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Summary: Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. Findings: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Interpretation: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. Funding: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

Nanoparticles open up new possibilities for treating skin problems. For the treatment of numerous skin problems, the topical route of administration has many advantages. This method avoids the hepatic first-pass impact, and many medications’ systemic availability is limited to skin cells like hair follicles, reducing undesired side effects and increasing localised therapeutic benefit. The skin's barrier function makes it difficult for nanoparticles to penetrate the tissue, even if the barrier is partially impaired in cases of damage or inflammation, such as in skin cancer. This could make nanoparticle penetration easier. Although a lot of work has gone into producing nanoparticles for topical distribution, there has been very little success in getting them to the clinic to treat skin malignancies. We review the various forms of skin malignancies and current clinical care strategies. Clinical therapy and management are also illustrated, explaining various skin cancer treatment options. In a brief manner, this study also emphasises the various nanoformulations that are being explored and reported, as well as the various types of nanoparticle systems. Hghlights Skin cancer is one of the widely occurring disease worldwide with varying mortality rates. Clinical supervision of skin cancer is crucial as it may lead to some serious consequences. Nanoparticle/nanovesicle systems would aid in better treatment and reduced adverse effects. Different nano systems are currently under development for the topical treatment of skin cancer. Penetration analysis of NPs is also important to develop a topical novel nanoformulation. Abbreviations: NMSC, non-melanoma skin cancer; MSC, melanoma skin cancer; BCC, basal cell carcinoma; cSCC, cutaneous squamous cell carcinoma; SC, stratum corneum; BCS, biopharmaceutics classification system; UV, ultraviolet; WHO, World Health Organization; AK, actnic keratosis; PDT, photo dynamic therapy; 5-FU, 5-fluorouracil; nm, nanometre; mV, millivolts; FDA, Food and drug administration; API, active pharmaceutical ingredient; NPs, nanoparticles; SLNs, solid-lipid nanoaparticles; NLCs, nanostructured lipid carriers; AuNPs, gold nanoparticles; QDs, quantumn dots; CNTs, carbon nanotubes

We investigate the prospect of reconstructing the “cosmic distance ladder” of the Universe using a novel deep learning framework called LADDER —Learning Algorithm for Deep Distance Estimation and Reconstruction. LADDER is trained on the apparent magnitude data from the Pantheon Type Ia supernova compilation, incorporating the full covariance information among data points, to produce predictions along with corresponding errors. After employing several validation tests with a number of deep learning models, we pick LADDER as the best-performing one. We then demonstrate applications of our method in the cosmological context, including serving as a model-independent tool for consistency checks for other data sets like baryon acoustic oscillations, calibration of high-redshift data sets such as gamma-ray bursts, and use as a model-independent mock-catalog generator for future probes. Our analysis advocates for careful consideration of machine learning techniques applied to cosmological contexts.

There is a large disparity between the demand and availability of organs for transplantation from within the UK's ethnic minority groups. Our aims were to identify the perceptions, knowledge of and level of engagement with organ donation since the law changed in England in 2020. A questionnaire survey using Google Forms was designed based on prior literature and information on NHSBT website. It was distributed through media outlets and cultural/professional organizations. Status on Organ Donation Registry and Quiz scores were analyzed against multiple variables. Three hundred and sixty-five people between 18 and 24 years old completed the questionnaire. 72.3% were female, 57% were health-care students, 86.3% were of South Asian ethnicity, and 11% were immigrant respondents. Overall, 43.6% were registered to donate. South Asian groups, particularly those of Pakistani ethnicity and migrant students, were less likely to register to donate. Being more knowledgeable about the organ donation process, females, nonreligious groups, and health-care students are more likely to be registered to donate. This study identified barriers around deceased organ donation decisions and demonstrates the need for further targeted and continual education to the young South Asians individuals, to produce positive associations that will percolate to older and future generations.

Background Many medical professionals seek to do good through their careers, which may involve pursuing non-clinical options such as research, policy, or education in addition to clinical work. Working out which paths will lead to the largest social impact is a challenging question and of interest to many doctors. However, there are few, if any, services that use an impact-oriented framework to support doctors who want to make career decisions based on impact. Objectives To describe the development of an 8-week fellowship programme to introduce medical professionals to careers paths and focus areas which could lead to a particularly large social impact. And to evaluate the programme in terms of engagement, utility, changes in knowledge and career attitudes of participants. Methods The ADDIE instructional design model was used to design and evaluate this fellowship programme. An 8-week curriculum was designed by medical professionals and delivered to medical students and doctors around the world utilising a flipped learning style. Quantitative and qualitative data on the programme were collected and analysed. Results There was more demand for the programme than anticipated. We found that the fellowship was engaging and useful to medical students and doctors. It resulted in an increase in knowledge and skills on how to consider impact in one’s own career and a change in participants’ attitudes and behaviours, with some participants making changes to their career and charitable giving following the programme. Conclusions We believe an impact-orientated, practical co-curricular programme is valuable to medical professionals exploring impactful career options and there is demand for further programmes in this space.

Aims: This research aimed to prepare and physically characterize methotrexate-encapsulated poly (n-methyl glycine) microspheres as a treatment option for rheumatoid arthritis. Background: Rheumatoid arthritis is an autoimmune disease that leads to cartilage destruction, synovial joint inflammation, and bacterial joint/bone infections. Methotrexate (MTX), commonly used in rheumatoid arthritis (RA), has severe adverse effects. Therefore, a reliable drug delivery system is required to control the release of Methotrexate during the treatment of Rheumatoid arthritis. Objective: The primary goal of this study was to develop and characterise methotrexate-loaded polysarcosine microspheres (MTX-PSar Microspheres), as well as to examine their physical characteristics, pharmacodynamics, and anti-rheumatic study effects. Method: Methotrexate (MTX) loaded Polysarcosine (PSar) Microsphere was developed using Mannitol, Magnesium hydroxide, Dichloromethane, Aqueous polyvinyl alcohol and Chitosan hydrochloride. The MTX-PSar Microsphere was developed by w/o/w multiple emulsions method in the current study to reduce inflammation and disease progression/joint stiffness caused by Rheumatoid Arthritis. FTIR, HPLC, XRD, DSC, and SEM were used to evaluate the physical properties of MTX-PSar Microspheres. Result: The physicochemical characterizations of microparticles by Fourier Transform Infrared Spectroscopy and X-Ray Diffraction have shown that drug encapsulated in the microparticles and lost its crystalline nature. The particle size, entrapment efficacy, reported in the range of 10–20 µm, 86.37 ± 0.65 %. Even after one month, the microsphere’s particle size maintained its spherical shape In-vitro drug release, pharmacodynamics study shows good anti-rheumatic study effects. Conclusion: The MTX-PSar Microsphere is a good option for treating RA despite the lack of in vivo action. Other: It is hoped that in future studies, Methotrexate-loaded polysarcosine microspheres (MTX-PSar Microsphere) will be used to conjugate ligands, and hence active targeting in rheumatoid arthritis would be possible.

Background and study aims While multiple interventional endoscopic ultrasound (EUS)-guided procedures have evolved over the past two decades, there is no model that allows for training in all of these procedures. We aimed to develop and validate an all-in-one hybrid model for stepwise learning in multiple EUS interventions. Methods A hybrid model was created utilizing a pig esophagus and stomach, a silicon-based duodenum and pancreato-biliary system, a pseudocyst, and biopsy targets. This model was designed to provide hands-on training in multiple interventional EUS procedures, such as EUS-guided fine-needle biopsy (EUS-FNB), biliary drainage (BD), pancreatic duct drainage (PD), pseudocyst drainage (PSD), and gastro-enterostomy (GE). Thirty-six trainees underwent training on this model over 6 days, in two batches. Lumen apposing metal stents were used for PSD and GE. Trainees were assessed for objective criteria of technical difficulties. Subjective assessment by trainees was done via a questionnaire. Results All the trainees were able to complete the requisite steps for all the procedures under supervision. On subjective assessment, 30 trainees (83 %) graded the model as good or excellent. A total of 107 technical difficulties were noted (scope position 55, duct puncture 27, guidewire-related problems 25). Time taken to complete the requisite steps of biopsy, PSD, and GE (10.5 minutes; range 3.5 to 22) was significantly less than that for BD and PD (28 minutes; range 17 to 40) (P

Objective Examine the association between the co-prescribing of opioids, benzodiazepines, gabapentinoids (pregabalin and gabapentin) and selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors (SSRI/SNRIs) in different combinations and the risk of falls and fractures.Design Retrospective cohort study from 2015 to 2018.Setting Medicare enrolment and claims data.Participants Medicare beneficiaries with both chronic pain and anxiety disorders in 2016 with continuous enrolments in Parts A and B from 2015 to 2016 who were prescribed any combination of opioid, benzodiazepine, gabapentinoid and SSRI/SNRI in 2017 for ≥7 days, as documented in their Medicare Part D coverage.Interventions Any combination of use of seven drug regimens (benzodiazepine +opioid; benzodiazepine +gabapentinoid; benzodiazepine +SSRI/SNRI; opioid +gabapentinoid; opioid +SSRI/SNRI; gabapentinoid +SSRI/SNRI; ≥3 drug classes).Main outcomes First event of fall and the first event of fracture after the index date, which was the first day of combination drug use that lasted ≥7 days in 2017.Results A total of 47 964 patients (mean [SD] age, 75.9 [7.1]; 78.0% woman) with diagnoses of both chronic pain and anxiety were studied. The median (Q1–Q3) duration of drug combination use was 26 (14-30) days. After adjusting for demographic characteristics, chronic conditions and history of hospitalisation and fall or fracture, the co-prescribing of ≥3 drugs (adjusted HR [aHR], 1.38; 95% CI 1.14 to 1.67) and opioid plus gabapentinoid (aHR, 1.18; 95% CI 1.02 to 1.37) were associated with a high fall risk, compared with benzodiazepineplus opioid co-prescribing, findings consistent with the secondary analysis using inverse probability of treatment weighting with propensity scores. The co-prescribing of benzodiazepine plus gabapentinoid (aHR, 0.76; 95% CI 0.59 to 0.98) was associated with lower fracture risk compared with the co-prescribing of benzodiazepine plus opioid, though this finding was not robust.Conclusions Our findings add to comparative toxicity research on different combinations of gabapentinoids and serotonergic agents commonly prescribed with or as substitutes for opioids and benzodiazepines in patients with co-occurring chronic pain and anxiety.

We study the prospects of Gaussian processes (GPs), a machine-learning (ML) algorithm, as a tool to reconstruct the Hubble parameter H ( z ) with two upcoming gravitational-wave (GW) missions, namely, the evolved Laser Interferometer Space Antenna (eLISA) and the Einstein Telescope (ET). Assuming various background cosmological models, the Hubble parameter has been reconstructed in a nonparametric manner with the help of a GP using realistically generated catalogs for each mission. The effects of early-time and late-time priors on the reconstruction of H ( z ), and hence on the Hubble constant ( H _0 ), have also been focused on separately. Our analysis reveals that a GP is quite robust in reconstructing the expansion history of the Universe within the observational window of the specific missions under consideration. We further confirm that both eLISA and ET would be able to provide constraints on H ( z ) and H _0 , which would be competitive to those inferred from current data sets. In particular, we observe that an eLISA run of a ∼10 yr duration with ∼80 detected bright siren events would be able to constrain H _0 as precisely as a ∼3 yr ET run assuming ∼1000 bright siren event detections. Further improvement in precision is expected for longer eLISA mission durations such as a ∼15 yr time frame having ∼120 events. Lastly, we discuss the possible role of these future GW missions in addressing the Hubble tension, for each model, on a case-by-case basis.

Background and study aims One-on-one endoscopic ultrasound (EUS) mentorship was not possible at most institutions during the COVID-19 pandemic. We decided to test the feasibility of structured training in EUS with virtual e-classes with live cases. The aim of this study was to assess the feasibility of a virtual EUS training course with objective end points. Patients and methods Twenty-one trainees were trained on a virtual platform over 16 classes of 90 minutes each, over 3 months. The virtual training screen had two equal parts, one showing the endoscopist’s hand movements, and another the resultant EUS display. The course curriculum included EUS anatomy of the mediastinum, pancreatico-biliary region and rectum. The assessment was done on videos of procedures performed by trainees. Results Twenty trainees performed 251 EUS procedures (range 8–25, mean 12.5 ± 4.9) at their institutions. At the end of the course, all students (100 %) could maneuver the echo-endoscope through to the duodenum. Fifteen trainees sent a video for final assessment. The successful specified area identification rates were 12 of 15 (80 %) for the subcarinal space, 10 of15 (66.6 %) for the head of the pancreas, 10 of 15 (66.6 %) for the common bile duct, and nine of 15 (60 %) for the tail of pancreas. The success rate of ability to get appropriate windows was 10 of 15 (67 %) for the subcarinal space, eight of 15 (53.3 %) for the head of the pancreas, seven of 15 (46.6 %) for the common bile duct and six of 15 (40 %) for the tail of pancreas. No adverse events were reported. Conclusions A virtual EUS training course with live cases appears feasible. It allows the possibility of training a large number of students. Further evaluation is needed, especially of virtual assessment methods and training benchmarks.

Aim: To evaluate the efficacy of open reduction and semirigid internal fixation in the management of displaced pediatric mandibular fractures. Method: Ten patients with displaced mandibular fractures treated with 1.5 mm four holed titanium mini-plate and 4 mm screws which were removed within four month after surgery. Results: All cases showed satisfactory bone healing without any growth disturbance. Conclusion: Open reduction and rigid internal fixation (ORIF) with 1.5 mm titanium mini- plates and 4 mm screws is a reliable and safe method in treatment of displaced paediatric mandibular fractures.

Dieulafoy's lesion (DL) is a relatively rare, but potentially life-threatening condition. It accounts for 1-2% of acute gastrointestinal bleedings. Its serious nature makes it necessary for early diagnosis and treatment. This is a case report of a patient who presented with life-threatening haematemesis due to gastric Dieulafoy's that was successfully treated laparoscopically after failed endotherapy.