Search

Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA -mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172)., Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability., Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response., Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

A tendency to merge mental representations of self and other is thought to underpin the intense and unstable relationships that feature in Borderline Personality Disorder (BPD). However, clinical theories of BPD do not specify, in computational terms, how the perspectives of self and other might become confused. To address this question, we used a probabilistic false belief task (p-FBT) to examine how individuals with BPD (N = 38) and matched controls from the general population (N = 74) selectively assigned beliefs to self or other. The p-FBT requires participants to track a gradually changing quantity, whilst also predicting another person's belief about that quantity. We found that BPD participants showed less selectivity in belief assignment compared with controls (Cohen's d = 0.64). Behaviourally, participants with BPD tended to predict that others' beliefs resembled their own. Modelling analysis revealed that BPD participants were prone to generalise their own learning signals to others. Furthermore, this generalising tendency correlated with BPD symptomatology across participants, even when controlling for demographic factors and affective psychopathology. Our results support a computational account of self-other mergence, based on a generalisation of learning across agents. Self-other generalisation in learning purports to explain key clinical features of BPD, and suggests a potential transdiagnostic marker of mentalising capability., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background and Purpose: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a relatively recently described disease, most commonly presenting with optic neuritis and longitudinally extensive transverse myelitis. Cerebral cortical encephalitis is a rare manifestation of MOGAD., Methods: We identified patients presenting with cerebral cortical encephalitis with positive MOG antibodies in serum across a large specialized service. Demographic and clinical information were collected. We describe clinical and laboratory characteristics, treatment response, and subsequent relapse risk in adults presenting with this phenotype., Results: We identified eight patients meeting clinical criteria for cerebral cortical encephalitis with MOG antibodies. All had seizures; four had focal onset seizures with or without secondary generalization. Two patients exhibited encephalopathy, and six demonstrated focal neurological deficits at presentation. All had fluid-attenuated inversion recovery hyperintensities. Five of eight displayed cerebral swelling, and two of eight displayed leptomeningeal enhancement. Where cerebrospinal fluid (CSF) results were available, five of seven had CSF pleocytosis, protein was raised in two of seven, and one patient had oligoclonal bands unique to CSF. Median time to seizure control was 1.25 months, and all clinical features and magnetic resonance imaging abnormalities resolved. Four of eight patients (50%) had a clinical relapse, with a median time to relapse of 6.4 months., Conclusions: Cerebral cortical encephalitis appears to share similar CSF findings, steroid responsiveness, and risk of relapse with other clinical manifestations of MOGAD. This informs treatment decisions and patient counselling., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Statement of Problem: Although the use of artificial intelligence (AI) seems promising and may assist dentists in clinical practice, the consequences of inaccurate or even harmful responses are paramount. Research is required to examine whether large language models (LLMs) can be used in accessing periodontal content reliably., Purpose: The purpose of this study was to evaluate and compare the evidence-based potential of answers provided by 4 LLMs to common clinical questions in the field of periodontology., Material and Methods: A total of 10 open-ended questions pertinent to periodontology were posed to 4 distinct LLMs: ChatGPT model GPT 4.0, Google Gemini, Google Gemini Advanced, and Microsoft Copilot. The answers to each question were evaluated independently by 2 periodontists against robust scientific evidence based on a predefined rubric assessing the comprehensiveness, scientific accuracy, clarity, and relevance. Each response received a score ranging from 0 (minimum) to 10 (maximum). After a period of 2 weeks from initial evaluation, the answers were re-graded independently to gauge intra-evaluator reliability. Inter-evaluator reliability was assessed using correlation tests, while Cronbach alpha and interclass correlation coefficient were used to measure overall reliability. The Kruskal-Wallis test was employed to compare the scores given by different LLMs., Results: The scores provided by the 2 evaluators for both evaluations were statistically similar (P values ranging from .083 to >;.999), therefore an average score was calculated for each LLM. Both evaluators gave the highest scores to the answers generated by ChatGPT 4.0, while Google Gemini had the lowest scores. ChatGPT 4.0 received the highest average score, while significant differences were detected between ChatGPT 4.0 and Google Gemini (P=.042). ChatGPT 4.0 answers were found to be highly comprehensive, with scientific accuracy, clarity, and relevance., Conclusions: Professionals need to be aware of the limitations of LLMs when utilizing them. These models must not replace dental professionals as improper use may negatively impact patient care. Chat GPT 4.0, Google Gemini, Google Gemini Advanced, and Microsoft CoPilot performed relatively well with Chat GPT 4.0 demonstrating the highest performance., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Heart shape captures variation in cardiac structure beyond traditional phenotypes of mass and volume. Although observational studies have demonstrated associations with cardiometabolic risk factors and diseases, its genetic basis is less understood. We utilised cardiovascular magnetic resonance images from 45,683 UK Biobank participants to construct a heart shape atlas from bi-ventricular end-diastolic surface mesh models through principal component (PC) analysis. Genome-wide association studies were performed on the first 11 PCs that captured 83.6% of shape variance. We identified 43 significant loci, 14 were previously unreported for cardiac traits. Genetically predicted PCs were associated with cardiometabolic diseases. In particular two PCs (2 and 3) linked with more spherical ventricles being associated with increased risk of atrial fibrillation. Our study explores the genetic basis of multidimensional bi-ventricular heart shape using PCA, reporting new loci and biology, as well as polygenic risk scores for exploring genetic relationships of heart shape with cardiometabolic diseases., Competing Interests: Competing interests Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb, Cytokinetics, Sanofi, Pfizer, Amicus and Alnaylam. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Proper anchorage control is crucial for predictable tooth movement and preventing inadequate torque during orthodontic treatment. Through clinical and radiographic parameters; this study assesses the association between mini-screws and periodontal health., Materials and Methods: A prospective observational study included 16 systemically healthy non-smoking individuals requiring mini-screws. Mini-screws with a rough, titanium oxide-coated surface were placed. Periodontal assessments (Plaque index, gingival index, probing pocket depth, gingival recession, bleeding on probing, mucosal discomfort, mucosal redness, keratinized tissue width, supracrestal tissue height, and transmucosal soft tissue thickness) were performed at 2nd week and 3 months post-placement. Radiographic evaluations measured distances between mini-screws and adjacent teeth using Image J software., Results: The study included 13 females and 3 males (mean age 21.9 ± 1.8 years) with 24 mini-screws. Early mini-screw loss was not observed. Significant reductions in site-level Gingival Index and bleeding on probing (p < 0.05) and full-mouth bleeding on probing (p < 0.05) were noted over time. Absence of significant differences was found in mucosal discomfort and redness, keratinized tissue width, or transmucosal soft tissue thickness, but supracrestal tissue height decreased significantly (p < 0.05). Radiographically, significant bone reduction around mini-screws was observed at 3 months, with torque gauge values significantly decreased as well (p < 0.05)., Conclusions: Orthodontic mini-screws can be effectively utilized in orthodontic treatment with proper planning and monitoring. While improvements in gingival health were observed with targeted oral care, the study underscores the need for careful consideration of potential risks to periodontal tissues, such as reductions in supracrestal tissue height and bone levels. A balanced approach that integrates preventive strategies with precise screw placement is essential to maximize the benefits of mini-screws while minimizing potential periodontal complications., Clinical Relevance: While proper oral hygiene can help control inflammation around mini-screw sites, clinicians must also be mindful of potential risks, such as reductions in bone levels and tissue height. Careful patient selection, precise placement, and regular follow-up are crucial to ensure the stability of mini-screws' stability and to prevent complications, ultimately contributing to better treatment outcomes in orthodontic care., Trial Registration: This study was registered on ClinicalTrials.gov with the registration number NCT06491849 on June 28, 2024., Competing Interests: Declarations Ethical approval This study was approved by Altınbas University Ethics Committee of Clinical Research (Dated 04/03/2021, Acceptance number: 2021/49) with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all participants who took part in the study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: One key focus in the literature is the need to better understand how males and females perform neuromuscular control, which requires consideration of muscle morphology, as it may change neural drive during force production. Although previous studies focused on muscles around the knee and ankle, it is crucial to explore the behavior of other muscles, such as the hip abductors, since many lower limb conditions more common in females have been associated with alterations in hip muscles., Research Questions: Are electromyography (EMG) variables (amplitude and low- and high frequency bands) of hip abductors during submaximal isometric tasks different between males and females? How is muscle size associated with EMG responses during these tasks?, Methods: Thirty-six participants (males, n = 18; females, n = 18) had muscle and subcutaneous thickness of gluteus medius (GMed) and tensor fascia latae (TFL) measured. They then performed an estimated one-repetition maximum (1RM) test in a side-lying hip abduction exercise, followed by two 10-s submaximal tasks: (i) side-lying hip abduction with 50 % 1RM and (ii) with 20 % 1RM. GMed and TFL EMG amplitude and frequency bands (low and high frequency components) were analyzed., Results: Females had higher GMed EMG amplitude, lower low-frequency, and higher high-frequency components than males in both tasks (p = 0.001-0.040). No differences were observed in TFL EMG variables. Greater GMed thickness was associated with lower amplitudes in the 50 % 1RM task (r = - 0.35; p = 0.03), while greater TFL thickness was associated with lower low-frequency [20 % 1RM: r = - 0.70; p = 0.002; 50 %-1RM: r = - 0.65; p = 0.005] and higher high-frequency components [20 % 1RM: r = 0.74; p = 0.001; 50 %-1RM: r = 0.76; p < 0.001] only in females., Significance: Males and females employ different neuromuscular control strategies, which vary among the synergists for hip abduction., Competing Interests: Declaration of Competing Interest We the undersigned declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from the GAIT AND POSTURE., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diagnostic boundaries between immune thrombocytopenia (ITP) and other thrombocytopenic states such as thrombocytopenic myelodysplastic syndromes, may be difficult to establish, and the detection of somatic mutations by next generation sequencing (NGS) may be of aid. Here we aimed at characterizing the prevalence and clinical significance of clonal hematopoiesis in ITP. In this multicentric retrospective observational study we enrolled 167 adult ITP patients, followed at 13 centers in Italy, UK, and USA. Patients underwent NGS evaluation after a median of 3.6 years from ITP onset and 83% had received at least one therapy line, median 2 (0-9) lines; 51 out of 167 patients had at least one mutation (30%). After exclusion of germline variants and polymorphisms, 18.5% (31/167) were defined as having clonal hemopoiesis. Most commonly mutated genes were TET2, DNMT3A, SRSF2, and ASXL1 (median VAF 29%); 19 of 31 subjects (68%) had high-risk variants, and 8 multiple mutations. Mutated patients were more frequently elderly males and showed a shorter time from first to second line therapy, particularly with TPO-RA. Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases, p=0.01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult ITP patients, being associated with older age, relapsed/refractory disease, and high risk of thrombotic complications., (Copyright © 2024 American Society of Hematology.)

Background: Previous research has suggested a heightened risk of acute myocarditis after COVID-19 infection. However, it is not clear from existing work whether this risk is higher than would be expected after comparable viral respiratory infections. This information is important to guide risk assessments and clinical practice., Methods: A retrospective cohort study of US administrative health claims was conducted to compare the rates of myocarditis after COVID-19 with that after influenza infection and describe the clinical use of diagnostic assessments.Patients with either incident COVID-19 diagnosis (between 1 January 2020 and 31 December 2021) or incident influenza diagnosis (between 1 January 2016 and 31 December 2018), with at least 12 months of continuous enrolment prior to index date and without a previous diagnosis of myocarditis were included.The primary outcome was clinically diagnosed acute myocarditis recorded after COVID-19 or influenza infection. Results are reported as covariate-adjusted subdistribution HRs from competing risk regression with COVID-19 considered as the exposure of interest and influenza as the reference group. Death was considered a competing risk., Results: 1 120 760 adult COVID-19 patients and 439 278 adult influenza patients were identified, of which 669 (0.06%) adult COVID-19 patients and 91 (0.02%) adult influenza patients received a diagnosis of myocarditis. The myocarditis rate per 1000 person-years was 0.73 (95% CI 0.67 to 0.78) for adult COVID-19 patients and 0.24 (95% CI 0.19 to 0.28) for adult influenza populations. In models comprehensively adjusted for demographic and clinical risk factors, COVID-19 diagnosis (compared with influenza diagnosis), cardiac comorbidities, being male and under the age of 30 were independently associated with an increased risk of myocarditis in the year after diagnosis., Conclusions: These findings support a distinct link between COVID-19 and myocarditis, which appears greater than after a similar viral respiratory infection. As such, a greater degree of clinical suspicion and investigation according to existing diagnostic pathways is recommended., Competing Interests: Competing interests: This study was performed as an academic and commercial partnership and funded by Bayer AG. OB, AKF and CH are Bayer AG employees. AM is an employee of Bayer Consumer Care AG. The academic authors were not paid to write this article and report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Vector Field Heterogeneity (VFH) is a novel omnipolar metric to quantify local propagation heterogeneities that may identify functionally critical sites for ablation in scar-related VT., Objective: Assess the diagnostic value of VFH to identify abnormal propagation patterns during ventricular substrate mapping and compare VFH in VT isthmus sites (IS), low-voltage bystander (LVA) and normal voltage areas (NVA)., Methods: Substrate maps acquired with a 16-pole grid catheter in patients with scar-related VT were segmented into sites corresponding to IS, LVA and NVA (defined as omnipolar voltages >&<1.5mV) based on corresponding VT activation maps. For each 4×4 electrode-array acquisition, omnipolar-derived vector maps of the directions of electrical propagation were computed offline and a VFH value per clique ranging from 0 (perfect planar wave) to 1 (maximal disorganisation) derived., Results: 16 patients were studied (56.3% ischemic) evaluating 9 endocardial/7 epicardial substrate maps. VFH metric at IS was 0.57±0.26, LVA 0.52±0.34, NVA 0.16±0.24. VFH at IS was higher (more disorganised) than at LVA (p<0.001). VFH in NVA was significantly lower (i.e. more homogenous) compared to IS and LVA (p<0.001, respectively). Within the isthmus, highest heterogeneity was recorded at entry (0.61±0.24), lowest at exit sites (0.44±0.27)., Conclusion: VFH mapping identified a significant increase in electrical heterogeneity at IS compared to bystanders with highest heterogeneity at the entrance. Absolute differences were small and substantial overlap between sites were recorded precluding its use as a stand-alone mapping approach. VFH may be integrated in existing mapping strategies as complementary information to support identification of ablation targets., (Copyright © 2024. Published by Elsevier Inc.)

Asymptomatic lymphocytosis poses a common challenge in haematology. Immunophenotyping can establish whether a clonal population is present, but it is expensive and the benefit of diagnosing asymptomatic patients is unproven. This study aimed to establish data to guide the use of immunophenotyping. We analysed the proportion of lymphocytosis in full blood count (FBC) samples across a five-year period within a large UK National Health Service (NHS) trust. Persistent lymphocytosis was present in 0.18% (437/242678) of repeat community samples. Of samples sent for immunophenotyping, 743/784 (95%) with a lymphocyte count > 10 × 10 9 /L had a clonal population, compared to 223/1696 (14%) with a lymphocyte count < 5 × 10 9 /L. We followed up a longitudinal cohort of asymptomatic patients with clonal lymphocytosis to determine how many required treatment. The minority (11/46) of patients needed treatment within 9 years of follow-up. Of patients needing treatment, 10/11 (91%) had a presenting lymphocyte count > 10 × 10 9 /L. In all cases, treatment was initiated when the patient became symptomatic. We propose a lymphocyte count threshold of > 10 × 10 9 /L for referral and immunophenotyping in patients with asymptomatic lymphocytosis. This approach aims to balance safety and cost-effectiveness and reflects uncertainty in the value of diagnosis for asymptomatic patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Background: Coronary microvascular function is impaired in patients with obesity, contributing to myocardial dysfunction and heart failure. Bariatric surgery decreases cardiovascular mortality and heart failure, but the mechanisms are unclear., Objectives: The authors studied the impact of bariatric surgery on coronary microvascular function in patients with obesity and its relationship with metabolic syndrome., Methods: Fully automated quantitative perfusion cardiac magnetic resonance and metabolic markers were performed before and 6 months after bariatric surgery., Results: Compared with age- and sex-matched healthy volunteers, 38 patients living with obesity had lower stress myocardial blood flow (MBF) (P = 0.001) and lower myocardial perfusion reserve (P < 0.001). A total of 27 participants underwent paired follow-up 6 months post-surgery. Metabolic abnormalities reduced significantly at follow-up including mean body mass index by 11 ± 3 kg/m 2 (P < 0.001), glycated hemoglobin by 9 mmol/mol (Q1-Q3: 4-19 mmol/mol; P < 0.001), fasting insulin by 142 ± 131 pmol/L (P < 0.001), and hepatic fat fraction by 5.6% (Q1-Q3: 2.6%-15.0%; P < 0.001). Stress MBF increased by 0.28 mL/g/min (Q1-Q3: -0.02 to 0.75 mL/g/min; P = 0.003) and myocardial perfusion reserve by 0.13 (Q1-Q3: -0.25 to 1.10; P = 0.036). The increase in stress MBF was lower in those with preoperative type 2 diabetes mellitus (0.1 mL/g/min [Q1-Q3: -0.09 to 0.46 mL/g/min] vs 0.75 mL/g/min [Q1-Q3: 0.31-1.25 mL/g/min]; P = 0.002). Improvement in stress MBF was associated with reduction in fasting insulin (beta = -0.45 [95% CI: -0.05 to 0.90]; P = 0.03)., Conclusions: Coronary microvascular function is impaired in patients with obesity, but can be improved significantly with bariatric surgery. Improvements in microvascular function are associated with improvements in insulin resistance but are attenuated in those with preoperative type 2 diabetes mellitus., Competing Interests: Funding Support and Author Disclosures Dr Joy has been supported by a British Heart Foundation Clinical Research Training Fellowship (FS/CRTF/21/2469). Dr McGowan was supported by project grants from Guys and St. Thomas’ Charity Grant, Janet James Fund; has undertaken advisory work for Novo Nordisk and Lilly; has performed educational work with Novo Nordisk and Biogen; has an academic grant with Novo Nordisk; and is a shareholder in Reset health. Dr Manisty has been supported by funding with the University Hospitals London NHS Trust National Institute for Health and Care Research Biomedical Research Centre. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

The European Academy of Dermatology and Venereology (EADV) Task Forces on quality of life (QoL) and patient-oriented outcomes and on urticaria and angioedema recommendations for the assessment of Health-related (HR) QoL in all patients with urticaria in research and practice are as follows: to use the DLQI for adults and the CDLQI for children as dermatology-specific and the CU-Q2oL as a disease-specific HRQoL instruments in urticaria; to use generic instruments to provide comparison of data on urticaria with non-dermatologic diseases, or to compare with healthy volunteers or the general population; to select validated HRQoL instruments with appropriate age limits; to present exact numeric data for HRQoL results; correct title of any HRQoL instrument should be used, along with its correct abbreviation and the reference to its original publication, where possible. The EADV TFs discourage the use of non-validated HRQoL instruments and modified HRQoL instruments that have not undergone standard validation., (© 2024 European Academy of Dermatology and Venereology.)

Arabic populations are underrepresented in large genome projects; therefore, the frequency of clinically actionable variants among Arabs is largely unknown. Here, we investigated genetic variation in 14,392 whole genomes from the Qatar Genome Program (QGP) across the list of 78 actionable genes (v3.1) determined by the American College of Medical Genetics and Genomics (ACMG). Variants were categorized into one of the following groups: (1) Pathogenic (P), (2) Likely pathogenic (LP), and (3) Rare variants of uncertain significance with evidence of pathogenicity. For the classification, we used variant databases, effect predictors, and the disease-relevant phenotypes available for the cohort. Data on cardiovascular disease, cancer, and hypercholesterolemia allowed us to assess the disease-relevant phenotype association of rare missense variants. We identified 248 distinct variants in 50 ACMG genes that fulfilled our criteria to be included in one of the three groups affecting 1036 genotype-positive participants of the QGP cohort. The most frequent variants were in TTN, followed by RYR1 and ATP7B. The prevalence of reportable secondary findings was 3.5%. A further 46 heterozygous variants in six genes with an autosomal recessive mode of inheritance were detected in 200 individuals, accounting for an additional 1.4%. Altogether, they affect 5% of the population. Due to the high consanguinity rate in the QGP cohort (28% in spouses and 60% in parents), P and LP variants both in genes with dominant and recessive inheritance are important for developing better treatment options and preventive strategies in Qatar and the Arabic population of the Middle East., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Ethical approval was provided by the institutional review board of the Qatar Biobank (QBB) Doha, Qatar (Protocol no. QF-QGP-RES-PUB-002). A signed consent was obtained from all participants by the QBB, and WGS data used in the current study was obtained from the QGP data., (© 2024. The Author(s).)

Objectives: Currently, non-invasive scoring systems to stage the severity of non-alcoholic fatty liver disease (NAFLD) do not consider markers of glucose control (glycated haemoglobin, HbA1c); this study aimed to define the relationship between HbA1c and NAFLD severity in patients with and without type 2 diabetes., Research Design and Methods: Data were obtained from 857 patients with liver biopsy staged NAFLD. Generalized-linear models and binomial regression analysis were used to define the relationships between histological NAFLD severity, age, HbA1c, and BMI. Paired biopsies from interventional studies (n = 421) were used to assess the impact of change in weight, HbA1c and active vs. placebo treatment on improvements in steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis., Results: In the discovery cohort (n = 687), risk of severe steatosis, NASH and advanced fibrosis correlated positively with HbA1c, after adjustment for obesity and age. These data were endorsed in a separate validation cohort (n = 170). Predictive modelling using HbA1c and age was non-inferior to the established non-invasive biomarker, Fib-4, and allowed the generation of HbA1c, age, and BMI adjusted risk charts to predict NAFLD severity. Following intervention, reduction in HbA1c was associated with improvements in steatosis and NASH after adjustment for weight change and treatment, whilst fibrosis change was only associated with weight change and treatment., Conclusions: HbA1c is highly informative in predicting NAFLD severity and contributes more than BMI. Assessments of HbA1c must be a fundamental part of the holistic assessment of patients with NAFLD and, alongside age, can be used to identify patients with highest risk of advanced disease., 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. Published by Elsevier B.V.)

Background: General practice has seen the widespread adoption of remote consulting and triage systems. There is a lack of evidence exploring how inclusion health populations have been impacted by this transformation., Aim: This study aimed to explore the post-pandemic GP access for inclusion health populations, through the lens of those with lived experience, and identify practical recommendations for improving access for this population., Design & Setting: A mixed-methods study exploring the direct experience of people from inclusion health groups trying to access GP care in 13 practices in east London., Method: A mystery shopper exercise involving 39 in-person practice visits and 13 phone calls were undertaken. The findings were reflected on by a multidisciplinary stakeholder group, which identified recommendations for improvements., Results: Only 31% of the mystery shopper visits ( n = 8) resulted in registration and the offer of an appointment to see a GP for an urgent problem. None of the mystery shoppers was able to book an appointment over the phone but n = 10/13 felt that they would be able to register and make an appointment if they followed the receptionist's instructions. Most mystery shoppers felt respected, listened to, and understood the information provided to them. Just under half of the practices (46%, n = 6) received positive comments on how accessible and supportive their spaces felt. Practice- and system-level recommendations were identified by the stakeholder group., Conclusion: Ongoing GP access issues persist for inclusion health populations. We identified practice- and system-level recommendations for improving access for this vulnerable population., (Copyright © 2024, The Authors.)

Background: Evisceration surgery is an important part of an ophthalmologist's skillset but is an uncommon procedure. Therefore, it is important for training ophthalmologists to have adequate knowledge and confidence in this procedure to maximise learning opportunities. Mixed reality involves the intertwining of real and virtual environments and has been used successfully in surgical training., Objectives: To improve participants' knowledge of the relevant anatomy, steps and confidence in performing evisceration surgery using an extended reality online webinar coupled with conventional teaching., Methods: The teaching session comprised of a short lecture introducing evisceration and explaining mixed reality technology including the Microsoft HoloLens headset. This was followed by a 3D demonstration of the orbit and globe, then the live evisceration procedure on a porcine cadaver, with the surgeon's point of view via the headset. There was expert live running commentary during the procedure with the use of virtual signposts on relevant anatomy. Participants were encouraged to be interactive and given the ability to share their annotations on-screen., Results: Ten doctors ranging from Foundation year 1 to Ophthalmology specialist training year 3 attended the 90-min session and completed pre- and post- session questionnaires (5-point Likert scales). Results showed statistically significant improvements in the knowledge, steps and confidence in performing the evisceration surgery (paired two-sample T-tests, SPSS version 29)., Conclusions: This study has demonstrated that utilisation of mixed reality with conventional teaching methods can provide a useful initial learning experience which may facilitate effective further learning of the evisceration surgery in a wet-lab or patient setting., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

The article 'Ocular Syphilis: An Update (2019)' provides a thorough review of the challenges in diagnosing ocular syphilis. However, our research on 'Dermatological and Ocular Manifestations of Syphilis,' identifies a significant gap in both literature and clinical practice: the lack of recognition of dermatological signs during ophthalmological assessments. Ocular syphilis often mimics other conditions and can remain undiagnosed for months or years. Detecting dermatological signs, such as the characteristic palmar rash of secondary syphilis and extragenital chancres, could prompt earlier investigation and serological testing, reducing unnecessary diagnostic workups and inappropriate management. Early recognition would facilitate timely administration of Penicillin G, helping prevent vision loss, which is often reversible with prompt treatment. We urge Ocular Immunology and Inflammation to highlight the importance of incorporating dermatological assessments in future ocular syphilis publications to improve diagnostic protocols and patient outcomes.

Introduction: People with dementia may benefit from psychological therapies for depression or anxiety, but evidence of their effectiveness in atypical dementia is limited., Methods: Using electronic health-care records of > 2 million people who attended psychological therapy services in England between 2012 and 2019, we examined pre-post therapy symptom changes and compared therapy outcomes among 523 people with atypical dementia, a matched cohort without dementia, and 1157 people with typical dementia., Results: People with atypical dementia experienced reductions in depression (Cohen d = -0.92 [-1.05 to -0.79]) and anxiety (d = -0.85 [-0.98 to -0.73]) symptoms. They had similar odds of improvement than people with typical dementia (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 0.85 to 1.34), but lower odds than people living without dementia (OR = 0.70, 95% CI: 0.53 to 0.91). Reasons for discharge were similar between all groups., Discussion: People with atypical dementia may benefit from primary care psychological therapies, but further research is needed to explore necessary adaptations., Highlights: Talking therapies for depression and anxiety may be beneficial for people with atypical dementia. Being younger and having a lower socioeconomic background are associated with poorer outcomes. Receiving more treatment sessions and shorter waiting times are associated with better outcomes., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Colonic motility in constipation can be assessed non-invasively using MRI., Objective: To compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response., Design: Part 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500-1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by 'tagging' were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation., Results: Part 1: Total CVs median (range) were significantly greater in IBS-C (776 (595-1033)) and FC (802 (633-951)) vs HV (645 (467-780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03)., Conclusion: An abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity., Trial Registration Number: The study was preregistered on ClinicalTrials.gov, Reference: NCT03226145., Competing Interests: Competing interests: RCS: Grants/research supports: Sanofi-Aventis Deutschland, Nestle Consultant to Enterobiotix. MC: Consultant: Sanofi, Takeda, Biocodex, Mayoly. SMS: honoraria for teaching for the Laborie Group. SAT: grant support from Takeda. Consultancy fees AstraZeneca, Sanofi-Aventis. Share holder Motilent., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFNγ) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer immunotherapy., Competing Interests: Declaration of interests C.K., E.F., C.E.C., S.L., M.F., M.C., M.D., J.G.C., E.B., C.A., P.L., A.d.G., and S. Agaugué are employees and shareholders of Imcheck Therapeutics. L.M. was a former employee of Imcheck. D.O. is a co-founder and shareholder of Imcheck, Alderaan Biotechnology, Emergence Therapeutics, Stealth IO, and Lurus. A.M. has been a recipient of commercial research grants from Sigma Tau, Roche, Novartis, Compugen, and Efranat and consultant/advisory board member/lecturer for Novartis, Roche, Ventana, Pierre Fabre, Verily, Abbvie, BMS, J&J, Compugen, Imcheck, Macrophage Therapeutics, AstraZeneca, Biovelocita, BG Fund, Third Rock, Verseau Therapeutics, and Olatec Therapeutics. C.G. is the recipient of research funding from Imcheck and Macrophage Therapeutics. A.M. and C.G. receive royalties for reagents related to innate immunity. E.F., C.E.C., K.-S.L., and D.O. are inventors of patents related to BTN2A1. A.M. and C.G. are inventors of patents related to other innate immunity molecules., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials we performed a five-step process including (1) a systematic review of available outcome measurement instruments, (2) an online survey on truth and feasibility of the available measurement instruments, (3) an assessment of the methodological quality of the selected outcome measurement instruments, (4) an online survey on the outcome measurement instruments as COS and (5) a consensus in-person meeting. Both surveys were completed by healthcare professionals and patients. The Outcome Measures in Rheumatology guidelines with a 70% threshold for consensus were followed. We identified 233 different outcome measurement instruments from 307 included studies; 177 were mapped within the International Scientific Tendinopathy Symposium Consensus core domains. 31 participants (12 patients) completed the first online survey (response rate 94%). 22/177 (12%) outcome measurement instruments were deemed truthful and feasible and their measurement properties were evaluated. 29 participants (12 patients) completed the second online survey (response rate 88%) and three outcome measurement instruments were endorsed: the Victorian Institute of Sports Assessment-Achilles questionnaire, the single-leg heel rise test and evaluating pain after activity using a Visual Analogue Scale (VAS, 0-10). 12 participants (1 patient) attended the final consensus meeting, and 1 additional outcome measurement instrument was endorsed: evaluating pain during activity/loading using a VAS (0-10). It is recommended that the identified COS-AT will be used in future clinical trials evaluating the effectiveness of an intervention. This will facilitate comparing outcomes of intervention strategies, data pooling and further progression of knowledge about AT. As COS-AT is implemented, further evidence on measurement properties of included measures and new outcome measurement instruments should lead to its review and refinement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The study aims to understand healthcare professionals' (HCPs) beliefs and practices in the treatment and rehabilitation of patients after ankle fracture surgery, with the goal of informing new rehabilitation interventions based on these insights., Background: There is considerable variation in postoperative rehabilitation advice given to patients with ankle fractures, leading to inconsistent care. Prior studies have primarily focused on patients' experiences, making it crucial to explore HCPs' perspectives to identify areas for intervention., Methods: The study utilised semi-structured interviews with HCPs involved in the multicentre randomised controlled Weightbearing in Ankle Fractures (WAX) trial. Interviewees included physiotherapists, consultant trauma and orthopaedic surgeons, and trainee surgeons. Interviews were conducted between February 2020 and December 2021. Data were analysed using a mixed deductive and inductive approach, aligning with the Behavioural Change Wheel framework to translate findings into potential intervention strategies., Results: 18 Interviews were conducted, revealing discrepancies between patient and HCP beliefs about recovery, particularly regarding weight-bearing and managing physical symptoms like swelling and numbness. HCPs expressed varying beliefs on the safety of early weight-bearing and recognised historical practice and medicolegal concerns influencing rehabilitation advice. Themes highlighted the need for clearer communication, standardised advice, and the impact of HCPs' remarks on patients' recovery confidence., Conclusions: Findings underscore the mismatch between patient expectations and HCP guidance, emphasising the need for consensus on rehabilitation protocols. The study advocates for tailored rehabilitation pathways that address individual patient recovery trajectories, reduce dependency on HCPs, and encourage patient self-management., Competing Interests: Declaration of competing interest There were no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Insects often show adaptive phenotypic plasticity where environmental cues during early stages are used to produce a phenotype that matches the environment experienced by adults. Many tropical satyrine butterflies (Nymphalidae: Satyrinae) are seasonally polyphenic and produce distinct wet- and dry-season form adults, providing tight environment-phenotype matching in seasonal environments. In studied Mycalesina butterflies, dry-season forms can be induced in the laboratory by growing larvae at low temperatures or on poor food quality. Since both these factors also tend to reduce larval growth rate, larval growth rate may be an internal cue that translates the environmental cues into the expression of phenotypes. If this is the case, we predict that slower-growing larvae would be more likely to develop a dry-season phenotype., Methods: We performed the first experimental study on seasonal polyphenism of a butterfly in the tribe Melanitini. We measured both larval growth rate and adult phenotype (eyespot size and wing shape) of common evening brown butterflies ( Melanitis leda ), reared at various temperatures and on various host-plant species. We constructed provisional reaction norms, and tested the hypothesis that growth rate mediates between external cues and adult phenotype., Results: Reaction norms were similar to those found in Mycalesina butterflies. We found that both among and within treatments, larvae with lower growth rates (low temperature, particular host plants) were more likely to develop dry-season phenotypes (small eyespots, falcate wing tips). However, among temperature treatments, similar growth rates could lead to very different wing phenotypes, and within treatments the relationships were weak. Moreover, males and females responded differently, and eyespot size and wing shape were not strongly correlated with each other. Overall, larval growth rate seems to be weakly related to eyespot size and wing shape, indicating that seasonal plasticity in M. leda is primarily mediated by other mechanisms., Competing Interests: The authors declare that they have no competing interests.

The aim of this study was to explore the associations between diet quality, socio-demographic measures, smoking, and weight status in a large, cross-sectional cohort of adults living in Yorkshire and Humber, UK. Data from 43, 023 participants aged over 16 years in the Yorkshire Health Survey, 2 nd wave (2013-2015) were collected on diet quality, socio-demographic measures, smoking, and weight status. Diet quality was assessed using a brief, validated tool. Associations between these variables were assessed using multiple regression methods. Split-sample cross-validation was utilised to establish model portability. Observed patterns in the sample showed that the greatest substantive differences in diet quality were between females and males (3.94 points; P < 0.001) and non-smokers vs smokers (4.24 points; P < 0.001), with higher diet quality scores observed in females and non-smokers. Deprivation, employment status, age, and weight status categories were also associated with diet quality. Greater diet quality scores were observed in those with lower levels of deprivation, those engaged in sedentary occupations, older people, and those in a healthy weight category. Cross-validation procedures revealed that the model exhibited good transferability properties. Inequalities in patterns of diet quality in the cohort were consistent with those indicated by the findings of other observational studies. The findings indicate population subgroups that are at higher risk of dietary-related ill health due to poor quality diet and provide evidence for the design of targeted national policy and interventions to prevent dietary-related ill health in these groups. The findings support further research exploring inequalities in diet quality in the population., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024.)

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 ×10 -7 ). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 × 10 -8 ), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 × 10 -5 ). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo . Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.

This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the 2021 report in presenting cardiovascular disease (CVD) statistics for the ESC member countries. This paper examines inequalities in cardiovascular healthcare and outcomes in ESC member countries utilizing mortality and risk factor data from the World Health Organization and the Global Burden of Disease study with additional economic data from the World Bank. Cardiovascular healthcare data were collected by questionnaire circulated to the national cardiac societies of ESC member countries. Statistics pertaining to 2022, or latest available year, are presented. New material in this report includes contemporary estimates of the economic burden of CVD and mortality statistics for a range of CVD phenotypes. CVD accounts for 11% of the EU's total healthcare expenditure. It remains the most common cause of death in ESC member countries with over 3 million deaths per year. Proportionately more deaths from CVD occur in middle-income compared with high-income countries in both females (53% vs. 34%) and males (46% vs. 30%). Between 1990 and 2021, median age-standardized mortality rates (ASMRs) for CVD decreased by median >50% in high-income ESC member countries but in middle-income countries the median decrease was <12%. These inequalities between middle- and high-income ESC member countries likely reflect heterogeneous exposures to a range of environmental, socioeconomic, and clinical risk factors. The 2023 survey suggests that treatment factors may also contribute with middle-income countries reporting lower rates per million of percutaneous coronary intervention (1355 vs. 2330), transcatheter aortic valve implantation (4.0 vs. 153.4) and pacemaker implantation (147.0 vs. 831.9) compared with high-income countries. The ESC Atlas 2023 report shows continuing inequalities in the epidemiology and management of CVD between middle-income and high-income ESC member countries. These inequalities are exemplified by the changes in CVD ASMRs during the last 30 years. In the high-income ESC member countries, ASMRs have been in steep decline during this period but in the middle-income countries declines have been very small. There is now an important need for targeted action to reduce the burden of CVD, particularly in those countries where the burden is greatest., (© European Society of Cardiology 2024.)

Background: Long non-coding RNAs (lncRNAs) are key regulators of cellular processes that underpin cancer development and progression. DRAIC is a migration inhibitor that has been linked with lung adenocarcinoma progression; however, its mechanisms remain to be studied. Methods: Several bioinformatics tools were used to explore the role of DRAIC in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Results: Our bioinformatics analysis illustrates that patients with low expression of DRAIC have poor overall survival outcomes. In addition, the mRNA of SH3 domain-binding kinase 1 (SBK1) was downregulated in this cohort of patients. Mechanistic analysis showed that SBK1 is under the DRAIC competing endogenous RNAs network, potentially through sponging of miRNA-92a. Conclusions: Consistent dysregulation of the DRAIC-SBK1 axis was linked to poor survival outcome in both LUAD and LUSC, suggesting a tumour inhibitor role and providing potential for new diagnostics and therapeutic approaches.

Background: The need for effective non-pharmaceutical infection prevention measures such as contact tracing in pandemics remains in care homes, but traditional approaches to contact tracing are not feasible in care homes. The CONTACT intervention introduces Bluetooth-enabled wearable devices (BLE wearables) as a potential solution for automated contact tracing. Using structured reports and reports triggered by positive COVID-19 cases in homes, we fed contact patterns and trends back to homes to support better-informed infection prevention decisions and reduce blanket application of restrictive measures. This paper reports on the evaluation of feasibility and acceptability of the intervention prior to a planned definitive cluster randomised trial of the CONTACT BLE wearable intervention., Methods: CONTACT was a non-randomised mixed-method feasibility study over 2 months in four English care homes. Recruitment was via care home research networks, with individual consent. Data collection methods included routine data from the devices, case report forms, qualitative interviews (with staff and residents), field observation of care, and an adapted version of the NoMaD survey instrument to explore implementation using Normalisation Process Theory. Quantitative data were analysed using descriptive statistical methods. Qualitative data were thematically analysed using a framework approach and Normalisation Process Theory. Intervention and study delivery were evaluated against predefined progression criteria., Results: Of 156 eligible residents, 105 agreed to wear a device, with 102 (97%) starting the intervention. Of 225 eligible staff, 82% (n = 178) participated. Device loss and damage were significant: 11% of resident devices were lost or damaged, ~ 50% were replaced. Staff lost fewer devices, just 6%, but less than 10% were replaced. Fob wearables needed more battery changes than card-type devices (15% vs. 0%). Structured and reactive feedback was variably understood by homes but unlikely to be acted on. Researcher support for interpreting reports was valued. Homes found information useful when it confirmed rather than challenged preconceived contact patterns. Staff privacy concerns were a barrier to adoption. Study procedures added to existing work, making participation burdensome. Study participation benefits did not outweigh perceived burden and were amplified by the pandemic context. CONTACT did not meet its quantitative or qualitative progression criteria., Conclusion: CONTACT found a large-scale definitive trial of BLE wearables for contact tracing and feedback-informed IPC in care homes unfeasible and unacceptable - at least in the context of shifting COVID-19 pandemic demands. Future research should co-design interventions and studies with care homes, focusing on successful intervention implementation as well as technical effectiveness., Trial Registration: ISRCTN registration: 11204126 registered 17/02/2021., (© 2024. The Author(s).)

Straintronics leverages mechanical strain to alter the electronic properties of materials, providing an energy-efficient alternative to traditional electronic controls while enhancing device performance. Key to the application of straintronics is bandgap engineering, which enables tuning of the energy difference between the valence and conduction bands of a material to optimize its optoelectronic properties. This mini-review highlights the fundamental principles of straintronics and the critical role of bandgap engineering within this context. It discusses the unique characteristics of various two-dimensional (2D) materials, such as graphene, transition metal dichalcogenides (TMDs), hexagonal boron nitride (h-BN), and black phosphorus, which make them suitable for strain-engineered applications. Detailed examples of how mechanical deformation can modulate the bandgap to achieve desired electronic properties are provided, while recent experimental and theoretical studies demonstrating the mechanisms by which strain influences the bandgap in these materials are reviewed, emphasizing their implications for device fabrication. The review concludes with an assessment of the challenges and future directions in the development of high-performing straintronic devices, highlighting their potential applications in flexible electronics, sensors, and optoelectronics.

Patients with triple-negative breast cancer (TNBC) have a relatively poor clinical outcome. The immune checkpoint inhibitor (ICI) pembrolizumab combined with chemotherapy is the current standard of care in TNBC patients with stage II and III. Monotherapy with ICIs has not been comprehensively assessed in the neoadjuvant setting in TNBC patients, given unfavorable results in metastatic trials. ICIs, however, have been tested in the window of opportunity (WOO) before surgery or standard chemotherapy-based neoadjuvant treatment. The WOO design is well suited to assess an ICI alone or in combination with other ICIs, targeted therapy, radiotherapy or cryotherapy, and measure their pharmacodynamic and clinical effect in this treatment-naive population. Some patients show a good response to ICIs in WOO studies. Biomarkers like tumor-infiltrating lymphocytes, programmed death ligand-1, and interferon-γ signature may predict activity and may identify patients likely to benefit from ICIs. Moreover, an increase in tumor-infiltrating lymphocytes, programmed death ligand-1 expression or T cell receptor expansion following administration of ICIs in the WOO setting could potentially inform of immunotherapy benefit, which would allow tailoring further treatment. This article reviews WOO trials that assessed immunotherapy in the early-stage TNBC population, and how these results could be translated to test de-escalation strategies of neoadjuvant chemotherapy and immunotherapy without compromising a patient's prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The differential diagnosis of suspected multiple sclerosis has been developed using data from North America, northern Europe, and Australasia, with a focus on White populations. People from minority ethnic and racial backgrounds in regions where prevalence of multiple sclerosis is high are more often negatively affected by social determinants of health, compared with White people in these regions. A better understanding of changing demographics, the clinical characteristics of people from minority ethnic or racial backgrounds, and the social challenges they face might facilitate equitable clinical approaches when considering a diagnosis of multiple sclerosis. Neuromyelitis optica, systemic lupus erythematous, neurosarcoidosis, infections, and cerebrovascular conditions (eg, hypertension) should be considered in the differential diagnosis of multiple sclerosis for people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia. The diagnosis of multiple sclerosis in people from a minority ethnic or racial background in these regions requires a comprehensive approach that considers the complex interplay of immigration, diagnostic inequity, and social determinants of health., Competing Interests: Declaration of interests LA has received research support from the National Multiple Sclerosis Society, National Institutes of Health National Institute of Neurological Disorders and Stroke, Bristol Myers Squibb Foundation, Race to Erase MS Foundation, and Biogen Idec; is a local Principal Investigator for commercial trials funded by Genentech, Sanofi, and Genzyme; and declares consulting fees from Biogen Idec, Novartis, Genentech, and EMD Serono. DR has received research support from MS Canada, the National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers, University of Toronto Division of Neurology, and Roche Canada; and has received speaker or consultant fees from Alexion, Biogen, EMD Serono, Horizon Therapeutics, Novartis, Roche, and Sanofi Aventis. OC is a member of the data and safety monitoring board for Novartis, has served on one advisory board for Biogen, and has received a speaker honorarium from Merck. DO has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis; and has received consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Janssen, Novartis, and Merck. MM has served on scientific advisory boards for Sanofi, Novartis, and Merck; and received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb. VR has received honoraria from the Autonomous University of Barcelona, Roche, Corne Neurosciences, and the Multiple Sclerosis Association of America; and is a consultant (Expert Opinion Program) for Teladoc Health International. DK has served as a consultant for CVS Health. RD has received research support from the UK MS Society, National Multiple Sclerosis Society, BMA Foundation, Horne Family Charitable Foundation, Biogen, and Merck; and has received honoraria for advisory boards and educational activities from Biogen, Novartis, Sandoz, Roche, Janssen, and Merck. MW is a co-investigator for a study funded by Genentech; has received honoraria and consulting fees from Alexion, Biogen Idec, Novartis, Genentech, Horizon Therapeutics, EMD Serono, Octave Biosciences, TG Therapeutics, and Sanofi/Genzyme; and has participated in speakers bureau for Biogen Idec, Genentech, EMD Serono, and TG Therapeutics. RAM is a co-investigator on a study funded in part by Biogen and Roche (no funds to her or her institution). JAC has received personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI; and serves as an Editor for Multiple Sclerosis. BB served as a consultant for Novartis, Roche, and UCB; and is funded by the National Multiple Sclerosis Society and National Institutes of Health for work unrelated to this paper. BH served on scientific advisory boards for Novartis; and has served as a data and safety monitoring board member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; and his institution has received institutional research grants from Roche. BH has received honoraria for counselling for the Gerson Lehrmann Group; and holds part of two patents: (1) the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis, and (2) genetic determinants of neutralising antibodies to interferon. SDN reports grants or contracts from Biogen, Roche, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute; reports personal compensation for consulting for Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, Horizon Therapeutics, and TG Therapeutics; and participates on a data safety monitoring board and advisory board for MedDay Pharmaceuticals; and reports support from the Stiff Person Syndrome Research Foundation. AJS reports grant funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and Bristol Myers Squibb; is contracted for research with Sanofi, Biogen, Novartis, Actelion, and Genentec; has received personal compensation for consulting from EMD Serono and Octave Bioscience; has received payment or honoraria for lectures for EMD Serono; has been called for expert testimony by The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; participates on a data safety monitoring board for Patient Centered Outcomes Research Institute and Yale University; participates on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics; and is content Chair for the American Academy of Neurology Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. WR3rd has research grant support from the National Institutes of Health and the Veterans Administration; reports honoraria, consulting fees, and support for advisory activities for the Consortium of Multiple Sclerosis Centers, the University of Maryland, the University of Calgary, Temple University, Thomas Jefferson University, the Chan Zuckerberg Initiative, the American Association for Cancer Research, and the Alzheimer's Association of Georgia; and receives compensation for serving as Director of specialty programming for Mediflix. AS and BT declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)