Characteristics and primary care experiences of people who self-report as autistic: a probability sample survey of adults registered with primary care services in England.

OBJECTIVES: Little is known about adults who self-report as autistic. This study aimed to profile the demographic characteristics, long-term health conditions and primary care experiences of adults who self-report as autistic (including those with and without a formal diagnosis). DESIGN/SETTING: A nationally representative cross-sectional survey of adults registered with National Health Service (NHS) General Practitioner (GP) surgeries in England. PARTICIPANTS: 623 157 survey respondents aged 16 and over, including 4481 who self-report as autistic. OUTCOMES: Weighted descriptive statistics, with 95% CIs. Logistic regression modelling adjusted for age, gender, ethnicity and area-level deprivation compared those who self-report as autistic with the rest of the population. RESULTS: A total of 4481 of the 623 157 survey participants included in the analysis self-reported autism, yielding a weighted proportion estimate of 1.41% (95% CI 1.35% to 1.46%). Adults self-reporting as autistic were more likely to be younger, male or non-binary, to identify as a gender different from their sex at birth, have a non-heterosexual sexual identity, be of white or mixed or multiple ethnic groups, non-religious, without caring responsibilities, unemployed, live in more deprived areas and not smoke. All chronic conditions covered were more prevalent among adults self-reporting as autistic, including learning disability, mental health conditions, neurological conditions, dementia, blindness or partial sight and deafness or hearing loss. Adults self-reporting as autistic were also less likely to report a positive experience of making an appointment (adjusted OR (aOR) 0.90, 95% CI 0.82 to 0.98) and navigating GP practice websites (aOR 0.78, 95% CI 0.70 to 0.87) and more likely to report seeking advice from a friend or family member prior to making an appointment (aOR 1.25, 95% CI 1.14 to 1.38) and having a preferred GP (aOR 2.25, 95% CI 2.06 to 2.46). They were less likely to report that their needs were met (aOR 0.73, 95% CI 0.65 to 0.83). CONCLUSIONS: Adults self-reporting as autistic have a distinctive sociodemographic profile and heightened rates of long-term conditions. They report challenges in both accessing primary care and having their needs met when they do. These findings should inform future care initiatives designed to meet the needs of this group.

CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant.

Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

The Natural History of Post-Chikungunya Viral Arthritis Disease Activity and T-cell Immunology: A Cohort Study.

Background: Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe the arthritis progression and T cell immunology over a two-year period. Methods: A cohort of 40 cases of serologically confirmed CHIKV from Magdalena and Atlántico, Colombia were followed in 2019 and again in 2021. Arthritis disease severity, disability, pain, stiffness, physical function, mobility, fatigue, anxiety, sleep disturbances and depression were assessed. Serum cytokines and T-cell subsets were measured and tested for change. Correlations within each of the 2 time periods for laboratory parameters were also examined. Results: Although, arthritis disease severity, as measured by the Disease Activity Score-28 (DAS-28) did not change significantly over a two-year period, a new metric- the Chikungunya Disease Activity Score (CHIK-DAS)- was more sensitive to detect changes in disease severity than the Disease Activity Score-28 (DAS-28) and showed some improvement in average disease severity from moderate to mild over two years. Cases were characterized by moderate disability, pain, and stiffness with mild alterations of physical function, mobility, fatigue, anxiety, sleep disturbances and depression that did not change significantly over time. Small joints including the fingers and wrists were most affected without significant change over time. The percentage of effector T cells (Teffs) and regulatory T cells (Tregs) of CD4+ T cells both decreased over time. Teff percentages decreased more significantly resulting in a halving of the Teff/Treg ratio two years later. Furthermore, markers of Treg immunosuppressive function such as CTLA4, Helios, CD28, CD45RA and 41bb decreased over time. Cytokines did not change significantly over time. Conclusions: The presented data suggest that arthritis persists almost seven years after chikungunya infection in some patients with waning Teff and Treg numbers and activation markers over time. Treg activation may be a promising therapeutic target for further investigation.

CRISPR Screening Uncovers a Long-Range Enhancer for ONECUT1 in Pancreatic Differentiation and Links a Diabetes Risk Variant.

Functional enhancer annotation is a valuable first step for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants for investigation. However, unbiased enhancer discovery in physiologically relevant contexts remains a major challenge. To discover regulatory elements pertinent to diabetes, we conducted a CRISPR interference screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers uncovered, we focused on a long-range enhancer ∼664 kb from the ONECUT1 promoter, since coding mutations in ONECUT1 cause pancreatic hypoplasia and neonatal diabetes. Homozygous enhancer deletion in hPSCs was associated with a near-complete loss of ONECUT1 gene expression and compromised pancreatic differentiation. This enhancer contains a confidently fine-mapped type 2 diabetes associated variant (rs528350911) which disrupts a GATA motif. Introduction of the risk variant into hPSCs revealed substantially reduced binding of key pancreatic transcription factors (GATA4, GATA6 and FOXA2) on the edited allele, accompanied by a slight reduction of ONECUT1 transcription, supporting a causal role for this risk variant in metabolic disease. This work expands our knowledge about transcriptional regulation in pancreatic development through the characterization of a long-range enhancer and highlights the utility of enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

Response Evaluation Criteria in Gastrointestinal and Abdominal Cancers: Which to Use and How to Measure.

As the management of gastrointestinal malignancy has evolved, tumor response assessment has expanded from size-based assessments to those that include tumor enhancement, in addition to functional data such as those derived from PET and diffusion-weighted imaging. Accurate interpretation of tumor response therefore requires knowledge of imaging modalities used in gastrointestinal malignancy, anticancer therapies, and tumor biology. Targeted therapies such as immunotherapy pose additional considerations due to unique imaging response patterns and drug toxicity; as a consequence, immunotherapy response criteria have been developed. Some gastrointestinal malignancies require assessment with tumor-specific criteria when assessing response, often to guide clinical management (such as watchful waiting in rectal cancer or suitability for surgery in pancreatic cancer). Moreover, anatomic measurements can underestimate therapeutic response when applied to molecular-targeted therapies or locoregional therapies in hypervascular malignancies such as hepatocellular carcinoma. In these cases, responding tumors may exhibit morphologic changes including cystic degeneration, necrosis, and hemorrhage, often without significant reduction in size. Awareness of pitfalls when interpreting gastrointestinal tumor response is required to correctly interpret response assessment imaging and guide appropriate oncologic management. Data-driven image analyses such as radiomics have been investigated in a variety of gastrointestinal tumors, such as identifying those more likely to respond to therapy or recur, with the aim of delivering precision medicine. Multimedia-enhanced radiology reports can facilitate communication of gastrointestinal tumor response by automatically embedding response categories, key data, and representative images. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

The Short-Term Cost-Effectiveness of a Fixed-Ratio Combination of Insulin Degludec and Aspart: A Cost of Control Analysis in Australia and India.

OBJECTIVES: The real-world ARISE study demonstrated initiation of fixed-ratio combination insulin degludec and aspart (IDegAsp) led to improvements in people achieving key glycemic control targets compared with prior therapies in Australia and India. This study evaluated the short-term cost-effectiveness of IDegAsp in these countries, in terms of the cost per patient achieving these targets. METHODS: A model was developed to evaluate the cost of control (treatment costs divided by the proportion of patients achieving each target) of IDegAsp versus prior therapies received in ARISE for 2 endpoints: glycated hemoglobin (HbA1c) <7.0%, and HbA1c less than a predefined individual treatment target. Costs, expressed from a healthcare payer perspective, were captured in 2022 Australian dollars (AUD) and 2022 Indian rupees (INR). RESULTS: The number of patients needed to treat to bring one to endpoints of HbA1c <7.0% and less than an individualized target with IDegAsp was 51% and 87% lower, respectively, than with prior therapies in Australia, and 52% and 66% lower, respectively, versus prior therapies in India. Cost of control was AUD 2449 higher and AUD 64 863 lower with IDegAsp versus prior therapies for endpoints of HbA1c <7.0% and less than an individualized target, respectively, in Australia and INR 211 142 and INR 537 490 lower with IDegAsp compared with prior therapies in India. CONCLUSIONS: IDegAsp was estimated to be cost-effective versus prior therapies when considering an individualized HbA1c target in Australia, and when considering an individualized HbA1c target and HbA1c <7.0% in India.

Correction: Physiotherapy and associated factors affecting mouth opening changes in noma patients during initial hospitalization at an MSF-supported hospital in Northwest Nigeria-A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pgph.0001995.].

Proportion of paediatric admissions with any stage of noma at the Anka General Hospital, northwest Nigeria.

INTRODUCTION: Noma is a rapidly spreading infection of the oral cavity which mainly affects young children. Without early treatment, it can have a high mortality rate. Simple gingivitis is a warning sign for noma, and acute necrotizing gingivitis is the first stage of noma. The epidemiology of noma is not well understood. We aimed to understand the prevalence of all stages of noma in hospitalised children. METHODS: We conducted a prospective observational study from 1st June to 24th October 2021, enrolling patients aged 0 to 12 years who were admitted to the Anka General Hospital, Zamfara, northwest Nigeria. Consenting parents/ guardians of participants were interviewed at admission. Participants had anthropometric and oral examinations at admission and discharge. FINDINGS: Of the 2346 patients, 58 (2.5%) were diagnosed with simple gingivitis and six (n = 0.3%) with acute necrotizing gingivitis upon admission. Of those admitted to the Inpatient Therapeutic Feeding Centre (ITFC), 3.4% (n = 37, CI 2.5-4.7%) were diagnosed with simple gingivitis upon admission compared to 1.7% of those not admitted to the ITFC (n = 21, CI 1.1-2.6%) (p = 0.008). Risk factors identified for having simple gingivitis included being aged over two years (2 to 6 yrs old, odds ratio (OR) 3.4, CI 1.77-6.5; 7 to 12 yrs OR 5.0, CI 1.7-14.6; p = <0.001), being admitted to the ITFC (OR 2.1; CI 1.22-3.62) and having oral health issues in the three months prior to the assessment (OR 18.75; CI 10.65, 33.01). All (n = 4/4) those aged six months to five years acute necrotizing gingivitis had chronic malnutrition. CONCLUSION: Our study showed a small proportion of children admitted to the Anka General Hospital had simple or acute necrotizing gingivitis. Hospital admission with malnutrition was a risk factor for both simple and acute necrotizing gingivitis. The lack of access to and uptake of oral health care indicates a strong need for oral examinations to be included in routine health services. This provision could improve the oral status of the population and decrease the chance of patients developing noma.

Early use of oral semaglutide in the UK: A cost-effectiveness analysis versus continuing metformin and SGLT-2 inhibitor therapy.

OBJECTIVES: Many people with type 2 diabetes experience clinical inertia, remaining in poor glycaemic control on oral glucose-lowering medications rather than intensifying treatment with a glucagon-like peptide-1 receptor agonist, despite an efficacious, orally administered option, oral semaglutide, being available. The present study evaluated the long-term cost-effectiveness of initiating oral semaglutide versus continuing metformin plus sodium-glucose cotransporter-2 (SGLT-2) inhibitor therapy in the UK. DESIGN: Outcomes were projected over patients' lifetimes using the IQVIA Core Diabetes Model (V.9.0). Clinical data were taken from the oral semaglutide and placebo arms of the patient subgroup receiving metformin plus an SGLT-2 inhibitor in PIONEER 4. Costs, expressed in 2021 Pounds sterling (GBP), were accounted from a healthcare payer perspective. INTERVENTIONS: Modelled patients received oral semaglutide immediately (in the first year of the analysis) or after a 2-year delay, after which all physiological parameters were brought to values observed in the immediate therapy arm. During the simulation, patients intensified with the addition of basal insulin and, subsequently, by switching to basal-bolus insulin. RESULTS: Immediate oral semaglutide therapy was associated with improvements in life expectancy of 0.17 (95% CIs 0.16 to 0.19) years, and quality-adjusted life expectancy of 0.15 (0.14 to 0.16) quality-adjusted life years (QALYs), versus a 2-year delay. Benefits were due to a reduced incidence of diabetes-related complications. Direct costs were estimated to be GBP 1423 (1349 to 1496) higher with immediate oral semaglutide therapy versus a 2-year delay, with higher treatment costs partially offset by cost savings from avoidance of diabetes-related complications. Immediate oral semaglutide therapy was therefore associated with an incremental cost-effectiveness ratio of GBP 9404 (8380 to 10 538) per QALY gained versus a 2-year delay. CONCLUSIONS: Immediate oral semaglutide is likely to represent a cost-effective treatment in people with type 2 diabetes with inadequate glycaemic control on metformin plus an SGLT-2 inhibitor in the UK. TRIAL REGISTRATION NUMBER: NCT02863419.

Physiotherapy and associated factors affecting mouth opening changes in noma patients during initial hospitalization at an MSF-supported hospital in Northwest Nigeria-A retrospective cohort study.

Noma is a rapidly progressing infection of the oral cavity, which can cause the disintegration of the cheek, nose and eye, in under a week. One of the most disabling sequelae is trismus, the restriction of mouth opening, which results in difficulties in speech, mastication, social feeding habits and maintenance of oral hygiene. Restriction of mouth opening among noma patients mostly begins during the transition between World Health Organisation (WHO) stage 3 (gangrene) and stage 4 (scarring) of the disease. This study aims to describe the impact of physiotherapy in noma patients hospitalised with stages 3 and 4 of the disease and to identify factors that influence change in mouth opening of noma patients. This study is a retrospective analysis of routinely collected data from patients admitted at Noma Children Hospital, Sokoto, Northwest Nigeria between 1 May 2018 and 1 May 2020. Eligible patients included stage 3 and 4 noma patients who had not undergone any surgical reconstruction or trismus release surgery but received physiotherapy assessment and treatment during initial hospitalization. Factors associated with a change in mouth opening were identified using paired t-test analysis, bivariate and multivariate analyses. The mean difference in the mouth opening from admission to discharge was 6.9mm (95% CI: 5.4 to 8.3, p < 0.0001). Increased number of physiotherapy sessions and patient age above three years were significant predictors of improvement in mouth opening (p-value 0.011, 0.001 respectively). Physiotherapy treatment received within an adequate number of physiotherapy sessions for stage 3 and 4 noma patients during the period of the first hospitalization is important and results in a significant increase in mouth opening. Hence, noma patients at these stages should routinely undergo physiotherapy as part of a holistic approach to treatment.

Insight into designing of 2-pyridone derivatives for COVID-19 drug discovery - A computational study.

Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure-property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors.

Intensity and Duration of Physical Activity and Cardiorespiratory Fitness.

OBJECTIVES: There is no clear guidance on the intensity and duration of physical activity (PA) that adolescents require to maximise cardiorespiratory fitness (CRF). We aimed to determine the strength of associations between each PA intensity and CRF, independently of other intensities, and the PA duration at each intensity associated with maximal CRF. METHODS: PA and CRF were assessed in 339 adolescents aged 13 to 14 years by wrist-worn accelerometers and 20-m shuttle runs, respectively. Partial regression modeling was used to construct residualized PA variables at each PA intensity that were uncorrelated with each other. Moving average models were optimally fitted to determine relationships between residualized PA variables and CRF. Threshold regression models determined the duration of PA above which CRF improvement was minimal. RESULTS: Greater vigorous PA (VPA) was associated with better CRF until about 20 minutes of daily VPA, when the relationship plateaued. Moderate and light PA, and sedentary time were not associated with CRF in partial models. Adolescents performing 14 (range 12-17) minutes of daily VPA had median CRF. Participants in the upper quartile of VPA had 1.03 z-scores higher CRF than those in the lowest quartile (95% confidence interval: 0.75 to 1.30). CONCLUSIONS: Our data suggest that 20 minutes of daily VPA may be best for maximizing CRF in adolescence. As moderate-to-vigorous PA guidelines can be satisfied by only undertaking moderate PA, with no apparent independent benefit, we suggest that future guidelines focus on VPA alone, simplifying public health messaging.

Association of Quality-of-Life Outcomes in Cancer Drug Trials With Survival Outcomes and Drug Class.

Importance: Although quality of life (QOL) is an important clinical end point, cancer drugs are often approved based on overall survival (OS) or putative surrogate end points such as progression-free survival (PFS) without QOL data. Objective: To ascertain whether cancer drug trials that show improvement in OS or PFS also improve global QOL of patients with cancer compared with the control treatment, as well as to assess how unchanged or detrimental QOL outcomes are reported in trial publications. Design, Setting, and Participants: This retrospective cohort study included all patients with cancer in the advanced setting who were enrolled into phase 3 randomized clinical trials (RCTs) of cancer drugs reporting QOL data and published in English language in a PubMed-indexed journal in the calendar year 2019. The systematic search of PubMed was conducted in July 2020. Main Outcomes and Measures: Association of QOL outcomes with OS and PFS, framing of unchanged QOL outcomes in trial publications, and the association of favorable framing with industry funding of the trials. Results: A total of 45 phase 3 RCTs enrolling 24 806 participants (13 368 in the experimental arm and 11 438 in the control arm) met the inclusion criteria and were included in the study analyses. Improvement in global QOL with the experimental agent was reported in 11 (24%) RCTs. The RCTs with improved QOL were more likely to also show improved OS vs trials with unimproved QOL (7 of 11 [64%] trials vs 10 of 34 [29%] trials; χ2 = 4.13; P = .04); there was no such association observed for PFS (6 of 11 [55%] trials vs 17 of 34 [50%] trials, χ2 = 0.03; P = .87). Six trials reported worsening QOL, of which 3 (50%) were trials of targeted drugs, and 11 trials reported improvement in QOL, of which 6 (55%) were trials of immunotherapy drugs. Of the 34 trials in which QOL was not improved compared with controls, 16 (47%) reported these results in a positive frame, an observation statistically significantly associated with industry funding (χ2 = 6.35; P = .01). Conclusions and Relevance: In this cohort study, a small proportion of RCTs of cancer drugs showed benefit in global QOL with the experimental agent. These results showed an association between QOL benefit and OS benefit but no such association with PFS benefit. Trials that failed to show improved QOL often reported their QOL outcomes more favorably. Non-immunotherapy-targeted drugs led to worse QOL more often than did cytotoxic agents.

Invariants in Polarimetric Interferometry: A Non-Abelian Gauge Theory.

The discovery of magnetic fields close to the M87 black hole using very long baseline interferometry by the Event Horizon Telescope collaboration utilized the novel concept of "closure traces," that are immune to element-based aberrations. We take a fundamentally new approach to this promising tool of polarimetric very long baseline interferometry, using ideas from the geometric phase and gauge theories. The multiplicative distortion of polarized signals at the individual elements are represented as gauge transformations by general 2×2 complex matrices, so the closure traces now appear as gauge-invariant quantities. We apply this formalism to polarimetric interferometry and generalize it to any number of interferometer elements. Our approach goes beyond existing studies in the following respects: (1) we use triangular combinations of correlations as basic building blocks of invariants, (2) we use well-known symmetry properties of the Lorentz group to transparently identify a complete and independent set of invariants, and (3) we do not need autocorrelations, which are susceptible to large systematic biases, and therefore unreliable. This set contains all the information, immune to corruption, available in the interferometer measurements, thus providing important robust constraints for interferometric studies.

Declining fitness and physical education lessons in UK adolescents.

OBJECTIVES: The objective was to determine recent cross-sectional trends in health-related fitness (HRF) in secondary school students by studying the 13-14 years old age group repeatedly over 6 years, considering parallel national trends in physical education (PE). METHODS: Height, weight, broad jump, grip strength, 20 m shuttle run and throwing and catching skills were measured by the same research team using standardised techniques from 2014 to 2019. Trends in these HRF measures were assessed by linear regression, adjusting for school, sex and height. Interactions with fitness and body mass index (BMI) were tested. The number of PE lessons reported in the UK Annual School Workforce Census between 2010 and 2019 for all state-funded secondary schools was analysed. RESULTS: Grip strength (B=-0.60, 95% CI -0.78 to -0.41), broad jump (B=-1.16, 95% CI -1.99 to -0.34), 20 m shuttle run (B=-1.85, 95% CI -2.58 to -1.12) and throwing and catching skills (B=-0.12, 95% CI -0.15 to -0.08) declined significantly over the study period. There was a greater reduction in broad jump and grip strength in adolescents with low fitness and a greater reduction in fitness and motor competence in adolescents with normal BMI. These declines coincided with a 16% reduction nationally in secondary school PE between 2010 (333 800 hours) and 2019 (280 725 hours). CONCLUSION: Adolescent HRF has declined in recent years, in parallel with PE lessons. Declines were observed across all young people and particularly those of low fitness and normal BMI. To reach the majority of young people, policy makers could increase PE in schools to increase activity and prevent worsening fitness and health in future generations.

Stage-dependent expression of fibrogenic markers in alcohol-related liver disease.

Alcohol-related liver disease (ALD) is the primary cause of liver-related mortality and morbidity. Liver fibrosis remains the best validated surrogate marker for patient prognosis and is usually assessed in liver biopsies using histochemical stains detecting collagen as the major extracellular matrix (ECM) component in ALD. Distinction of collagen subtypes is of clinical interest, as they, including their cleavage products, have different functions. Changes in production, distribution, and composition of specific collagen subtypes and other extracellular matrix (ECM) components as well as markers for their main cellular source (activated hepatic stellate cells (aHSCs) and myofibroblasts (MFBs)) have not been fully elucidated in ALD. Our aims were to investigate the stage-dependent expression of collagen subtypes and markers for aHSCs and MFBs in ALD. We included liver biopsies from 49 ALD patients with fibrosis stages F0-F4. Biopsies were classified according to the semi-quantitative non-alcoholic fatty liver disease (NAFLD) activity score (NAS-CRN). Slides were stained with H&E, Sirius Red, and immunohistochemically with antibodies against collagen types I, III, IV and VI, and aHSC/MFB markers α-SMA, osteonectin, and CD271. Expression was examined using automated digital imaging analysis (DIA), by calculating the positive area relative to the total liver biopsy area (proportionate area). Likewise, collagen-proportionate area (CPA) was assessed using DIA of Sirius Red stained slides. CPA correlated highly with fibrosis stage (rs = 0.88, P = 5.9E-17) and moderately with activity score (rs = 0.58, P = 0.00001). Collagen type I proportionate area increased from 0.3% (± 0.1) at F1 to 10.2% (± 1.6) at F4 (P < 0.001). Collagen type III proportionate area increased from 0.6% (± 0.2) at F0 to 11.9% (± 1.7) at F4 (P < 0.001). Collagen type IV proportionate area increased from 17.0% (± 2.5) at F0 to 27.0% (± 3.9) at F4 (P = 0.079). Collagen type VI proportionate area increased from 14.8% (± 1.4) at F0 to 31.4% (± 2.4) at F4 (P < 0.001). Proportionate areas for α-SMA and CD271 increased from 10.7% (± 1.6) and 6.5% (± 1.0) at F0 to 29.5% (± 3.4) and 22.1% (± 2.2) at F4 (P < 0.001). Proportionate area for osteonectin increased from 1.4-1.8% at F0-F2 to 3.1% (± 0.5) at F3 and 3.2% (± 0.6) at F4 (P < 0.05). In conclusion, our data indicate that collagen types I, III and VI and the aHSC/MFB markers α-SMA and CD271 show a stage-dependent increase in ALD. In early ALD, collagen types IV and VI are important components of the perisinusoidal and pericellular fibrosis. Immunohistochemistry is a valuable additional tool to characterize the ECM changes in ALD. Further research is needed to explore the functional role of CD271 and the stage-dependent expression of other collagen subtypes in ALD.

Multimodality imaging of adrenal gland pathologies: A comprehensive pictorial review.

The assessment of acute abdominal and pelvic emergencies typically involves a multimodal approach consisting of plain radiographs, ultrasound, computed tomography (CT), and rarely magnetic resonance imaging (MRI). Although MRI is not traditionally employed in acute care settings, there are several instances in which MRI provides superior functional and prognostic information. In this manuscript, we highlight multimodal findings of adrenal gland emergencies: Hemorrhage, infarction, and infection. The purpose of our study is to highlight significant findings in various modalities, including CT, MRI, ultrasound, and PET/CT. Due to the scarcity of published data and limited clinical use, primary ultrasound findings are limited in our multimodal review. In conclusion, we find that synergistic use of CT, MRI, and functional imaging provides an effective tool for evaluation and management of adrenal pathology.

Patient-specific fluid simulation of transcatheter mitral valve replacement in mitral annulus calcification.

Introduction: Transcatheter mitral valve replacement is a promising alternative to open-heart surgery in elderly patients. Patients with severe mitral annulus calcification (MAC) are a particularly high-risk population, where postprocedural complications can have catastrophic effects. Amongst these, obstruction of the left ventricular outflow tract can lead to ventricular hypertrophic remodeling and subsequent heart failure, while subclinical valve thrombosis can result in early bioprosthetic valve failure. Methods: To elucidate the mechanisms of left ventricular outflow tract obstruction and valve thrombosis following valve-in-MAC procedures, we used image processing and Computational Fluid Dynamics (CFD) software to generate patient- and device-specific models based on preprocedural CT data. Personalized computer simulations were performed to predict the left ventricular haemodynamics after implantation in three patients with severe MAC. Results: The simulations have successfully captured the increased pressure gradient in the left ventricular outflow tract as a result of the partial obstruction due to the implanted valve. Regions of wall shear stress above the threshold value for platelet activation were also observed on the bioprosthetic frame as a result of the reduced outflow tract area, which led to increases in flow resistance and blood residence time inside the ventricle. Consistent with these findings, areas of slow recirculating flow and blood stasis formed near the valve frame, creating potential pro-thrombotic conditions. Discussion: This study provides insight into the relationship between size and shape of the outflow tract post-implantation, pressure gradients and pro-thrombotic flow metrics such as wall shear stress and blood residence time. Results show the potential of CFD modeling to bring key functional metrics into preprocedural assessment for a comprehensive evaluation of post-procedural risks beyond anatomical factors. Following further validation and extension to the atrial chamber, this approach can provide an in-depth analysis of the likelihood of valvular thrombosis.

Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB.

Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.

Model of care, Noma Children's Hospital, northwest Nigeria.

The Nigerian Ministry of Health has been offering care for noma patients for many years at the Noma Children's Hospital (NCH) in Sokoto, northwest Nigeria, and Médecins Sans Frontières has supported these initiatives since 2014. The comprehensive model of care consists of four main components: acute care, care for noma sequelae, integrated hospital-based services and community-based services. The model of care is based on the limited evidence available for prevention and treatment of noma and follows WHO's protocols for acute patients and best practice guidelines for the surgical treatment of noma survivors. The model is updated continually as new evidence becomes available, including evidence generated through the operational research studies performed at NCH. By describing the model of care, we wish to share the lessons learned with other actors working in the noma and neglected tropical disease sphere in the hope of guiding programme development.