Search

Background Studies focused on C‐reactive protein (CRP) as a marker of difficult laparoscopic cholecystectomy are limited to small case series. The aim of this study was to evaluate the association between preoperative CRP concentration and difficulty of laparoscopic cholecystectomy in patients admitted with a biliary emergency presentation. Methods Patients with an emergency admission for biliary disease treated between 2012 and 2017 with a documented preoperative CRP level were analysed. Elective patients and those with other concurrent causes of increased CRP concentration were excluded. The intraoperative difficulty grade was based on the Nassar scale. Statistical analysis was conducted to determine the association of preoperative CRP level with difficulty grading, adjusted for the interval to surgery. Results A total of 804 emergency patients were included. The mean preoperative peak CRP level was 64·7 mg/l for operative difficulty grade I, 69·6 mg/l for grade II, 98·2 mg/l for grade III, 217·5 mg/l for grade IV and 193·1 mg/l for grade V, indicating a significant association between CRP concentration and Nassar grade (P

In this study, we report on longitudinal kinetics of cellular immune subsets following SARS-CoV-2 infection in a cohort of hospitalized individuals and evaluate the interplay of these profiles with infecting viral variants, humoral immunity including neutralizing responses, vaccination history, and clinical outcomes. A cohort of 121 SARS-CoV-2-infected individuals exhibiting varying disease states were prospectively evaluated for lymphopenic profiles, antiviral humoral responses and infecting viral variants for a period of up to 90 d spanning the period of February 2021 to January 2022 (second and third waves of infection). A total of 51 participants received at least 1 vaccine dose of indigenous vaccines (Covishield or Covaxin) prior to recruitment. When stratified in terms of mortality, B and natural killer cells, in contrast to the T cell compartment, did not recover from nadir levels in nonsurvivors who were largely unvaccinated. No discriminatory signature was identified for nonsurvivors in terms of anti-nucleocapsid or anti-S1-RBD IgG chemiluminescent immunoassay profiles including GenScript S1-RBD assays. Evaluation of sVCAM and sMAdCAM revealed opposing dynamics that correlated with disease severity and convalescence respectively. Viral variant analysis revealed Delta and Omicron variants to comprise the majority of the infections, which reflected national transmission kinetics during the period of recruitment. Our results demonstrate the importance of monitoring circulating biomarkers for convalescence as well as mortality in COVID-19 progression. Delta variants of SARS-CoV-2 clearly demonstrated increased pathogenicity and warrants sustained viral surveillance for re-emergence of these strains. Our findings with respect to vaccination advocate for continued vaccine development and administration of COVID-19 vaccines., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: While there is evidence that COVID-19 vaccination protects against development of post-COVID conditions (PCC) after severe infection data are limited on whether vaccination reduces the risk after cases of less-severe non-hospitalized COVID-19 disease with more recent SARS-CoV-2 variant viruses. This study assessed whether COVID-19 vaccination was protective against subsequent development of PCC in persons with predominantly mild initial infections during both Delta and Omicron variant predominance., Methods: This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with PCR-confirmed SARS-CoV-2 infection between 6/28/2021 and 9/14/2022 were surveyed for PCC, defined by symptoms lasting >1 month after initial infection Cases were participants self-reporting PCC and controls were participants that did not self-report PCC. The exposure was mRNA COVID-19 vaccination (2 or 3 monovalent doses) versus no COVID-19 vaccination. Logistic regression was used to compare the odds of PCC among vaccinated and unvaccinated persons; additional analyses evaluating PCC subtypes were also performed., Results: A total of 936 participants with documented SARS-CoV-2 infection were included; of these 23.6% (221) reported PCC and 83.3% (779) were vaccinated. Participants who received a 3rd COVID-19 monovalent mRNA dose prior to infection had lower odds of PCC-related gastrointestinal, neurological, and other symptoms compared to unvaccinated participants (aOR: 0.37; 95% CI: 0.16-0.85; aOR: 0.56; 95% CI: 0.32-0.97; aOR:0.48; 95% CI: 0.25-0.91)., Conclusions: COVID-19 vaccination protected against development of PCC among persons with mild infection during both Delta and Omicron variant predominance, supporting vaccination as an important tool for PCC prevention., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: The objective of the current study was to estimate the prevalence and associated factors of overweight/obesity among Bangladeshi adolescents aged 15-19 y and to identify whether wealth-related inequality exists for overweight/obesity among Bangladeshi older adolescents., Methods: We analyzed publicly available national representative secondary data from the 2019-2020 Bangladesh Adolescent Health and Wellbeing Survey. This cross-sectional survey was carried out among 18 249 adolescents aged 15-19 y regardless of their marital status using a two-stage stratified sampling technique (the data of 9128 eligible adolescents were included in this analysis). The WHO reference population for body mass index-for-age (1+Z score) was considered as overweight/obesity., Results: We found that girls had significantly (p<0.05) higher prevalence of overweight/obesity (11.63%) than boys (8.25%); however, their biological sex as well their age were not significantly associated with higher odds of overweight/obesity. Those who were in their higher grade (grade 11 and higher) in the school and had been exposed to media were more likely (1.67 and 1.39 times, respectively) to be overweight/obesity compared with primary grade (0-5) and those who experienced no media exposure, respectively. Inequality analysis revealed that adolescents belonging to wealthy households had significantly higher rates of overweight/obesity than those in poorer households (concentration index=0.093)., Conclusions: The study exhibited the multifaceted nature of overweight/obesity among Bangladeshi older teenagers, revealing that their school grade, exposure to media content and wealth-related inequality emerged as significant contributing factors. The findings underscore the urgent need for targeted interventions and public health strategies to address the escalating burden of overweight and obesity in this age group., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Motivation: O-linked glycosylation, an essential post-translational modification process in Homo sapiens, involves attaching sugar moieties to the oxygen atoms of serine and/or threonine residues. It influences various biological and cellular functions. While threonine or serine residues within protein sequences are potential sites for O-linked glycosylation, not all serine and/or threonine residues undergo this modification, underscoring the importance of characterizing its occurrence. This study presents a novel approach for predicting intracellular and extracellular O-linked glycosylation events on proteins, which are crucial for comprehending cellular processes. Two base multi-layer perceptron models were trained by leveraging a stacked generalization framework. These base models respectively use ProtT5 and Ankh O-linked glycosylation site-specific embeddings whose combined predictions are used to train the meta-multi-layer perceptron model. Trained on extensive O-linked glycosylation datasets, the stacked-generalization model demonstrated high predictive performance on independent test datasets. Furthermore, the study emphasizes the distinction between nucleocytoplasmic and extracellular O-linked glycosylation, offering insights into their functional implications that were overlooked in previous studies. By integrating the protein language model's embedding with stacked generalization techniques, this approach enhances predictive accuracy of O-linked glycosylation events and illuminates the intricate roles of O-linked glycosylation in proteomics, potentially accelerating the discovery of novel glycosylation sites., Results: Stack-OglyPred-PLM produces Sensitivity, Specificity, Matthews Correlation Coefficient, and Accuracy of 90.50%, 89.60%, 0.464, and 89.70%, respectively on a benchmark NetOGlyc-4.0 independent test dataset. These results demonstrate that Stack-OglyPred-PLM is a robust computational tool to predict O-linked glycosylation sites in proteins., Availability and Implementation: The developed tool, programs, training, and test dataset are available at https://github.com/PakhrinLab/Stack-OglyPred-PLM., (© The Author(s) 2024. Published by Oxford University Press.)

Competing Interests: The authors report no competing interests.

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by diaphyseal dysplasia of long bones, bone marrow fibrosis, and steroid-responsive anemia. Patients with this disease have a mutation in the thromboxane-AS1 (TBXAS1) gene located on chromosome 7q33.34. They present with short stature, varying grades of myelofibrosis, and, hence cytopenias. Patients with the above presentation were evaluated through clinical presentation, X-ray of long bones, bone marrow examinations, and confirmed by genetic testing. In this article, we present two cases: The first case is a 3-year-old boy who presented with progressive pallor and ecchymotic patches for a year. On investigation, he had bicytopenia and bone marrow fibrosis. His anemia was steroid responsive and was finally diagnosed as GHDD. The second case is a 20-month-old girl who presented with blood in stools, developmental delay, anemia, and increased intensity of long bones on X-ray. Since other investigations were normal, suspicion of GHDD was raised, and a genetic workup was conducted which suggested mutation in TBXAS1 gene, confirming the diagnosis of GHDD. Children with refractory anemia and cortical thickening on skeletogram should always be evaluated for dysplasias. Timely treatment with steroids reduces transfusion requirements and halts bone damage, thus leading to better growth and improved quality of life., (© The Author(s) [2024]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This article presents an overview of Aga Khan University's (AKU) pioneering medical education initiatives over the past 40 years, exploring its impact on healthcare in the region and its commitment to advancing medical education and research in the developing world. Established in 1983 as the first private university in Pakistan, AKU has evolved into a global institution with a focus on improving healthcare standards and addressing healthcare needs in the developing world. The article also discusses the undergraduate and postgraduate medical education programs at AKU Medical College, Pakistan, highlighting their unique features and pioneering approaches to medical education. The institution's journey highlights its ability to adapt to the evolving healthcare landscape while maintaining a focus on quality and excellence, offering a model for other institutions striving to meet healthcare needs in low- and middle-income countries., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

To compare 5-year gastroesophageal reflux outcomes following Laparoscopic Vertical Sleeve Gastrectomy (LVSG) and Laparoscopic Roux-en-Y gastric bypass (LRYGB) based on high quality randomized controlled trials (RCTs). We conducted a sub-analysis of our systematic review and meta-analysis of RCTs of primary LVSG and LRYGB procedures in adults for 5-year post-operative complications (PROSPERO CRD42018112054). Electronic databases were searched from January 2015 to July 2021 for publications meeting inclusion criteria. The Hartung-Knapp-Sidik-Jonkman random effects model was utilized to estimate weighted mean differences where meta-analysis was possible. Bias and certainty of evidence was assessed using the Cochrane Risk of Bias Tool 2 and GRADE. Four RCTs were included (LVSG n = 266, LRYGB n = 259). An increase in adverse GERD outcomes were observed at 5 years postoperatively in LVSG compared to LRYGB in all outcomes considered: Overall worsened GERD, including the development de novo GERD, occurred more commonly following LVSG compared to LRYGB (OR 5.34, 95% CI 1.67 to 17.05; p = 0.02; I2 = 0%; (Moderate level of certainty); Reoperations to treat severe GERD (OR 7.22, 95% CI 0.82 to 63.63; p = 0.06; I2 = 0%; High level of certainty) and non-surgical management for worsened GERD (OR 3.42, 95% CI 1.16 to 10.05; p = 0.04; I2 = 0%; Low level of certainty) was more common in LVSG patients. LVSG is associated with the development and worsening of GERD symptoms compared to LRYGB at 5 years postoperatively leading to either introduction/increased pharmacological requirement or further surgical treatment. Appropriate patient/surgical selection is critical to minimize these postoperative risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the impact of the COVID-19 pandemic on antimicrobial consumption and trends of therapeutic drugs for COVID-19 treatments, including corticosteroids, remdesivir and monoclonal antibodies (tocilizumab) from April 2017 to September 2022 in a secondary care NHS Trust in England., Methods: A retrospective intervention time series analysis was conducted for April 2017 to September 2022 at the Mid Yorkshire Teaching NHS Trust. Data were retrieved from the pharmacy dispensing system as defined daily doses (DDDs) monthly and reported per 1000 occupied bed days (OBDs). Antimicrobial consumption and COVID-19 treatment options were measured. DDDs were calculated according to the classification of antimicrobials for systemic use (J01) and for other drugs classification. Trends for antimicrobial consumption and other therapeutic drugs for treating COVID-19 were also determined in each wave in England., Results: During the pandemic: total antibiotic consumption decreased from 826.4 to 728.2 DDDs per 1000 OBDs ( P  = 0.0067); piperacillin/tazobactam use increased ( P  < 0.0001) and ciprofloxacin use decreased ( P  < 0.0001); there were no changes in Access, Watch, Reserve antibiotic use, and the proportion of antifungal consumption was consistent throughout the study. The use of total antibiotics ( P  = 0.024), levofloxacin ( P  = 0.0007), piperacillin/tazobactam ( P  = 0.0015) and co-amoxiclav ( P  = 0.0198) increased during wave one. Consumption of COVID-19 treatment drugs was highest during wave two, with 624.3 DDDs per 1000 OBDs for dexamethasone ( P  = 0.4441), 6.8 DDDs per 1000 OBDs for remdesivir ( P  < 0.0001) and 35.01 DDDs per 1000 OBDs for tocilizumab ( P  = 0.2544)., Discussion: This study determined the consumption of antimicrobials trends before and during the pandemic. The individual wave antimicrobial consumption indicates maximum consumption in the first wave, advocating for antimicrobial stewardship and preparedness for future pandemics., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The most prevalent cancer treatments cause cell death through DNA damage. However, DNA damage response (DDR) repair pathways, initiated by tumor cells, can withstand the effects of anticancer drugs, providing justification for combining DDR inhibitors with DNA-damaging anticancer treatments., Methods: Cell viability assays were performed with CellTiter-Glo assay. DNA damage was evaluated using Western blotting analysis. RNA-seq and single-cell level expression were used to identify the DDR signatures. In vivo, studies were conducted in mice to determine the effect of ATris on TMZ sensitization., Results: We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia-telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). Interestingly, most synergistic cell lines had O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, indicating that ATRi mainly benefits tumors with no MGMT repair. Further, TMZ activated the ATR-checkpoint kinase 1 (Chk1) axis in an MGMT-dependent way. TMZ caused ATR-dependent Chk1 phosphorylation and DNA double-strand breaks as shown by increased γH2AX. Increased DNA damage and decreased Chk1 phosphorylation were observed upon the addition of ATRis to TMZ in MGMT-methylated (MGMT-) GSCs. TMZ also improved sensitivity to ATRis in vivo, as shown by increased mouse survival with the TMZ and ATRi combination treatment., Conclusions: This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ., Competing Interests: A.W.K.Y. serves as a consultant with DNATrix. The rest of the authors have no conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Primary cutaneous leiomyosarcoma (LMS) is a rare soft tissue tumour type with two subtypes, dermal and subcutaneous. As deeper tumours confer a worse prognosis, they require a more aggressive approach. Conversely, a more conservative surgical approach for dermal LMS has been suggested. Few studies have comprehensively reported both clinical surgical and histological excision margins. Therefore, we sought to provide margin recommendations based on our experience and review of the existing literature. We undertook a retrospective case-note review (1998-2019) of cutaneous LMS management to establish histological/surgical margins using pathology/electronic patient records. The diagnosis was made and classified by an experienced dermatopathologist according to the World Health Organization classification. In the dermal LMS cohort (n = 35), mean peripheral and deep histological margins were 5.4 mm (range 0.5-20) and 5.6 mm (range 0.1-14.5), respectively. The incomplete excision rate was 31% (11 of 35). There were no recurrences. In the subcutaneous LMS cohort (n = 10), mean peripheral and deep histological margins were 5.7 mm (range 0.2-14) and 1.1 mm (range 0.2-1.7), respectively. The incomplete excision rate was 40% (4 of 10). The recurrence rate was 20% (2 of 10) despite achieving histological clearance after 1 year. One lung metastasis occurred 1 year following an adequately excised primary scalp LMS. Thus, for dermal LMS we propose a clinical margin of 5-10 mm (depending on lesion size) at the initial excision or at scar re-excision following involved/close histological peripheral and/or deep margins (i.e. < 1 mm). For subcutaneous LMS, we suggest a clinical margin of 15-20 mm (depending on lesion size) to achieve a peripheral histological clearance of 10 mm and negative deep margin (i.e. > 1 mm), down to the periosteum/fascia/muscle according to anatomical site. If this is not achieved, a re-excision would be recommended. However, prospective studies are needed for optimal guidance., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Speech and language processing involve complex interactions between cortical areas necessary for articulatory movements and auditory perception and a range of areas through which these are connected and interact. Despite their fundamental importance, the precise mechanisms underlying these processes are not fully elucidated. We measured BOLD signals from normal hearing participants using high-field 7 Tesla fMRI with 1-mm isotropic voxel resolution. The subjects performed 2 speech perception tasks (discrimination and classification) and a speech production task during the scan. By employing univariate and multivariate pattern analyses, we identified the neural signatures associated with speech production and perception. The left precentral, premotor, and inferior frontal cortex regions showed significant activations that correlated with phoneme category variability during perceptual discrimination tasks. In addition, the perceived sound categories could be decoded from signals in a region of interest defined based on activation related to production task. The results support the hypothesis that articulatory motor networks in the left hemisphere, typically associated with speech production, may also play a critical role in the perceptual categorization of syllables. The study provides valuable insights into the intricate neural mechanisms that underlie speech processing., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Staphylococcus is a genus of Gram-positive bacteria, known to cause food poisoning and gastrointestinal illness in humans. Additionally, the emergence of methicillin-resistant S. aureus (MRSA) strains has caused a major health care burden worldwide. Cronobacter is a group of Gram-negative bacteria that can survive in extreme dry conditions. Cronobacter sakazakii is known to contaminate powdered infant formula and cause life-threatening infections in neonates. Vibrio is a genus of human-pathogenic Gram-negative bacteria that can cause foodborne illness by consuming undercooked or raw seafood. Vibrio parahaemolyticus can cause serious gastrointestinal disease in humans. Thus, rapid identification of Staphylococcus spp., Cronobacter spp., and Vibrio spp. is crucial for the source tracking of contaminated food, as well as to measure the transmission dynamics of these bacterial pathogens causing foodborne diseases and outbreaks., Objective: This single-laboratory performance evaluation study used the VITEK MS system to evaluate the potential of MALDI-TOF MS technology for rapid identification of S. aureus-like, C. sakazakii-like, and V. parahaemolyticus-like isolates of public health importance., Method: A total of 226 isolates recovered from various food, environmental surveillance samples, and other sources were identified by bioMérieux VITEK 2 and VITEK MS systems as Staphylococcus spp., Cronobacter spp., and Vibrio spp. Five American Type Culture Collection (ATCC) reference Gram-positive and Gram-negative bacterial isolates were also tested to complete the study. In addition, for some Staphylococcus spp. isolates, whole genome sequencing (WGS) and DNA sequencing of 16S rRNA partial region were also performed for species identification., Results: The VITEK MS system was able to provide species identification to all 96 isolates of Staphylococcus spp. and to all 29 isolates of Vibrio spp. examined with a high confidence value (99.9%). Similarly, species identification was observed for the majority of spots (245 of 303) for the 101 Cronobacter spp. isolates (∼82.0%) with a high confidence value (99.9%), and genus level identification was noticed for the rest of the Cronobacter spp. isolates (18.0%; 58 of the 303 spots) analyzed. Species identification data generated by VITEK 2 system were comparable to data obtained by the VITEK MS system., Conclusions: The VITEK MS system is a reliable high-throughput platform that can rapidly identify Staphylococcus, Vibrio, and Cronobacter to the genus level, as well as S. aureus, C. sakazakii, V. parahaemolyticus, and other closely related foodborne isolates and bacterial isolates from additional sources, in most cases., Highlights: The VITEK MS system can be used in the rapid genus and species identification of human-pathogenic Staphylococcus spp., Cronobacter spp., and Vibrio spp. isolates., (Published by Oxford University Press on behalf of AOAC INTERNATIONAL 2023.)

Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma., Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation., Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (β-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors., Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling., Competing Interests: J.F.D. is consulting/advisory board member for Carthera, Haihe Pharmaceuticals, MundiPharma, Insightec, BioAsis Technologies, Kintara, Kazia, Monteris Medical, Karyopharm, Sumitomo Dainippon Pharma Oncology, Merck, Sapience, VBI Vaccines, Chimerix, Midatech, Aucentra Therapeutics, Servier, Telix, Alpha Pharmaceuticals, Chimerix, and Cure Brain Cancer Foundation. W.K.A.Y. serves as a consultant with DNATrix, Roche, and Denovo. The rest of the authors have no conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objectives: Healthcare institutions implement antimicrobial stewardship (AMS) programmes to optimize the use of antibiotics. The focus is often on inpatient rather than outpatient settings. We aimed to explore perceptions of AMS stakeholders on effective interventions for appropriate antibiotic use in outpatient settings, and the role of clinical pharmacists in the AMS multidisciplinary team., Methods: A qualitative semi-structured interview study using thematic analysis by two researchers independently. Participants that practice AMS programmes were recruited from healthcare facilities in the United Arab Emirates (UAE). Interviews were conducted face to face or online and transcribed verbatim., Results: Four themes emerged: (i) Perceived factors leading to unnecessary or inappropriate antibiotic prescribing and their impact on patients and the community; (ii) current outpatient AMS activities and perceived barriers and facilitators for their sustainability; (iii) suggested outpatient AMS strategies to be implemented in outpatient settings; and (iv) perceived future AMS implementation barriers and suggested mitigation strategies., Conclusions: Several AMS interventions, together with the presence of a clinical pharmacist, may be effective in improving antibiotic use in UAE outpatient settings. Future research should investigate the most appropriate AMS strategy considering barriers and possible mitigation strategies to ensure sustainability., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Introduction: Cervical spine immobilization in a low-resource environment is difficult secondary to limited equipment, prolonged transportation, and secondary complications. A structural aluminum malleable (SAM) splint is commonly utilized because of its availability and multipurpose intention. A one-step spray-on foam immobilization technique (Fast Cast) has been shown to be effective in lower-extremity splinting. The aim of this study was to demonstrate the ability of the Fast Cast to effectively immobilize the cervical spine in a head-to-head comparison against the SAM splint. We hypothesized that there would be no difference in surgeon scoring between Fast Cast and SAM splints for the immobilization of the cervical spine., Methods: This was a cadaveric experimental comparative study that compared a SAM splint versus Fast Cast for the immobilization of an unstable cervical spine. Each of the three cadaveric specimens had a corpectomy without fixation performed. A board-certified emergency medicine physician specialized in disaster medicine performed all SAM immobilizations. An orthopedic surgeon performed Fast Cast immobilizations. Each method of immobilization was done on each cadaver. Lateral fluoroscopic imaging was taken before and after immobilization and after log roll/gravity stress. Five board-certified orthopedic surgeons served as graders to independently score each splint. A 5-point Likert scale based on 10 splinting criteria (50 total points possible) was utilized to evaluate cervical spine immobilization. The lead statistical analyst was blinded to the immobilization groups. The statistical significance was assessed via a Wilcoxon signed-rank test and chi-square Fisher's exact test with significance between groups set at α < .05. Inter-rater reliability of the Likert scale results was assessed with the interclass correlation coefficient., Results: Inter-rater reliability for the current Likert scale in the evaluation of cervical spine stabilization was good (interclass correlation coefficient = 0.76). For the cumulative Likert scale score, Fast Cast (32 [28-34]) exhibited a higher total score than SAM (44 [42-47]; P < .01). Likewise, Fast Cast exhibited a greater likelihood of higher Likert scores within each individual question as compared to SAM (P ≤ 0.04). In 100% of cases, raters indicated that Fast Cast passed the gravity stress examination without intrinsic loss of reduction or splinting material, whereas 33% of SAM passed (P < .01). In 100% of cases, raters indicated that Fast Cast passed the initial radiographic alignment following immobilization, whereas 66% of SAM passed (P = .04). In 100% of cases, raters indicated that Fast Cast passed radiographic alignment after the gravity stress examination, whereas 47% of SAM passed (P < .01)., Conclusion: The Fast Cast exceeded our expectations and was shown to be rated not equivalent but superior to SAM splint immobilization for the cervical spine. This has significant clinical implications as the single-step spray-on foam is easy to transport and has multifaceted applications. It also eliminates pressure points and circumferential wrapping and obstruction to airway/vascular access while immobilizing the cervical spine and allowing for radiographic examination. Further studies are needed for human use and application., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: This study examined user behavior, e-cigarette dependence, and device characteristics on nicotine intake among users of pod-mod e-cigarettes., Aims and Methods: In 2019-2020, people who use pod-mods in the San Francisco Bay Area completed questionnaires and provided a urine sample for analysis of total nicotine equivalents (TNE). The relationship between TNE and e-cigarette use, e-cigarette brands, e-liquid nicotine strength, e-cigarette dependence, and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), as a measure of combustible cigarette exposure, were examined., Results: Of 100 participants (64% male, 71% in the 18-34 age group, 45% white), 53 used JUUL primarily, 12 used Puff Bar primarily, and 35 used other brands, including Suorin; 48 participants reported current cigarette smoking. Participants most often reported use of e-liquid with 4.5%-6.0% nicotine (68%), fruit (35%), tobacco (28%), and menthol or mint flavors (26%), used e-cigarettes on 25.5 (SD = 6.3) days a month, 10.2 (SD = 14.2) times a day, and 40% used 1-2 pods/cartridges per week. In bivariate analysis, urinary TNE was higher with greater frequency (days used) and intensity (number of pods used) of e-cigarette use, e-cigarette dependence, and combustible cigarette use. In multivariable analysis, days of e-cigarette use in the last 30 days, number of pods used per week, and NNAL levels were significantly associated with TNE. There was no significant impact of e-liquid nicotine strength on TNE., Conclusions: Nicotine intake among people who used pod-mod e-cigarettes increased with e-cigarette consumption and e-cigarette dependence, but not with e-liquid nicotine strength. Our findings may inform whether FDA adopts a nicotine standard for e-cigarettes., Implications: The study examined how device and user characteristics influence nicotine intake among pod-mod e-cigarette users. Nicotine intake increased with frequency (days of e-cigarette use in past 30 days) intensity of use (number of pods used per day) and e-cigarette dependence but not with the flavor or nicotine concentration of the e-liquids. Regulation of nicotine concentration of e-liquids is unlikely to influence nicotine exposure among adult experienced pod-mod users., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

Glaciers in high-altitude mountain regions are retreating rapidly due to global warming, exposing deglaciated soils to extreme environmental conditions, and microbial colonization. However, knowledge about chemolithoautotrophic microbes, which play important roles in the development of oligotrophic deglaciated soils prior to plant colonization, remains elusive in deglaciated soils. Using real-time quantitative PCR and clone library methods, the diversity and succession of the chemolithoautotrophic microbial community harboring the cbbM gene across a 14-year deglaciation chronosequence on the Tibetan Plateau were determined. The abundance of the cbbM gene remained stable for the first 8 years after deglaciation and then increased significantly, ranging from 105 to 107 gene copies g-1 soil (P < 0.001). Soil total carbon increased gradually to 5-year deglaciation and then decreased. While total nitrogen and total sulfur levels were low throughout the chronosequence. Chemolithoautotrophs were related to Gammaproteobacteria and Betaproteobacteria, with the former dominating early deglaciated soils and the latter dominating older deglaciated soils. The diversity of chemolithoautotrophs was high in mid-age deglaciated soils (6-year-old) and was low in early (3-year-old) and older deglaciated soils (12-year-old). Our findings revealed that chemolithoautotrophic microbes colonize deglaciated soils quickly and follow a clear successional pattern across recently deglaciated chronosequences., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ motif containing GTPase activating protein 1 is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQ motif containing GTPase activating protein 1 bind to each other and are highly colocalized in sensory dorsal root ganglia neurons in mice. The expression of IQ motif containing GTPase activating protein 1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of dorsal root ganglia neurons catalysed by the small GTPase Cdc42 associated with IQ motif containing GTPase activating protein 1, leading to functional sensitization of the channel. Activation of protein kinase A is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQ motif containing GTPase activating protein 1. Concordantly, deletion of IQ motif containing GTPase activating protein 1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQ motif containing GTPase activating protein 1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Reference letters play an important role for both postgraduate residency applications and medical faculty hiring processes. This study seeks to characterise the ways in which gender bias may manifest in the language of reference letters in academic medicine. In particular, we conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched Embase, MEDLINE and PsycINFO from database inception to July 2020 for original studies that assessed gendered language in medical reference letters for residency applications and medical faculty hiring. A total of 16 studies, involving 12 738 letters of recommendation written for 7074 applicants, were included. A total of 32% of applicants were women. There were significant differences in how women were described in reference letters. A total of 64% (7/11) studies found a significant difference in gendered adjectives between men and women. Among the 7 studies, a total of 86% (6/7) noted that women applicants were more likely to be described using communal adjectives, such as "delightful" or "compassionate", while men applicants were more likely to be described using agentic adjectives, such as "leader" or "exceptional". Several studies noted that reference letters for women applicants had more frequent use of doubt raisers and mentions of applicant personal life and/or physical appearance. Only one study assessed the outcome of gendered language on application success, noting a higher residency match rate for men applicants. Reference letters within medicine and medical education exhibit language discrepancies between men and women applicants, which may contribute to gender bias against women in medicine., (© The Author(s) 2021. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The cases described in this Report were presented at the Society for Neuro-Oncology Pediatric Molecular Neuro-Oncology Tumor Board Quarterly Series, March 22, 2022. The authors have nil else to declare.

We used magnetoencephalography (MEG) and event-related potentials (ERPs) to track the time-course and localization of evoked activity produced by expected, unexpected plausible, and implausible words during incremental language comprehension. We suggest that the full pattern of results can be explained within a hierarchical predictive coding framework in which increased evoked activity reflects the activation of residual information that was not already represented at a given level of the fronto-temporal hierarchy ("error" activity). Between 300 and 500 ms, the three conditions produced progressively larger responses within left temporal cortex (lexico-semantic prediction error), whereas implausible inputs produced a selectively enhanced response within inferior frontal cortex (prediction error at the level of the event model). Between 600 and 1,000 ms, unexpected plausible words activated left inferior frontal and middle temporal cortices (feedback activity that produced top-down error), whereas highly implausible inputs activated left inferior frontal cortex, posterior fusiform (unsuppressed orthographic prediction error/reprocessing), and medial temporal cortex (possibly supporting new learning). Therefore, predictive coding may provide a unifying theory that links language comprehension to other domains of cognition., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)