 6 PFAS [perfluorooctane sulfonate; perfluorooctanoate (PFOA); perfluorohexane sulfonate; perfluorononanoate; 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA); 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA)] in >98 % of samples. Sixty percent of lactating women terminated breastfeeding by 9 months postpartum. Women with higher plasma concentrations of PFOA, EtFOSAA, and MeFOSAA had a greater hazard of terminating breastfeeding in the first 9 months postpartum [HR (95 % CI) per doubling concentration: 1.20 (1.04, 1.38) for PFOA; 1.10 (1.01, 1.20) for EtFOSAA; 1.18 (1.08, 1.30) for MeFOSAA]. In the quantile g-computation model, simultaneously increasing all PFAS in the mixture by one quartile was associated with 1.17 (95 % CI: 1.05, 1.31) greater hazard of terminating breastfeeding in the first 9 months., Conclusion: Our findings suggest that exposure to PFAS may be associated with reduced breastfeeding duration and draw further attention to environmental chemicals that may dysregulate human lactation., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Integration of a sensitive point-of-care (POC) HIV viral load (VL) test into screening algorithms may help detect acute HIV infection earlier, identify people with HIV (PWH) who are not virally suppressed, and facilitate earlier referral to antiretroviral therapy (ART), or evaluation for pre-exposure prophylaxis (PrEP). This report describes a randomized clinical trial sponsored by the Centers for Disease Control and Prevention (CDC): "Ending the HIV Epidemic Through Point-of-Care Technologies" (EHPOC). The study's primary aim is to evaluate the use of a POC HIV VL test as part of a testing approach and assess the impact on time to linkage to ART or PrEP. The study will recruit people in Baltimore, Maryland, including patients attending a hospital emergency department, patients attending an infectious disease clinic, and people recruited via community outreach. The secondary aim is to evaluate the performance characteristics of two rapid HIV antibody tests approved by the United States Food and Drug Administration (FDA)., Methods: The study will recruit people 18 years or older who have risk factors for HIV acquisition and are not on PrEP, or PWH who are not taking ART. Participants will be randomly assigned to either the control arm or the intervention arm. Participants randomized to the control arm will only receive the standard-of-care (SOC) HIV screening tests. Intervention arm participants will receive a POC HIV VL test in addition to the SOC HIV diagnostic screening tests. Follow up will consist of an interim phone survey conducted at week-4 and an in-person week-12 visit. Demographic and behavioral information, and oral fluid and blood specimens will be collected at enrollment and at week-12. Survey data will be captured in a Research Electronic Data Capture (REDCap) database. Participants in both arms will be referred for either ART or PrEP based on their HIV test results., Discussion: The EHPOC trial will explore a novel HIV diagnostic technology that can be performed at the POC and provide viral assessment. The study may help inform HIV testing algorithms and contribute to the evidence to support same day ART and PrEP recommendations., Trial Registration: NIH ClinicalTrials.gov NCT04793750. Date: 11 March 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Recognition of aberrant gene isoforms due to DNA events can impact risk stratification and molecular classification of hematolymphoid tumors. In myelodysplastic syndromes, KMT2A partial tandem duplication (PTD) was one of the top adverse predictors in the International Prognostic Scoring System-Molecular study. In B-cell acute lymphoblastic leukemia (B-ALL), ERG isoforms have been proposed as markers of favorable-risk DUX4 rearrangements, whereas deletion-mediated IKZF1 isoforms are associated with adverse prognosis and have been extended to the high-risk IKZF1 plus signature defined by codeletions, including PAX5. In this limited study, outlier expression of isoforms as markers of IKZF1 intragenic or 3' deletions, DUX4 rearrangements, or PAX5 intragenic deletions were 92.3% (48/52), 90% (9/10), or 100% (9/9) sensitive, respectively, and 98.7% (368/373), 100% (35/35), or 97.1% (102/105) specific, respectively, by targeted RNA sequencing, and 84.0% (21/25), 85.7% (6/7), or 81.8% (9/11) sensitive, respectively, and 98.2% (109/111), 98.4% (127/129), or 98.7% (78/79) specific, respectively, by total RNA sequencing. Comprehensive split-read analysis identified expressed DNA breakpoints, cryptic splice sites associated with IKZF1 3' deletions, PTD of IKZF1 exon 5 spanning N159Y in B-ALL with mutated IKZF1 N159Y, and truncated KMT2A-PTD isoforms. Outlier isoforms were also effective targeted RNA markers for PAX5 intragenic amplifications (B-ALL), KMT2A-PTD (myeloid malignant cancers), and rare NOTCH1 intragenic deletions (T-cell acute lymphoblastic leukemia). These findings support the use of outlier isoform analysis as a robust strategy for detecting clinically significant DNA events., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Carcinogenic colorectal hemorrhage can cause severe blood loss and longitudinal ulcer, which ultimately become fatal if left untreated. The present study was aimed to formulate targeted release gemcitabine (GC)-containing magnetic microspheres (MM) of halloysite nanotubes (MHMG), chitosan (MCMG), and their combination (MHCMG). The preparation of MM by magnetism was confirmed by vibrating sample magnetometry (VSM), the molecular arrangement of NH 2 , alumina, and silica groups was studied by X-ray diffraction (XRD) and energy-dispersive spectroscopy (EDS), the hollow spherical nature of the proposed MM was observed by scanning electron microscopy (SEM), functional groups were characterized by Fourier transform infrared (FTIR) spectroscopy and thermochemical modification was studied by thermogravimetric analysis (TGA). In vitro thrombus formation showed a decreasing trend of hemostatic time for MMs in the order of MHMG3 < MCMG3 < MHCMG7, which was confirmed by whole blood clotting kinetics. Interestingly, rat tail amputation and liver laceration showed 3 folds increased clotting efficiency of optimized MHCMG7 compared to that of control. In vivo histopathological studies and cell viability assays confirmed the regeneration of epithelial cells. The negligible systemic toxicity of MHCMG7, more than 90% entrapment of GC and high % release in alkaline medium made the proposed MM an excellent candidate for the control of hemorrhage in colorectal cancer. Conclusively, the healing of muscularis and improved recovery of the colon from granulomas ultimately improved the therapeutic effects of GC-containing MMs. The combination of both HNT and CTS microspheres made them more targeted., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (This journal is © The Royal Society of Chemistry.)

Clerkship grading is a core feature of evaluation for medical students' skills as physicians and is considered by most residency program directors to be an indicator of future performance and success. With the transition of the U.S. Medical Licensing Examination Step 1 score to pass/fail, there will likely be even greater reliance on clerkship grades, which raises several important issues that need to be urgently addressed. This article details the current landscape of clerkship grading and the systemic discrepancies in assessment and allocation of honors. The authors examine not only objectivity and fairness in clerkship grading but also the reliability of clerkship grading in predicting residency performance and the potential benefits and drawbacks to adoption of a pass/fail clinical clerkship grading system. In the promotion of a more fair and equitable residency selection process, there must be standardization of grading systems with consideration of explicit grading criteria, grading committees, and/or structured education of evaluators and assessors regarding implicit bias. In addition, greater adherence and enforcement of transparency in grade distributions in the Medical Student Performance Evaluation is needed. These changes have the potential to level the playing field, foster equitable comparisons, and ultimately add more fairness to the residency selection process., (Copyright © 2023 by the Association of American Medical Colleges.)

Introduction With the advancing age of the population, there are an increasing number of patients with geriatric hip fractures. Despite the advancement of surgical knowledge and improvement of implant designs to treat geriatric hip fractures, mortality and morbidity remain high among these frail patients. In conjunction with the COVID-19 pandemic, the collateral damage dealt to these patients remains unknown as scarce resources are funneled to deal with the pandemic. This study is geared to investigate the surgical outcomes of patients with geriatric hip fractures who were admitted during the initial phase of the COVID-19 pandemic. Methods This retrospective study was carried out at Hospital Kuala Lumpur, the largest public hospital in the capital of Malaysia, from March 1, 2020, to March 1, 2021. All patients of age 60 years and above were screened for suitability. Only patients who had undergone surgical intervention during the study period were included in this study. Patients' demographic data, mechanism of injury, waiting time for surgery, type of surgery, complications and ambulatory status were obtained from the medical records. Univariate analysis was performed to determine the factors associated with complications as well as the post-operative ambulatory status of the patients. Results A total of 52 patients were included in this study, with a median age of 72 years. The majority of the patients were Chinese (n=21, 40.4%). This was followed by Malay and Indian (n=14, 26.9% each) and other ethnicity (n=3, 5.8%). More than three-quarters of the patients had a trivial injury such as a fall due to a miss-step (n=16, 30.8%) and slip (n=16, 30.8%) and a fall due to dizziness (n=8, 15.4%). Only 12 patients (23.1%) sustained hip fractures due to trauma. The median time to surgery for these patients was 5 days (interquartile range: 4 days). Most of these patients underwent total hip replacement (n=30, 57.7%). This was followed by unipolar hemiarthroplasty (n=11, 21.2%), bipolar hemiarthroplasty (n=10, 19.2%) and internal fixation (n=1, 1.9%). Among these patients, six of them had documented complications. There were periprosthetic joint infection (n=2, 3.8%), dislocation (n=2, 3.8%), hematoma formation (n=1, 1.9%) and seroma (n=1, 1.9%). Six months after the surgery, most of the patients were able to ambulate, albeit some patients required walking aid such as walking stick and walking frame. Univariate analysis showed that all the factors were not associated with the complications and the post-operative ambulatory status of the patients. Conclusion  The incidence of geriatric hip fractures remains high during the COVID-19 pandemic despite the movement control order (MCO) being enforced in Malaysia. With prompt surgical intervention, most of the patients can regain ambulatory status, albeit with a walking aid., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Anwarali Khan et al.)

We predicted that the relationship between helping strangers and life satisfaction would depend partially on the wealth of the country in which one lives. We argue that wealthy societies provide a wide range of welfare provisions for assisting their citizens. By contrast, people living in poorer countries with associated lower individualism, lower generalised trust, and higher religiosity have fewer financial and institutional supports for their daily welfare. They thus receive greater personal and interpersonal rewards for helping strangers in their societies and experience greater life satisfaction. Using a 137-country sample, we found that the relationship between helping strangers and life satisfaction was weaker in wealthier nations and in nations with more individualistic, more trusting, but less religious citizens. When all four moderators were used, only trust and religiosity remained significant moderators. In a supplementary mediated moderation model, we also found that trust and religiosity mediated the effect of national wealth on the relationship between kindness and life satisfaction. We conclude that the relationship between kindness and life satisfaction depends on various aspects of national culture that may reduce or increase people's dependence in their daily lives on the help of others as opposed to dependence on welfare institutions., (© 2022 International Union of Psychological Science.)

Background: With the recent changes to the U.S. Medical Licensing Examination grading system, an understanding of the factors that influence the neurological surgery residency match process is crucial for residency directors. The aim of the present retrospective study was to explore the associations of medical school location, ranking, private school status, size, and presence of an American Association of Neurological Surgeons (AANS) chapter or neurological surgery interest group (NSIG) with the neurosurgery match outcomes., Methods: An enrollment list of all accredited U.S. neurosurgery residency programs was compiled on June 28, 2021. For the included residents, the residency program, degree, and previously attended medical school were retrieved. The geographic location, ranking, private school status, and size were collected for the residency programs and medical schools attended by the residents at each program., Results: A total of 1437 residents from 101 neurosurgery residency programs (89%) were included. Graduates from the top 25 medical schools were more likely to match into their home residency programs (P < 0.001) and highly ranked residency programs (P < 0.001). Students from larger medical schools were also more likely to match into larger (P < 0.001) and highly ranked (P < 0.001) programs than were applicants from smaller schools. Students from medical schools with an AANS chapter or NSIG were also more likely to match into top ranked programs (P < 0.001 for both)., Conclusions: Medical students from the top 25 medical schools, private medical schools, medical schools with an AANS chapter, and medical schools with an NSIG were more likely to match into a prestigious residency program. These findings suggest that underlying biases might be present for program directors to consider in the resident selection process., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This paper provides a unique perspective for understanding cultural differences: representation similarity-a computational technique that uses pairwise comparisons of units to reveal their representation in higher-order space. By combining individual-level measures of trust across domains and well-being from 13,823 participants across 15 nations with a measure of society-level tightness-looseness, we found that any two countries with more similar tightness-looseness tendencies exhibit higher degrees of representation similarity in national interpersonal trust profiles. Although each individual's trust profile is generally similar to their nation's trust profile, the greater similarity between an individual's and their society's trust profile predicted a higher level of individual life satisfaction only in loose cultures but not in tight cultures. Using the framework of representation similarity to explore cross-cultural differences from a multidimensional, multi-national perspective provide a comprehensive picture of how culture is related to the human activities., (© 2022 British Psychological Society.)

Introduction: A SeDeM expert tool-driven I-optimal mixture design has been used to develop a directly compressible multiparticulate based extended release minitablets for gastro-retentive drug delivery systems using loxoprofen sodium as a model drug. Methods: Powder blends were subjected to stress drug-excipient compatibility studies using FTIR, thermogravimetric analysis, and DSC. SeDeM diagram expert tool was utilized to assess the suitability of the drug and excipients for direct compression. The formulations were designed using an I-optimal mixture design with proportions of methocel K100M, ethocel 10P and NaHCO 3 as variables. Powder was compressed into minitablets and encapsulated. After physicochemical evaluation lag-time, floating time, and drug release were studied. Heckel analysis for yield pressure and accelerated stability studies were performed as per ICH guidelines. The in silico PBPK Advanced Compartmental and Transit model of GastroPlus™ was used for predicting in vivo pharmacokinetic parameters. Results: Drug release follows first-order kinetics with fickian diffusion as the main mechanism for most of the formulations; however, a few formulations followed anomalous transport as the mechanism of drug release. The in-silico -based pharmacokinetic revealed relative bioavailability of 97.0%. Discussion: SeDeM expert system effectively used in QbD based development of encapsulated multiparticulates for once daily administration of loxoprofen sodium having predictable in-vivo bioavailability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rauf-ur-Rehman, Shoaib, Ahmed, Yousuf, Siddiqui, Saleem, Qazi, Khan, Irshad, Bashir, Naz, Farooq and Mahmood.)

Rats ( Rattus species) are the most notorious vertebrate pests in Malaysian oil palm plantations. Although many studies have been conducted on Asian rats, little attention has been paid to their species composition and phylogenetic relationships in oil palm plantations in Peninsular Malaysia. We determined the mitochondrial cytochrome oxidase subunit I (COI) gene sequence (708 bp) for 216 individual rats collected from five oil palm plantations in Peninsular Malaysia. Phylogenetic analysis in conjunction with comparison with sequences from the nucleotide sequence database revealed five distinct lineages in the Malaysian oil plantations: Rattus tiomanicus , Rattus argentiventer , Rattus exulans , Rattus tanezumi , and a taxon corresponding to the Malayan house rat, which was most frequently observed (∼50%). The last taxon has traditionally been classified as a synonym of Rattus rattus ( Rattus rattus diardii ) or Rattus tanezumi , but our phylogenetic analysis placed it as an independent lineage, which is not particularly closely related to R. rattus or R. tanezumi , and which we refer to as Rattus diardii . The construction of the network showed that there is considerable genetic variation within the lineages of R. diardii and R tiomanicus , suggesting that these two species are native to the Malay Peninsula.

Schools are considered sensitive areas to noise pollution. The objective of this study is to ascertain the sound level in schools with respect to different sampling time sessions and sampling points. Five sampling points, consisting of two classrooms (Classroom A and Classroom B), a canteen, a staffroom and a field, were chosen to obtain an overview of the noise level within the whole school in three different time sessions (morning, afternoon and evening), as well as 8-h continuous sampling in both classrooms and the staffroom. The average noise level (L Aeq,10min ) obtained in this school was found to be in the range of 48.8 dBA to 83.7 dBA, where most of the values exceeded the permissible maximum sound pressure level set by the Malaysian Department of Environment (DOE). Classroom B recorded the highest average noise level (L Aeq,8h ) of 77.9 dBA, which exceeded the maximum value set by the Department of Environment.

The study is based on using SeDeM expert system in developing controlled-release tramadol HCl osmotic tablets and its in-silico physiologically based pharmacokinetic (PBPK) modeling for in-vivo pharmacokinetic evaluation. A Quality by Design (QbD) based approach in developing SeDEM-driven full factorial osmotic drug delivery was applied. A 2 4 Full-factorial design was used to make the trial formulations of tramadol HCl osmotic tablets using NaCl as osmogen, Methocel K4M as rate controlling polymer, and avicel pH 101 as diluent. The preformulation characteristics of formulations (F1-F16) were determined by applying SeDeM Expert Tool. The formulation was optimized followed by in-vivo predictive pharmacokinetic assessment using PBPK "ACAT" model of GastroPlus™. The FTIR results showed no interaction among the ingredients. The index of good compressibility (ICG) values of all trial formulation blends were ≥5, suggesting direct compression is the best-suited method. Formulation F3 and F4 were optimized based on drug release at 2, 10, and 16 h with a zero-order kinetic release ( r 2 = 0.992 and 0.994). The SEM images confirmed micropores formation on the surface of the osmotic tablet after complete drug release. F3 and F4 were also stable (shelf life 29.41 and 23.46 months). The in vivo simulation of the pharmacokinetics of the PBPK in-silico model revealed excellent relative bioavailability of F3 and F4 with reference to tramadol HCl 50 mg IR formulations. The SeDeM expert tool was best utilized to evaluate the compression characteristics of selected formulation excipients and their blends for direct compression method in designing once-daily osmotically controlled-release tramadol HCl tablets. The in-silico GastroPlus™ PBPK modeling provided a thorough pharmacokinetic assessment of the optimized formulation as an alternative to tramadol HCl in vivo studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saleem, Shoaib, Yousuf, Ahmed, Ahmed, Siddiqui, Mahmood, Sikandar and Imtiaz.)

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has stressed the global health system to a significant level, which has not only resulted in high morbidity and mortality but also poses a threat for future pandemics. This situation warrants efforts to develop novel therapeutics to manage SARS-CoV-2 in specific and other emerging viruses in general. This study focuses on SARS-CoV2 RNA-dependent RNA polymerase (RdRp) mutations collected from Saudi Arabia and their impact on protein structure and function. The Saudi SARS-CoV-2 RdRp sequences were compared with the reference Wuhan, China RdRp using a variety of computational and biophysics-based approaches. The results revealed that three mutations-A97V, P323I and Y606C-may affect protein stability, and hence the relationship of protein structure to function. The apo wild RdRp is more dynamically stable with compact secondary structure elements compared to the mutants. Further, the wild type showed stable conformational dynamics and interaction network to remdesivir. The net binding energy of wild-type RdRp with remdesivir is -50.76 kcal/mol, which is more stable than the mutants. The findings of the current study might deliver useful information regarding therapeutic development against the mutant RdRp, which may further furnish our understanding of SARS-CoV-2 biology.

Air pollution exposure disparities by race/ethnicity and socioeconomic status have been analyzed using data aggregated at various spatial scales. Our research question is this: To what extent does the spatial scale of data aggregation impact the estimated exposure disparities? We compared disparities calculated using data spatially aggregated at five administrative scales (state, county, census tract, census block group, census block) in the contiguous United States in 2010. Specifically, for each of the five spatial scales, we calculated national and intraurban disparities in exposure to fine particles (PM 2.5 ) and nitrogen dioxide (NO 2 ) by race/ethnicity and socioeconomic characteristics using census demographic data and an empirical statistical air pollution model aggregated at that scale. We found, for both pollutants, that national disparity estimates based on state and county scale data often substantially underestimated those estimated using tract and finer scales; in contrast, national disparity estimates were generally consistent using tract, block group, and block scale data. Similarly, intraurban disparity estimates based on tract and finer scale data were generally well correlated for both pollutants across urban areas, although in some cases intraurban disparity estimates were substantially different, with tract scale data more frequently leading to underestimates of disparities compared to finer scale analyses., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Purpose: Halloysite nanotubes (HNTs) are a versatile and highly investigated clay mineral due to their natural availability, low cost, strong mechanical strength, biocompatibility, and binding properties. The present work explores its role for retarding and controlling the drug release from the composite polymer matrix material., Methods: For this purpose, nanocomposite films comprising propranolol HCl and different concentrations of HNTs were formulated using the "solution casting method". The menthol in a concentration of 1% w/v was used as a permeation enhancer, and its effect on release and permeation was also determined. Quality characteristics of the nanocomposite were determined, and in vitro release and permeation studies were performed using the Franz diffusion system. The data was analyzed using various mathematical models and permeation parameters. Optimized formulation was also subjected to skin irritation test, FTIR, DSC, and SEM study. Systemic absorption and disposition of propranolol HCl from the nanocomposites were predicted using the GastroPlus TCAT® model., Results: The control in drug release rate was associated with the higher concentration of HNTs. F8 released 50% of propranolol within 8 hours (drug, HNTs ratio, 1:2). The optimized formulation (F6) with drug: HNTs (2:1), exhibited drug release 80% in 4 hours, with maximum flux of 145.812 µg/cm 2 hr. The optimized formulation was found to be a non-irritant for skin with a shelf life of 35.46 months (28-30 ℃). The in silico model predicted C max , T max , AUC t , and AUC inf as 32.113 ng/mL, 16.58 h, 942.34 ng/mL×h, and 1102.9 ng/mL×h, respectively., Conclusion: The study demonstrated that HNTs could be effectively used as rate controlling agent in matrix type transdermal formulations., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Sikandar et al.)

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background/objectives: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial., Methods: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival., Results: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008)., Conclusion: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase., (© 2022 Wiley Periodicals LLC.)

Background: Obesity rates have been rising steeply across the globe in recent decades, posing a major threat to global human health. Despite this almost universal increase, differences between countries remain striking, even among equally developed societies., Methods: We test if two cultural dimensions derived from a revised Hofstede model of culture from Minkov (2018), namely collectivism vs. individualism and monumentalism vs. flexibility, could help explain national variations in prevalence of obesity (BMI ≥ 30) among women and men around the world. We develop a theoretical framework that links these two cultural dimensions with obesity and then test their association empirically in analyses including 51 countries from all regions of the world as well as using imputed data for a total of 155 countries, representing 98% of the global population., Results: In contrast to previous studies, we find that, adjusting for undernourishment and other potential confounds, individualism is associated with higher obesity prevalence in the male population, but not among the female population. We explain these findings by pointing to the different mechanisms through which individualism relates to health behavior, some of which are more gender-specific than others. A further novel finding is that flexibility, a national cultural trait that emphases humility, self-control, and restraint of desires, is a strong negative predictor of obesity in both genders beyond various potential confounds and is highly robust in specification curve analyses., Conclusions: Our findings suggest that taking national culture into account can enhance our understanding of the obesity pandemic and should thus be considered by policy-makers in their design of interventions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

KMT2A partial tandem duplication (KMT2A-PTD) is an adverse risk factor in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a potential therapeutic target, and an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. Although KMT2A-PTD has been reported to affect only a single allele, it has been theorized but not proven that genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including copy-neutral loss of heterozygosity and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML vs MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Clotting time of lower gastro intestinal bleeding (LGIB) can be reduced by using simple, cost-effective, and naturally occurring halloysite nanotubes (HNTs). The present study aimed to decrease the clotting time by the application of chitosan (CHT) and its microcomposites (MCs) prepared by suspension emulsification technique with HNTs (CHT/HNTs MC). Physicochemical properties, X-Ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and percentage release of ciprofloxacin from CHT/HNTs MCs was evaluated. In-vitro procoagulant activity of CHT, HNTs and their complexes CHT/HNTs MCs was performed on rabbit blood which was confirmed by a rat tail amputation. Direct relation of HNTs was observed for the whole-blood clotting kinetics i.e., 2% HNTs showed a maximum 66.0% increase in the clotting ability as compared with pure CHT. Interestingly, rat-tail amputation studies showed comparative results of CHT, HNTs, and CHT/HNTs MCs. A total of 75% permeation of ciprofloxacin of CHT/HNTs MCs on rat intestinal membrane was observed within 3 h, confirming their SR behavior. Furthermore, improved hemostatic and clotting properties were CHT/HNTs MC 1  > CHT/HNTs MC 2  > CHT/HNTs MC 3  > CHT > HNTs, respectively. Thus, it provided the control of bleeding disorders in LGIB with any antibacterial agents, particularly ciprofloxacin., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study was conducted to determine the various socio-demographic, economic, and clinical variables (SDECVs) which influence the health-related quality of life (HRQoL) of hypertensive patients. Three hundred and fifty hypertensive patients participated in this study through a structured questionnaire and EQ 5D 5L. 211(60.28%) participants had stage 1, and 139 (39.7%) had stage 2 hypertension. No participants reported severe problems in any domain on EQ 5D 5L. Generalize Linear Model (GLM) was used to assess the association between HRQoL and SDECVs. The mean utility and VAS score was 0.64 (±0.15) and 63.17 (±11.01) respectively. The participants of the stage 1 hypertension group had a significantly better score on each domain of EQ 5D 5L as compared to stage 1 (0.027, 0.010, 0.00, 0.00, 0.048). No participant in either group reported extreme problems in any domain. Among socio-demographic factors, the males, non-smokers, income sharing, and healthy normal hypertensive patients had better HRQoL (0.009, 0.016, 0.019, and 0.003). A lower cost of treatment was also associated with better HRQoL (0.017). Among clinical variables, stage 1 hypertension had better HRQoL than stage 2(0.035). The number of prescribed antihypertensive drugs had no effect on the quality of life (0.253), however, the non-pharmacologic interventions such as reduction in salt and oil consumption (0.035), reduction in beverages consumption (0.0014) and increased water intake (0.010) had resulted in better QoL. The patients who reported dizziness had poor HRQoL while patients who had cardiac problems and diabetes reported a significantly lower EQ-VAS score. The effect of gender on the HRQoL of hypertensive patients who had comorbid conditions was significant in the case of renal, respiratory, visual problems, and dizziness where females had a lesser utility score than males. The study reports on significant determinants which should be taken into account in an attempt to improve the health-related quality of life of hypertensive patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents., Methods: We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals., Results: Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15-22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3-4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months., Conclusion: Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3-4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen., Prospero Number: CRD42022309230., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saint-Lary, Dassi Tchoupa Revegue, Jesson, Renaud, Penazzato, Townsend, O'Rourke, Leroy and WHO HIV Hepatitis and STIs (HHS) Department.)

A man in his 30s with a history of cocaine and intranasal heroin use presented to the emergency department with severe leg pain and weakness. Physical examination findings were significant for tachycardia, absence of dorsalis pedis pulses, tense and painful calf muscles along with absence of plantar reflexes in bilateral lower extremities. Laboratory investigations were significant for positive urinary drug screen for cocaine, severe rhabdomyolysis and acute kidney injury. Given the absence of dorsalis pedis pulses in bilateral lower extremities and radiological evidence of oedematous changes in calf muscles with perimuscular oedema, a diagnosis of compartment syndrome was made. He was treated with bilateral lower extremity four-compartment fasciotomies and haemodialysis for acute kidney injury. Rhabdomyolysis has been attributed to cocaine use; however, compartment syndrome is a very rare complication, especially in the absence of trauma or prolonged immobilisation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)