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Resting energy expenditure (REE) and metabolic fuel utilization (carbohydrate or fat) proxied by respiratory quotient (RQ) from indirect calorimetry enables more precise measurement of energy needs and fat oxidation capacity. The study compared the effectiveness of providing energy expenditure information during diet and exercise weight intervention versus standard of care (SOC) on weight loss outcomes. Fifty-two participants with obesity were recruited from a specialist weight loss service, randomized 1:1 to intervention (INT) or SOC only. Participants in INT received four-weekly dietetic counselling, using biofeedback from energy expenditure data to recommend caloric restriction and physical activity goals, in addition to SOC. The primary outcome was the mean difference in weight loss between both groups after 24 weeks. Secondary outcomes include participant acceptability and tolerability using indirect calorimetry. Participants in the INT group demonstrated additional weight loss (-2.3 kg [95% CI: -3.1, -1.5]; p <.001), reduced waist circumference (-3.9 cm [95% CI: -5.48, -2.26]; p <.001), and decreased body fat percentage (-1.5% [95% CI:-2.31, -0.72], p <.001), compared to SOC, after adjusting for baseline body mass index, age, and sex. Forty-two percent (10/24) of participants in INT group achieved the minimum clinically significant threshold of 5% weight loss from baseline, compared to 8% (2/26) in the SOC group (p = .007). Participant acceptability and tolerability of indirect calorimetry were high, with mean scores of 4.5 ± 0.6 and 4.2 ± 0.7 (5-point Likert scale). The study establishes the safety and practical integration of biofeedback using indirect calorimetry promoting improved self-regulation and enhancing weight loss., (© 2024 The Author(s). Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Objectives: The 24-month, prospective, non-interventional, European multicenter A-SURE study evaluated the real-world effectiveness of prophylaxis using an extended half-life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half-life (SHL) FVIII products in patients with hemophilia A., Methods: Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses., Results: Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of -0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of -54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development., Conclusions: rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Pancreas Transplantation (PT) provides optimal treatment for patients with severe complicated Type 1 Diabetes Mellitus (T1DM). Restoration of beta-cell mass allows return to euglycaemia and insulin independence. We aimed to examine its impact on the secondary complications associated with severe T1DM including diabetic eye disease, neuropathy and cardiovascular disease., Methods: A database search using MedLINE to identify publications to April 2023 was conducted. Searches were performed using MeSH terms 'Pancreas Transplantation' AND 'Diabetes Mellitus, Type 1' 'Diabetic Retinopathy' OR 'Heart Disease' OR 'Cardiovascular Diseases' OR 'Peripheral Vascular Disease' OR "Amputation' OR 'Neuropathy.", Results: All articles were retrospective with 51.1 % (n = 23) case control studies and 48.9 % (n = 22) cohort studies. 82.2 % (n = 37) examined simultaneous pancreas and kidney (SPK) transplantation and 17.8 % (n = 8) analysed pancreas transplant alone (PTA). Heterogenous outcomes metrics were employed. 15 studies examined diabetic retinopathy (DR) with 53.3 % (n = 8) demonstrated improvements after PT, while the remainder (n = 7) exhibited stabilisation. 16 studies assessed neuropathy and 87.5 % (n = 14) demonstrated beneficial effects of PT on nerve conduction studies, vibration perception threshold or corneal confocal microscopy. There was a positive effect on cardiovascular disease by reduction in the incidence of cardiac events, improvement in metabolic profile and increased left ventricular ejection fraction. 14 studies examined cardiovascular disease (71.4 % (n = 10) improvement; 14.2 % (n = 2) stabilisation; 14.2 % (n = 2) progression)., Conclusion: SPK and PTA have beneficial effects in ameliorating or stabilising diabetes complications. Future work should seek to reduce heterogeneity of outcome metrics assessing T1DM complication profile to facilitate robust comparison of beta-cell replacement interventions., 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. DD is a UKRI Medical Research Council and Breakthrough T1D Clinical Research Training Fellow (MR/X00211X/1)., (Copyright © 2025. Published by Elsevier Inc.)

A short systematic review was undertaken to assess whether intradermal sterile water injections (ISWI) provide effective pain relief in adult patients presenting to the Emergency Department (ED) with renal colic. MEDLINE, Embase, Cochrane and Google Scholar databases were searched, identifying seven relevant studies. Study information, patient characteristics, key results and methodological weaknesses were tabulated. Our results indicate that ISWI provides rapid and effective pain relief within the first 15-30 min, comparable to non-steroidal anti-inflammatory drugs, with fewer adverse effects. The short follow-up periods, exclusion of more comorbid patients and variability in study design limit the generalisability of the findings. Further research is needed to establish the long-term effectiveness of ISWI in the management of renal colic in the ED., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Importance: Development of myocardial fibrosis in patients with aortic stenosis precedes left ventricular decompensation and is associated with an adverse long-term prognosis., Objective: To investigate whether early valve intervention reduced the incidence of all-cause death or unplanned aortic stenosis-related hospitalization in asymptomatic patients with severe aortic stenosis and myocardial fibrosis., Design, Setting, and Participants: This prospective, randomized, open-label, masked end point trial was conducted between August 2017 and October 2022 at 24 cardiac centers across the UK and Australia. Asymptomatic patients with severe aortic stenosis and myocardial fibrosis were included. The final date of follow-up was July 26, 2024., Intervention: Early valve intervention with transcatheter or surgical aortic valve replacement or guideline-directed conservative management., Main Outcomes and Measures: The primary outcome was a composite of all-cause death or unplanned aortic stenosis-related hospitalization in a time-to-first-event intention-to-treat analysis. There were 9 secondary outcomes, including the components of the primary outcome and symptom status at 12 months., Results: The trial enrolled 224 eligible patients (mean [SD] age, 73 [9] years; 63 women [28%]; mean [SD] aortic valve peak velocity of 4.3 [0.5] m/s) of the originally planned sample size of 356 patients. The primary end point occurred in 20 of 113 patients (18%) in the early intervention group and 25 of 111 patients (23%) in the guideline-directed conservative management group (hazard ratio, 0.79 [95% CI, 0.44-1.43]; P = .44; between-group difference, -4.82% [95% CI, -15.31% to 5.66%]). Of 9 prespecified secondary end points, 7 showed no significant difference. All-cause death occurred in 16 of 113 patients (14%) in the early intervention group and 14 of 111 (13%) in the guideline-directed group (hazard ratio, 1.22 [95% CI, 0.59-2.51]) and unplanned aortic stenosis hospitalization occurred in 7 of 113 patients (6%) and 19 of 111 patients (17%), respectively (hazard ratio, 0.37 [95% CI, 0.16-0.88]). Early intervention was associated with a lower 12-month rate of New York Heart Association class II-IV symptoms than guideline-directed conservative management (21 [19.7%] vs 39 [37.9%]; odds ratio, 0.37 [95% CI, 0.20-0.70])., Conclusions and Relevance: In asymptomatic patients with severe aortic stenosis and myocardial fibrosis, early aortic valve intervention had no demonstrable effect on all-cause death or unplanned aortic stenosis-related hospitalization. The trial had a wide 95% CI around the primary end point, with further research needed to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT03094143.

Backgrounds/aims: Irreversible electroporation (IRE) may have a potential application as either a "back-up therapy" or for margin accentuation during trial dissection of locally advanced pancreatic cancer (LAPC). The aim of this report was to describe our experience with IRE in terms of its potential applications mentioned above., Methods: A clinical policy to use IRE in LAPC patients undergoing exploratory surgery after neoadjuvant therapy (NAT) was initiated in 2017. If resection was feasible, IRE was used for margin accentuation. If not, then IRE was undertaken as a "back-up therapy" of non-resectable tumor. Data on baseline characteristics, perioperative 90-day morbidity, recurrence-free survival (RFS) and overall survival (OS) were collected., Results: IRE was successfully performed in 18 (95%) patients. IRE was abandoned in one case for technical reasons. Nine patients who were found to have an unresectable disease underwent IRE as a "back-up therapy" while the remaining patients received IRE for margin accentuation. Complications were recorded in 33% patients. There was no procedure-related mortality. In the group receiving IRE for margin accentuation, the median RFS was 10.0 months (range, 4.5-15.0 months). The median OS of our cohort was 22 months (range, 14.75-27.50 months)., Conclusions: This report shows that in patients with LAPC undergoing exploratory surgery following NAT, IRE seems technically feasible for margin accentuation or as a "back-up therapy". More data are needed to determine procedure-related morbidity, mortality, and any effects of IRE on cancer-related survival.

Data on the impact of ethnic and socioeconomic factors on Chimeric antigen receptor (CAR) T-cell therapy (access and outcomes are limited, but key to understand whether results from the registration trials are generalizable to real-world patient populations. Here, we analysed ethnicity, socioeconomic deprivation and referral patterns in a cohort of 314 large B-cell lymphoma patients approved for third-line CD19 CAR-T across three large UK CAR-T centres. Patients from deprived areas had a lower infusion rate compared to low deprivation areas (73% vs. 86%, p = 0.04). CAR-T response rates, toxicities, progression-free survival or non-relapse mortality were similar with respect to ethnicity or deprivation. We did not find evidence of referral barriers according to ethnicity, but potential regional barriers for socioeconomically deprived patients in two of three centres. Intention-to-treat overall survival was significantly inferior in patients from deprived areas (1-year OS 44.5% vs. 58% for high vs. low deprivation; p = 0.02), likely reflecting general health disparities and higher drop-out rates in this group. Our data suggest similar outcomes of CD19 CAR-T-treated patients across a socioeconomically and ethnically heterogeneous real-world population. Results demonstrate broad access to CAR-T within the UK national delivery system, but the high drop-out rate and potential regional referral barriers for deprived communities should be further investigated., (© 2025 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Head and neck squamous cell carcinoma from unknown primary (HNSCCUP) is a rare and challenging condition. This study aimed to investigate the diagnostic pathways of suspected HNSCCUP patients in the United Kingdom., Methods: A retrospective observational cohort study was conducted, over 5 years from January 2015, in UK Head and Neck centres of consecutive adults undergoing 18F-Fluorodeoxyglucose-PET-CT (PET-CT) within 3 months of diagnosis with metastatic cervical squamous cell carcinoma. Patients with no primary site on examination and no previous head and neck cancer were eligible., Results: Data for 965 patients were received from 57 centres; 68.5% were HPV-related disease. Three investigation cycles were observed: ultrasound with biopsy, cross-sectional imaging (MRI and/or CT) and PET-CT, at median times of 17, 29.5 and 46 days from referral. No primary was identified on PET-CT in 49.8% (n = 478/960). Diagnostic tonsillectomy was performed in 58.2% (n = 278/478) and tongue base mucosectomy (TBM) in 21.7% (n = 104/479). Ipsilateral tonsillectomy carried the highest diagnostic yield (18.7%, n = 52/278), followed by TBM (15.4%, n = 16/104). Contralateral tonsillectomy, performed in 49.0% (n = 234/478), carried the lowest yield (0.9%, n = 2/234). PET-CT with concurrent MRI was associated with higher primary site detection than PET-CT with concurrent CT (p = 0.003). A minority of patients undergoing treatment with curative intent received first-definitive-treatment within 62 days of referral (15.2%, n = 77/505, median 92 days, IQR: 71-117)., Conclusions: Most patients experienced a protracted diagnostic pathway and waited over 3 months for definitive treatment. Earlier PET-CT with concurrent MRI may expedite diagnosis. TBM appears more productive than contralateral tonsillectomy for primary site detection., (© 2025 John Wiley & Sons Ltd.)

The genus Neisseria includes two major human pathogens: N. meningitidis causing bacterial meningitis/septicemia and N. gonorrhoeae causing gonorrhoea. Mathematical models have been used to simulate their transmission and control strategies, and the recent observation of a meningococcal B (MenB) vaccine being partially effective against gonorrhoea has led to an increased modeling interest. Here we conducted a systematic review of the literature, focusing on studies that model vaccination strategies with MenB vaccines against Neisseria incidence and antimicrobial resistance. Using journal, preprint, and grey literature repositories, we identified 52 studies that we reviewed for validity, model approaches and assumptions. Most studies showed a good quality of evidence, and the variety of approaches along with their different modeling angles, was assuring especially for gonorrhoea studies. We identified options for future research, including the combination of both meningococcal and gonococcal infections in studies to have better estimates for vaccine benefits, and the spill over of gonorrhoea infections from the heterosexual to the MSM community and vice versa. Cost-effectiveness studies looking at at-risk and the wider populations can then be used to inform vaccine policies on gonorrhoea, as they have for meningococcal disease., Competing Interests: RB performs contract research on behalf of UKHSA for GSK, Pfizer, and Sanofi. RV has received research funding on behalf of Public Health England from GSK and Gilead Sciences in the past. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist., (Copyright: © 2025 Metelmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. P.F. Halloran holds shares in Transcriptome Sciences Inc., a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between Transcriptome Sciences Inc. and Thermo Fisher Scientific, and by a research grant from Natera, Inc. P.F. Halloran is a consultant to Natera, Inc. and Argenx BV. The other authors have declared no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574 ., Competing Interests: Competing interests: K.C.: consulting/advisory role: Roche, Takeda, Celgene, Atara, Gilead, KITE, Janssen, Incyte and AbbVie; speakers’ bureau: Roche, Takeda, KITE, Gilead and Incyte; conferences/travel support: Roche, Takeda, KITE, Janssen and BMS. G.I.: honoraria and travel support: Novartis, Kite/Gilead, Bristol Myers Squibb, AbbVie, Autolus, Sandoz, Miltenyi and AstraZeneca. E.T.: speaker fees: Astellas, Jazz, Kite/Gilead, Pfizer and Vertex; ad boards: Autolus, BMS/Celgene, Jazz, Janssen and Vertex. M.P.: owns stock in and has research funding and salary contribution from Autolus. D.I.: travel grants and honoraria: Kite/Gilead and Janssen. T.M.: travel grants: Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene/BMS, Kite/Gilead, Janssen and Takeda; honoraria for advisory board meetings: Kite/Gilead, Amgen, Novartis, Pfizer, Celgene/BMS, Daiichi Sankyo, Atara, Roche and Janssen; honoraria for lectures: Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis, Celgene/BMS, Pfizer and Incyte; research funding: Janssen, AstraZeneca and Novartis. T.M.: consulting/advisory role: Roche/Ventana, Haematogenix and Autolus. P.M.: Autolus: stock holder and research funding. UCL business: patent royalties. All employees of Autolus have no competing interests., (© 2024. The Author(s).)

Factor H-Binding Protein (fHbp) is a key component of meningococcal vaccines such as MenB-fHbp, licensed in the EU, UK, and other countries. Sufficient expression of fHbp on the bacterial surface is necessary for vaccine-induced antibodies to bind and exert bactericidal activity. The flow cytometric MEASURE assay quantifies fHbp expression in vitro, and previous studies have shown that strains with a Mean Fluorescence Intensity (MFI) >1000 are likely to be killed by MenB-fHbp-induced antibodies. This study assessed fHbp peptide distribution and expression among 451 invasive group B strains collected in 2016 across England, Wales, and Northern Ireland (EW&NI), Germany, Italy, and Spain. We found that 92% of the strains expressed fHbp above the MFI 1000 threshold. The strain distribution across EW&NI, Germany, and Italy was similar, with coverage ranging from 92.1% to 94.6%, dominated by a small number of clonal complexes and fHbp peptides. Although, the Spanish subset had a higher proportion of lower-expressing strains, particularly clonal complex 213, resulting in a lower predicted coverage for Spain (84%). These results, along with other published MEASURE data, can provide a basis for genotypic MenB-fHbp coverage predictions, however, inclusion of the upstream intergenic sequence of the fHbp gene in the prediction improved its accuracy by distinguishing between low- and high-expressing strains. Future MEASURE analyses of strains with less common fHbp variants would serve to further refine vaccine coverage predictions.

Aims/Background Symptomatic abdominal aortic aneurysms carry significant mortality risk. This is supplemented by the Royal College of Emergency Medicine guidelines which suggest imaging for patients 50 years of age or older presenting with unexplained abdominal, flank, or back pain. This study aimed to evaluate the prevalence and mortality rates of patients with symptomatic abdominal aortic aneurysms in a high-risk population and to assess scanning rates in the accident and emergency department. Methods Retrospective analysis of patients presenting to the accident and emergency department at a district general hospital over 6 months was performed. Patients 50 years of age or older presenting with abdominal, flank, or back pain were included. Collected data points included; whether or not a scan was performed in the emergency department, the modality of imaging, whether an abdominal aortic aneurysm was identified on the scan, the age of patients with an abdominal aortic aneurysms identified on the scan, size of the identified abdominal aortic aneurysms, primary diagnosis at the time of review in the emergency department, and all-cause mortality rates. Results 361 patients were identified to have an indicated scan, of which only 122 (33.8%) had a scan in the emergency department. In the syndromic group, the prevalence and 30-day mortality of patients with an abdominal aortic aneurysm were 5.5% and 1.1% respectively. Only 12 out of 20 patients with an abdominal aortic aneurysm were identified in the emergency department. Conclusion The criteria outlined by the Royal College of Emergency Medicine does well at identifying patients with abdominal aortic aneurysms when followed. However, this study reveals that scanning rates in the emergency department are low. The encouragement of scanning and improved ultrasound skills among emergency medicine clinicians can reduce missed diagnoses. Additionally, we recommend further studies to assess the mortality rates of emergent abdominal aortic aneurysm presentations.

Background: Diabetic nephropathy remains a strong risk factor for chronic kidney disease progression. Hemoglobin A1C (HBA1C) has historically been used as a marker for complications related to diabetes. The purpose of this study is to examine the relationship between HBA1C and clinical complications in a patient population with end stage renal disease., Methods: This was a prospective study performed using patients from multiple outpatient dialysis centers in Texas, United States. All patients included patients must have end stage renal disease and were receiving either hemodialysis or peritoneal dialysis. An HBA1C ≥ 6.5% was used as a cutoff to differentiate patients with well controlled versus uncontrolled diabetes in this population., Results: HBA1C ≥ 6.5% was strongly associated with both minor (P = 0.0014) and major (P = 0.006)amputation. Patients with HBA1C ≥ 6.5% was associated with lower mortality compared to patients with HBA1C < 6.5%, P = 0.007., Conclusions: HBA1C remains a reliable marker for amputation in patients with end-stage renal disease; however, there is skepticism in using HBA1C as a marker for survival in these patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We report a case of non-ST elevation myocardial infarction in a 36-year-old man with Erdheim-Chester disease (ECD). Multimodality assessment revealed acute coronary thrombus with simultaneous recurrent pulmonary embolism in spite of compliance with a direct oral anticoagulant. Prior case reports of acute myocardial infarction in this population have not outlined the role of catheter based intravascular assessment and treatment in this rare clinical entity., Competing Interests: No conflict of interest., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Bullying, harassment, and undermining behaviour has a profound detrimental effect on the multi-professional team, patient safety, and clinical outcomes. Bullying creates a poor working and training environment , increasing stress, damaging confidence, and impairing wellbeing. We sought to characterize the prevalence and nature of bullying, harassment and undermining within cardiothoracic surgery in the United Kingdom and Republic of Ireland., Methods: A 21-question survey was sent to all members of the Society for Cardiothoracic Surgery (SCTS) in Great Britain & Ireland. Participants were asked about baseline demographics and their experience of bullying as victim or witness., Results: The survey was sent to 1,326 SCTS members and there were 278 responses (21.0%). Most respondents were physicians (75.2%, n = 209) and most were male (58.3%, n = 162). The majority (79.1%, n = 220) had experienced or witnessed bullying in some form within the last three years (or appointment as a professional). This was experienced directly the majority of respondents (62%, n=136) and a large minority (23.6%, n = 52) had witnessed it in their workplace CONCLUSIONS: Bullying is observed or experienced by a concerning proportion of healthcare professionals working in cardiothoracic surgery. Ongoing initiatives to reduce this within British and Irish healthcare need to be strengthened to improve prevention, reporting and investigation, and support for victims and perpetrators to keep workplaces safe for teams and individuals and to facilitate the delivery of the best possible patient care., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: A recent paper by Moore, Lowe and Cox has proposed guidelines for diagnosing noise-induced hearing loss (NIHL). It is referred to here as the MLC guidelines. Our aim was to assess the specificity of those guidelines (i.e., freedom from false-positive outcomes) and compare with pre-existing guidelines., Design: We applied the MLC guidelines and pre-existing guidelines to three data sets composed of adults who do not have a history of material noise exposure and therefore cannot have NIHL., Setting: National Health Service (NHS) ENT clinic., Participants: Five hundred thirty-six patients with hearing difficulty and/or tinnitus who denied material noise exposure. Two large archival population studies of hearing were also assessed, which included 3250 participants without material noise exposure., Main Outcome Measure: False-positive outcome from guidelines., Results: The MLC guidelines demonstrated moderate or high false-positive rates overall, the magnitude depending on the noise exposure scenario and whether clinical or population samples were considered. For the procedure applicable to steady broadband noise exposure, the false-positive rate averaged 56% in the population samples, compared to 31% for previous guidelines. For exposure to intense impulse sounds, the MLC guidelines take a different approach and the false-positive rate was about 70% in the population samples and even higher in the clinic sample. For exposure to intense tones, the MLC guidelines take yet another approach and the false-positive rate reached 80%., Conclusions: The MLC guidelines demonstrate poorer specificity than previous guidelines. Medical experts should be aware of their poor specificity and consequential likelihood of false-positive diagnoses of NIHL., (© 2024 The Author(s). Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Pharmacogenetic-guided prescribing can lead to more accurate medicine selection and dosing, improving patient outcomes and leading to better use of health care budgets. Loss-of-function variants in CYP2C19 influence an individual's ability to metabolize clopidogrel, increasing the risk of secondary vascular events following ischemic stroke and percutaneous coronary intervention. In acute clinical contexts, centralized laboratory-based testing is too slow to inform timely clinical decision-making. This work reports the development and analytical validation of the Genedrive CYP2C19 ID Kit, which provides rapid point-of-care genotyping from a buccal swab in approximately 1 hour. Buccal samples were collected from a total of 204 individuals between September 2023 and July 2024, alongside a blood or saliva sample for comparison with laboratory testing. In the final cohort of 202 patients, all point-of-care results were concordant with laboratory testing. In this assessment, the sensitivity and specificity of the CYP2C19 ID Kit was 100% (95% CI, 95.0%-100%) and 100% (95% CI, 97.2%-100%), respectively. The failure rate of the CYP2C19 ID Kit was 0.98%. This study confirms the analytical validity of the Genedrive CYP2C19 ID Kit. The Genedrive system is able to provide an accurate, rapid, noninvasive alternative to standard laboratory testing and can be used as a point-of-care test in the clinical environment., Competing Interests: Disclosure Statement J.H.M., V.S., and W.G.N. are cofounders of Fava Health, a health technology consultancy. Genedrive was one of several industry coapplicants with the authors on the Innovate UK-funded Development and Validation of Technology for Time Critical Genomic Testing Programme (10058536), which supported this work. The other authors have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Lower diversity of the gut microbiome prior to allogeneic haematopoietic cell transplantation (HCT) correlates with reduced survival after the intervention. Most patients undergoing HCT for a haematological malignancy have previously received intensive chemotherapy, resulting in prolonged neutropenic episodes requiring broad-spectrum antibiotics; use of these has been linked to reduced microbiome diversity. Intestinal microbiota transplant (IMT) is a novel treatment approach that restores this diversity. We hypothesised that IMT performed prior to initiation of HCT conditioning restores microbiome diversity during the early stages of HCT, leading to decreased frequency of complications and improved outcomes of HCT., Methods and Analysis: 50 adult patients receiving allogeneic HCT will be recruited into this phase IIa trial and randomised 1:1 to receive capsulised IMT or matched placebo shortly prior to initiation of HCT conditioning and followed for up to 12 months. The primary outcome will be to assess the increase in alpha diversity between pre-IMT and that measured at ~42 days after IMT administration (day +28 of HCT), comparing the difference between patients receiving IMT compared with placebo. Secondary outcomes will include tolerability, the dynamics of gut microbiome diversity metrics and taxonomy over all time points assessed, as well as clinical outcomes (including burden of invasive infections, days of fever, admission to intensive care, development of graft-vs-host disease and mortality)., Ethics and Dissemination: This study was approved by a UK Research Ethics Committee (REC reference: 23/NE/0105). Dissemination of results will be in concert with patient and public involvement group input and is expected to be primarily via abstract presentation at conferences and manuscripts in peer-reviewed journals., Trial Registration Numbers: NCT6355583; EudraCT: 2022-003617-10., Competing Interests: Competing interests: GW is an employee of and holds share in GSK. All other authors have nothing to report, (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)

Myeloid chimerism better reflects donor stem cell engraftment than whole-blood chimerism in assessing graft function following allogeneic hematopoietic stem cell transplant (HCT). We describe our experience with 130 patients aged younger than 18 years, treated with allogeneic HCT using bone marrow or PBSC from HLA-matched donors for non-malignant diseases, whose pre-transplant conditioning therapy included alemtuzumab and who were monitored with lineage-specific chimerism after transplant. At 6 years post-transplant, overall survival (OS) was 91.1% and event-free survival (EFS) was 81.5%, with no grade III-IV acute GvHD or chronic GVHD observed. Recipient T-cells did not contribute to graft loss. Mixed T-cell chimerism (MC) did not affect EFS, and there was no connection between T-cell chimerism and myeloid chimerism in patients with MC or graft loss. MC significantly correlated with virus infection; more children with MC were CMV seropositive than those with complete chimerism (CC). Additionally, MC was more common in patients with CMV viramia post-transplant. CD8 T-cell reconstitution was affected by viral reactivation, including CMV, with CD8 T-cell counts higher in the MC group than in the CC group. Mixed T-cell chimerism is due to autologous, virus-specific, predominantly CD8, T-cell expansion, and is protective and not deleterious to the recipient.

Laparoscopic cholecystectomy is a widely performed procedure, with securing the cystic duct being a critical step to prevent bile leakage. Traditional metal clips are commonly used, but alternative methods, such as non-absorbable polymer clips, absorbable clips, sutures, and ultrasonic shears, are also utilized. This systematic review and meta-analysis evaluates the safety and efficacy of various cystic duct securing techniques. Following PRISMA guidelines, a comprehensive search was conducted across the EMBASE, MEDLINE, and Cochrane databases without date restrictions. Eligible studies compared different techniques for cystic duct closure in laparoscopic cholecystectomy, focusing on bile leakage as a primary outcome. Data extraction and synthesis were performed using a binary random-effects model. Meta-analyses were conducted for absorbable clips, sutures, hem-o-lok clips, and ultrasonic devices compared to standard metal clips. A total of 26 studies met the inclusion criteria. Absorbable polymer clips demonstrated a statistically significant reduction in postoperative bile leakage compared to metal clips (OR 0.159; 95% CI 0.031-0.818; P=0.028). In contrast, no significant differences were observed when comparing metal clips with suture ties (OR 0.459, 95% CI 0.139-1.522, P =0.203), non-absorbable clips (OR 0.166, 95% CI 0.025-1.109, P =0.064), or the clipless technique with a harmonic device (OR 1.332, 95% CI 0.425-4.169, P =0.623)., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Verani et al.)

Background: Obecabtagene autoleucel (obe-cel) is an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy which uses an intermediate-affinity CAR to reduce toxic effects and improve persistence., Methods: We conducted a phase 1b-2 multicenter study of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease. The primary end point was overall remission (complete remission or complete remission with incomplete hematologic recovery) in cohort 2A. Secondary end points included event-free survival, overall survival, and safety., Results: Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obe-cel and were evaluable. In cohort 2A (94 patients; median follow-up, 20.3 months), overall remission occurred in 77% (95% confidence interval [CI], 67 to 85), with complete remission in 55% (95% CI, 45 to 66) and complete remission with incomplete hematologic recovery in 21% (95% CI, 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and complete remission (≤20%) were rejected (P<0.001). In the 127 patients who received at least one obe-cel infusion (median follow-up, 21.5 months), the median event-free survival was 11.9 months (95% CI, 8.0 to 22.1); estimated 6- and 12-month event-free survival was 65.4% and 49.5%, respectively. The median overall survival was 15.6 months (95% CI, 12.9 to not evaluable); estimated 6- and 12-month overall survival was 80.3% and 61.1%, respectively. Grade 3 or higher cytokine release syndrome developed in 2.4% of the patients, and grade 3 or higher immune effector cell-associated neurotoxicity syndrome developed in 7.1% of the patients., Conclusions: Obe-cel resulted in a high incidence of durable response among adults with relapsed or refractory B-cell ALL, with a low incidence of grade 3 or higher immune-related toxic effects. (Funded by Autolus Therapeutics; FELIX ClinicalTrials.gov number, NCT04404660.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To compare cochlear implant (CI) speech perception outcomes in patients with sporadic vestibular schwannoma (VS) managed with observation, radiosurgery, or microsurgery., Study Design: Retrospective review., Setting: Eleven tertiary academic medical centers., Patients: One hundred patients with sporadic VS who received an ipsilateral CI., Interventions: Ipsilateral cochlear implantation., Main Outcome Measures: Pure-tone thresholds, monosyllabic speech perception testing scores, and rates of open-set speech acquisition., Results: Of the 100 patients studied, 54 underwent microsurgery, 26 underwent radiosurgery, 19 continued observation, and 1 underwent multimodal therapy. Among all patients, the median post-implantation pure-tone average was 31 dB (interquartile range [IQR] 25-39 dB) and the median monosyllabic speech perception score was 30% (IQR 0-60%) at a median of 12 months (IQR 5-25 months) post-implantation. Patients who were managed with microsurgery (median speech perception score 11%, IQR 0-52%) exhibited poorer implant outcomes overall compared with those managed with observation (median speech perception score 52%, IQR 40-72%) or radiosurgery (median speech perception score 30%, IQR 16-60%). Open-set speech perception was achieved in 61% of patients managed with microsurgery, 100% with observation, and 80% with radiosurgery. In a multivariable setting, those managed with observation (p = 0.02) or who underwent radiosurgery (p = 0.04) were significantly more likely to achieve open-set speech perception compared with patients who underwent microsurgery., Conclusions: Cochlear implants offer benefit in selected patients with sporadic VS. Although achieved in over half of people after microsurgery, open-set speech perception is more reliably attained in patients who are treated with observation or radiosurgery compared with microsurgical resection. These data may inform patient counseling and VS tumor management in people who may benefit from implantation., (Copyright © 2024, Otology & Neurotology, Inc.)

Osteoarthritis (OA) of the foot and ankle is prevalent and often debilitating, necessitating effective treatment options. This study evaluates the analgesic efficacy of corticosteroid injections in individual foot and ankle joints. Stepping Hill Hospital conducted a retrospective audit of 166 patients who received guided corticosteroid injections. We assessed pain relief using a questionnaire to obtain numerical pain scores before and after the injections. Of the 166 patients evaluated, 51% (85) reported complete pain relief and 32% (53) reported partial relief following the injections, with a significant mean pain score reduction from 8.45 (pre-injection) to 3.42 (post-injection) (p<0.05). A total of 83 patients (47.6%) sought re-injection, which also provided significant pain relief, although slightly less effective than the first injection (pain scores: 3.42 (pre-injection) vs. 4.90 (post-injection), p<0.05). Patient satisfaction was 83% overall, with the highest satisfaction at tarsometatarsal joint injections (95%). Corticosteroid injections for foot and ankle OA demonstrate significant analgesic benefits with high patient satisfaction. While first injections were most effective, re-injections remain a viable option, particularly for patients postponing surgery. These results support corticosteroid injections as an essential component of OA management in foot and ankle conditions., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vincent et al.)

Patellar tendinopathy is a highly prevalent clinical diagnosis supported by ultrasound changes. Numerous interventions are targeted at improving both symptoms and structure of dysfunctional tendons, however little is known of the diagnostic value in a changing ultrasound profile whilst patient-reported outcome measures (PROMs) determine recovery. The aim is to assess if changes in ultrasound measures are congruent with changes in Victorian Institute of Sports Assessment - Patella (VISA-P) scores, thereby supporting the use of ultrasound to assess patellar tendinopathy during symptom improvement. Four databases (PubMed, Web of Science, Embase, CINAHL) were searched in January 2019. Studies selected contained ultrasound and VISA-P scores from ≥ 2 type points. All included studies were quality assessed depending on the type and available data and underwent meta-analysis. A total of 10 papers of varying study types, limited to high quality, were synthesized. The meta-analysis indicated that changes in ultrasound measures were not congruent with changes in the VISA-P score. The variation in study quality, along with significant heterogeneity of ultrasound measure outcomes and reporting may influence the congruency of the data, but the association between gradual structure change and varying vascularity with pain or function is questionable throughout tendinopathy literature. The small study yield coupled with omission of data, along with alterations to form coherent analysis may impact outcomes, with an absence of homogeneity throughout studies. Ultrasound assessment is not useful in the follow-up of patellar tendinopathy after treatment and is of limited use as an indicator of normal function., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Parks et al.)

In recent years, major advances in our understanding of risk factors implicated in the development of cardiovascular disease (CVD), in available tools for early detection of CVD, and in effective interventions to prevent subclinical or clinically manifest disease, have led to an increasing appreciation of prevention as a major pillar of cardiovascular (CV) medicine. Preventive Cardiology has evolved into a dynamic sub-speciality focused on the promotion of CV health through all stages of life, and on the management of individuals at risk of developing CVD or experiencing recurrent CV events, through interdisciplinary care in different settings. As the level of knowledge, specialized skills, experience, and committed attitudes related to CV prevention has exceeded core cardiology training, the European Association of Preventive Cardiology (EAPC) has placed major emphasis on continuous education and training of physicians and allied professionals involved in CV prevention, with the aim of setting standards for practice and improving quality of care. The EAPC recognizes the need for a comprehensive educational offer across different levels of training (from core cardiology to sub-speciality to expert training) as well as the need for interdisciplinary approaches that will promote synergies among allied professionals involved in CV prevention. This statement by the EAPC aims to highlight current gaps and unmet needs and to describe the framework to help standardize, structure, and deliver comprehensive, up-to-date, interactive, and high-quality education using a combination of traditional and novel educational tools. The document aims to form the basis for ongoing refinements of the EAPC educational offer, with the ultimate goal of ensuring that new evidence in the field will translate to better CV practice and improved outcomes for our patients., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Patients with Gorlin (basal cell nevus) syndrome (GS) have numerous phenotypic abnormalities due to over-activity of the hedgehog (HH) signaling pathway, most commonly due to a heritable mutation in the PTCH1 gene, which encodes a major inhibitor of this pathway. HH inhibitors (HHi) taken orally can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit:risk ratio, we have developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop treatment with oral HHis., Objectives: This study attempts to determine whether or not Patidegib Topical Gel, 2% or 4%, can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects that are typical of oral HHi treatment., Methods: We conducted a small, randomized, double blinded Phase 2A trial at two sites in the United Kingdom to assess the clinical and molecular efficacy and adverse effects of 6 months of twice daily application of Patidegib Topical Gel to the entire face as well as to treatment-targeted surgically-eligible BCCs at other anatomical sites., Results: Post hoc analyses suggested that Patidegib Topical Gel reduced the number of new surgically-eligible BCCs and the level of HH signaling with minimal adverse effects., Conclusions: Patidegib Topical Gel warrants further clinical development., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) characterised by endoscopic inflammation, progressive bowel damage and gastrointestinal lesions. Although treatment strategies for CD have traditionally focused on a stepwise pharmacological approach to achieve clinical remission or symptom resolution, these treatment goals correlate poorly with disease activity. Thus, achieving full clinical remission and full endoscopic healing alone may be insufficient, as patients may remain at risk of inflammatory complications. Individualised 'treat-to-target' (T2T) pharmacological and treatment approaches represent a promising strategy for improving endoscopic remission and symptom resolution among patients with CD. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) and STRIDE-II guidelines, launched in 2013 and later renewed, identified individualised targets for a T2T therapeutic approach for patients with IBD. These guidelines facilitate the individualisation of target treatment goals through evidence-based, long-term (health-related quality of life, absence of disability, endoscopic healing) and intermediate/short-term (abdominal pain, stool frequency, normalisation of biomarker levels) treatment targets, allowing patients and clinicians to consider the risk-to-benefit balance of goals and selected therapeutic strategies. This article aims to summarise the STRIDE-II guidelines and provide intellectual guidance for healthcare professionals to apply the STRIDE-II principles to current clinical practice in the United Kingdom (UK). Management recommendations for primary and secondary first-line non-responders are provided, along with suggestions for utilising the endoscopic outcomes scoring system in UK clinical practice., Competing Interests: KK reports speaker fees from AbbVie, Celltrion, Ferring, Galapagos, Janssen, Takeda and Tillotts and for other educational activities from AbbVie, Galapagos, Takeda, Tillotts. MS reports advisory fees from AbbVie, Bristol-Myers Squibb, Galapagos, Janssen, Sandoz, Samsung Bioepis, Takeda and Tillotts, as well as lecture fees from AbbVie, Bristol-Myers Squibb, Falk, Galapagos, Janssen, MSD and Takeda. AV reports research grants from Thermo Fisher Scientific; speaker fees from AbbVie, Celltrion, Ferring, Takeda and UCB pharma limited; and for other educational activities from AbbVie, Celltrion, Galapagos NV, Takeda and Tillotts. AL reports speaker and consulting fees from Bristol-Myers Squibb, Celltrion, Ferring, Janssen, Medtronic, Pfizer, Takeda and Vifor Pharma and for other educational activities from Celltrion., (© The Author(s), 2024.)

Background: Previous meta-analyses have yielded conflicting results on the optimal surgical treatment strategy in patients with synchronous colorectal liver metastases (sCRLM). This network meta-analysis aims to provide an overview on colorectal-, liver first and simultaneous resections to treat sCRLM., Methods: A search was conducted in MEDLINE, Embase and Cochrane CENTRAL (inception-July 11,2023). Pairwise and network meta-analyses were conducted to compare the three strategies, using colorectal-first resections as reference group., Results: Overall, 46 studies with a total of 20,991 patients were included, a significant portion at a high risk of bias. Simultaneous resections were associated with less blood loss (MD -145.44 ml, 95%CI -239.40 to -51.48) and shorter hospital stays (MD -6.39 days, 95%CI -7.78 to -4.99). Liver-first resections were associated with more transfusions (OR 1.89, 95%CI 1.04 to 3.42) and shorter hospital stays (MD -4.53 days, 95%CI -7.99 to -1.06). Simultaneous resections were associated with less incomplete macroscopic disease clearances (OR 0.33, 95%CI 0.12 to 0.92), while liver-first resections were associated with more incomplete macroscopic disease clearances (OR 2.80, 95%CI 1.16 to 6.73) and less microscopically radical (R0) resections (OR 0.64, 95%CI 0.45 to 0.90). There were no significant differences in morbidity, mortality, disease-free or overall survival., Conclusion: Based on meta-analysis of mainly observational studies, simultaneous resections were associated with less blood loss, shorter length of stay and more complete macroscopic disease clearances., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Blood pressure (BP) is a key contributor to the lifetime risk of preclinical organ damage and cardiovascular disease. Traditional clinic-based BP readings are typically measured infrequently and under standardized/resting conditions and therefore do not capture BP values during normal everyday activity. Therefore, current hypertension guidelines emphasize the importance of incorporating out-of-office BP measurement into strategies for hypertension diagnosis and management. However, conventional home and ambulatory BP monitoring devices use the upper-arm cuff oscillometric method and only provide intermittent BP readings under static conditions or in a limited number of situations. New innovations include technologies for BP estimation based on processing of sensor signals supported by artificial intelligence tools, technologies for remote monitoring, reporting and storage of BP data, and technologies for BP data interpretation and patient interaction designed to improve hypertension management ("digital therapeutics"). The number and volume of data relating to new devices/technologies is increasing rapidly and will continue to grow. This International Society of Hypertension position paper describes the new devices/technologies, presents evidence relating to new BP measurement techniques and related indices, highlights standard for the validation of new devices/technologies, discusses the reliability and utility of novel BP monitoring devices, the association of these metrics with clinical outcomes, and the use of digital therapeutics. It also highlights the challenges and evidence gaps that need to be overcome before these new technologies can be considered as a user-friendly and accurate source of novel BP data to inform clinical hypertension management strategies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others., Background: Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking., Methods: International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored 6 standardized case vignettes. This variability and the "within centers" variability were calculated for 2-fold scoring (no complication/grade A vs grade B/C) and 3-fold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula, postpancreatoduodenectomy hemorrhage, chyle leak, bile leak, and delayed gastric emptying. Interobserver variability is presented with Gwet AC-1 measure for agreement., Results: Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for 2-fold scoring was 68% (95% CI: 55%-81%, AC1 score: moderate agreement), and for 3-fold scoring 55% (49%-62%, AC1 score: fair agreement). The mean "within centers" agreement for 2-fold scoring was 84% (80%-87%, AC1 score; substantial agreement)., Conclusions: The interobserver variability for the ISGPS-defined complications of pancreatoduodenectomy was too high even though the "within centers" agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Irregular sleep duration may disrupt circadian rhythms and contribute to metabolic, behavioral, and mood changes, potentially increasing the risk for obesity. However, quantitative data on the relationship between sleep duration irregularity and weight change are lacking. In this prospective study, we analyzed data from 10,572 participants (mean age: 63 years) in the UK Biobank who wore accelerometers for a week between 2013-2015 and had two body mass index (BMI; kg/m 2 ) measurements on average 2.5 years apart. Irregular sleep duration was assessed by the within-person standard deviation (SD) of 7-night accelerometer-measured sleep duration. Participants with sleep duration SD >60 minutes versus ≤30 minutes had 0.24 kg/m 2 (95% CI: 0.08, 0.40) higher BMI change (kg/m 2 ), standardized to three-year intervals, and 80% (95% CI: 1.28, 2.52) higher risk for incident obesity, after adjusting for sociodemographic factors, shift work, and baseline BMI or follow-up period ( p -trend<0.02 for both). These associations remained consistent after adjusting for lifestyle, comorbidities, and other sleep factors, including sleep duration. Age, sex, baseline BMI, and genetic predisposition to higher BMI (measured with a polygenic risk score) did not appear to modify the association. Since irregular sleep duration is common, trials of interventions targeting sleep irregularity might lead to new public health strategies that tackle obesity., Competing Interests: Conflicts of Interest: MKR reports receiving consultancy fees from Eli Lilly and has modest stock ownership in GSK, unrelated to this work. The other authors have no conflicts of interest to declare.

Venous thromboembolism (VTE), particularly portal vein thrombosis, is common in patients with cirrhosis. Misconceptions around the increased bleeding risk in this patient group may lead to delayed and/or inadequate anticoagulation. This nutshell review focusses on the approach to management including the role of direct oral anticoagulants in the treatment of VTE in patients with cirrhosis., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

We report a case of a giant tortuous right coronary artery to coronary sinus fistula with severe tricuspid regurgitation in a 78-year-old female. The initial working diagnosis was based on clinical manifestations and echocardiography, further supported with computed tomography coronary angiography. The fistula was surgically closed with satisfactory results. This case highlights the rarity and complexity of giant right coronary artery fistulas, and the current challenges of diagnosing and managing these fistulas, particularly in older adults. It explores the role of imaging in clinical evaluation, and the ongoing need for research and monitoring of long-term postoperative outcomes., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: Following the CHAMPION-NMOSD trial, the FDA recently granted approval for ravulizumab, a humanized monoclonal antibody against complement C5 protein in AQP-4 seropositive neuromyelitis optica spectrum disorder (NMOSD). Similar to eculizumab, ravulizumab offers near-complete prevention of NMOSD relapses, but has a longer half-life, providing decreased infusion frequency and increased convenience for patients. While targeting the complement pathway has clear advantages, patients are at risk for infection with encapsulated organisms, in particular Neisseria meningitidis ., Areas Covered: In this paper, we discuss the details of the CHAMPION-NMOSD trial and discuss challenges in meningitis prevention and strategies for switching therapies., Expert Opinion: Ravulizumab improves on eculizumab's success as a highly effective NMOSD therapy by decreasing infusion frequency, thereby increasing patient convenience. We predict that ravulizumab will eventually replace eculizumab but may not have a similar impact on inebelizumab or satralizumab. Patients taking C5 complement inhibitors have an increased risk of serious meningococcal infections, such as invasive meningococcal disease (IMD), and have incomplete protection against IMD despite immunization. Thus, we recommend that in addition to standard pre-immunizations against Neisseria meningitidis , patients should also be assessed for starting on appropriate antibiotic prophylaxis against IMD, based on local resistance patterns.

This study investigated in-hospital outcomes and related factors in patients diagnosed with postearthquake crush syndrome after the earthquakes in Kahramanmaraş, Türkiye. One thousand twenty-four adult patients diagnosed with crush syndrome were analyzed. Data on demographic characteristics, clinical presentation, laboratory values, treatments, and outcomes were collected. A total of 9.8% of patients died during their hospital stay. Nonsurvivors were generally older, more likely to have preexisting chronic kidney disease, and faced more severe injuries and complications, including hypotension-shock, arrhythmias, elevated markers of renal dysfunction, and higher rates of acute kidney injury (AKI) and compartment syndrome. In addition, intensive care unit needs were higher. Multivariate analysis confirmed that age, injury severity, shock, high potassium, uric acid, and lactate levels on admission, development of AKI, compartment syndrome, and intensive care unit admission were significant predictors of mortality. Better disaster preparedness and improved health care infrastructure could be potential explanations for improved in-hospital mortality in the current era, as compared to previous earthquakes., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: The contemporary management of patients with colorectal cancer and synchronous liver metastases is complex. This study appraises the recommendations made by national/international guidelines for the diagnosis and management of patients with synchronous liver metastases from colorectal cancer., Methods: A systematic review of national and international guidelines published between 2011 and 2024 was carried out using PubMed, OvidSP and Guidelines International Network databases. The quality of guidelines was evaluated using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument. Guidelines were assessed for the quality of advice for specific scenarios. The protocol was registered with PROSPERO (CRD42021243744)., Results: The search strategy returned ninety unique articles with 11 guidelines eligible for inclusion. Of these, one (9 %) guideline defined 'synchronous disease' at outset, eight (73 %) recommended neoadjuvant chemotherapy as first intervention. Seven (64 %) guidelines supported synchronous hepatic resection with colectomy. One (9 %) recommended against synchronous surgery., Conclusions: This study demonstrates important variations between international clinical guidelines on diagnostic workup and management of synchronous liver metastases in colorectal cancer. [167 words]., Competing Interests: None., (© 2024 The Authors.)

Background: Endovascular aneurysm repair (EVAR) represents a pivotal advancement in the treatment of abdominal aortic aneurysm (AAA)., Objective: The primary objective of this study is to present a comprehensive overview of the EVAR service in a district-level vascular centre and to compare it with the national outcome to outline a service model for other district general hospitals., Method: Patients who underwent an EVAR procedure from 2015 over seven years were included. Retrospective data were collected from post-EVAR surveillance, and the National Vascular Registry (NVR) database was included., Result: A total of 99 patients were included. Most of the patients (96%) who underwent EVAR were over 65 years old at the time of the procedure and predominantly male, accounting for 90%. The 30-day post-EVAR mortality rate was low (0.9%). Most of the patients had no primary endoleaks (80%), which was almost comparable to the national standard (82.5%)., Conclusion: This study showed the feasibility of successful implementation and safety of the EVAR program in a small district-level hospital. The outcome was comparable to the national standard. This study has identified the strengths and areas for improvement in the EVAR programme in such a setting., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Clinical Audit Department issued approval P102. This retrospective study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and is in line with the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals. This study was approved by the relevant hospital body and all data were anonymised in view of data protection. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Avabde et al.)

Purpose: The objective of this consensus is to provide otolaryngologists with appropriate strategies in the management of external auditory canal (EAC) carcinoma., Methods: In the absence of randomized controlled trials, the consensus is based on expert opinions utilizing the Rand/UCLA appropriateness method [Fitch and Aguilar in The RAND/UCLA appropriateness method user's manual, RAND Corporation, Santa Monica, CA, 2001], drawing from existing literature and clinical experience., Results: The management recommendations are structured around 12 key areas, including: definition and pathology, pathogenesis, clinical manifestations, work-up, tumor staging system, surgical management of primary tumor, surgical management of the parotid gland and the temporomandibular joint, lymph node metastasis, radiotherapy, chemotherapy, reconstruction, and follow-up., Conclusion: Management strategies for EAC carcinoma rely on tumor extension and histopathological features. Surgical removal with free surgical margins or combination with radiotherapy, chemotherapy are most often the best options. Given the rarity of the disease, prospective, randomized, multi-institutional clinical trials should be designed to enable reliable comparisons of the outcomes of EAC carcinoma treatments, thereby providing evidence-based clinical data to establish widely accepted guidelines. It emphasizes the need for a multidisciplinary team to be involved in the management of EAC carcinoma, and regular follow-up should be implemented postoperatively., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Prescription opioids for noncancer pain in the United Kingdom have increased over the past 2 decades, alongside associated harms. Policies addressing opioid prescribing must be tailored to individual patient needs with specific disease systems. The aim of this study was to evaluate clinical conditions associated with new opioid initiation in noncancer pain using nationally representative UK data. Primary care electronic health records from January 1, 2006, to September 31, 2021, were used from the Clinical Research Practice Datalink to identify incident opioid prescriptions. Patient histories were reviewed using code lists for opioid-related conditions with a 5-year look-back for chronic conditions and a 1-year look-back for surgical indications before opioid initiation. In total, 3,030,077 new opioid use episodes in 2,027,402 patients were identified, with 61% being women, 77% aged 45 years and older, and 48% from the highest deprivation quintile. Ten systems associated with opioid initiation were identified, which were not mutually exclusive, as patients could have opioids prescribed for multiple indications. The most common were musculoskeletal (80.8%), respiratory (57.6%), infections (30.4%), trauma/injury (20.4%), neurology (19.9%), and postsurgical indications (5.5%). Osteoarthritis (60.7%) and low back pain (41.0%) were the most frequent musculoskeletal conditions. Orthopedic surgeries accounted for 41.2% of all postsurgical indications. This is the first study in the United Kingdom evaluating large-scale national data to assess indications associated with opioid initiation. Nearly 3 quarters of new opioid prescriptions for noncancer pain were in patients with musculoskeletal conditions, often for conditions with limited evidence for opioid efficacy. These findings could inform targeted interventions and future policies to support nonpharmacological interventions in the most common conditions where opioid harms outweigh benefits., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objective: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD)., Summary Background Data: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system., Methods: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades., Results: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001)., Conclusions: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective was to evaluate the safety and efficacy of ultra-rapid-acting insulin with the Boost and Ease-off features of the Cambridge hybrid closed-loop system., Methods: A secondary analysis of Boost and Ease-off from two double-blind, randomized, crossover hybrid closed-loop studies comparing (1) Fiasp to insulin aspart (n = 25), and (2) Lyumjev to insulin lispro (n = 26) was carried out. Mean glucose on initialization of Boost and Ease-off, change in glucose 60 and 120 minutes after initialization, duration and frequency of use, mean glucose, and time in, above, and below target glucose range were calculated for periods of Boost use, Ease-off use, or neither., Results: Participants used Boost for longer with Fiasp than insulin aspart (median [interquartile range, IQR] = 75 [53-125] minutes vs 60 [49-75] minutes; P = .01). Mean glucose on Boost initialization with Fiasp was 238 ± 62 mg/dL compared with 218 ± 45 mg/dL with insulin aspart ( P = .08). Fiasp use resulted in a greater glucose reduction 120 minutes after Boost initialization [-59 ± 34 mg/dL vs -43 ± 31 mg/dL; P = .02]. There were no statistically significant differences in sensor glucose endpoints during Boost or Ease-off periods between Fiasp and aspart. There were no statistically significant differences during Boost or Ease-off periods when comparing Lyumjev with insulin lispro. There were no safety issues when using Boost and Ease-off with ultra-rapid insulins., Conclusions: The use of Fiasp and Lyumjev during Boost or Ease-off resulted in comparable safety and efficacy to using insulin aspart and lispro., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CB is a consultant at CamDiab and has received speaker honoraria from Ypsomed. MN has received travel grant support from Sanofi, Janssen, and Eli Lilly and was previously chair of the Young Diabetologists’ and Endocrinologists’ Forum in the United Kingdom, which uses unrestricted sponsorship from industry partners to deliver educational programs for health care professionals. SH serves as a member of Medtronic advisory board, is a director of Ask Diabetes Ltd, providing training and research support in health care settings, and reports having received training honoraria from Medtronic and Sanofi and consulting fees for CamDiab. MEW is a consultant to CamDiab and reports patents related to closed loop. JW has received speaker honoraria from Ypsomed and Novo Nordisk. HT receives consulting fees and speaker honoraria from Eli Lilly and Dexcom Inc, reports having received research support from Dexcom Inc, and participated in advisory groups for Medtronic, Abbott Diabetes Care, and Roche Diabetes Care. JKM is a member in the advisory boards of Abbott Diabetes Care, Becton-Dickinson/Embecta, Biomea, Eli Lilly, Medtronic, Novo Nordisk, Pharmasens, Roche Diabetes Care, Sanofi, and Viatris; received speaker honoraria from Abbott Diabetes Care, A. Menarini Diagnostics, Becton-Dickinson/Embecta, Boehringer-Ingelheim, Eli Lilly, MedTrust, Novo Nordisk, Roche Diabetes Care, Sanofi, and Ypsomed; and is shareholder of decide Clinical Software GmbH and elyte Diagnostics. LB reports having participated in advisory boards of Eli Lilly, Novo Nordisk, Oviva, Roche Diabetes Care, Sanofi, and Ypsomed and received speaker fees from Dexcom, Ypsomed, and Oviva. LL has received research support from Abbott Diabetes Care and Dexcom, participated in advisory groups for Abbott Diabetes Care, Insulet, Dexcom, Medtronic, and Roche Diabetes, and received fees for speaking from Sanofi, Insulet, Medtronic, and Abbott Diabetes Care. MLE has been a member of advisory panels and/or received speaker fees from Novo Nordisk, Eli Lilly, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, Ypsomed, Pila Pharma, and Zucara. RH reports having received speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk; receiving license fees from B. Braun; patents related to closed-loop; being consultant to Abbott Diabetes Care; and being director at CamDiab. CR, RL, and JMA report no conflicts of interest related to the present paper.

Objective: To compare immunological responses of preterm infants to a four-component meningococcal B vaccine (4CMenB; Bexsero) following a 2+1 vs a 3+1 schedule, and to describe reactogenicity of routine vaccines., Design: An open-label, phase IV randomised study conducted across six UK sites., Setting: Neonatal units, postnatal wards, community recruitment following discharge., Participants: 129 preterm infants born at a gestation of <35 weeks (64 in group 1 (2+1), 65 in group 2 (3+1)) were included in the analysis. Analysis was completed for postprimary samples from 125 participants (59 in group 1, 66 in group 2) and for postbooster samples from 118 participants (59 in both groups)., Interventions: Infants randomised to 4CMenB according to a 2+1 or a 3+1 schedule, alongside routine vaccines., Main Outcome Measures: Serum bactericidal antibody (SBA) assays performed at 5, 12 and 13 months of age: geometric mean titres (GMTs) and proportions of infants achieving titres ≥4 compared between groups., Results: There were no significant differences in SBA GMTs between infants receiving a 2+1 compared with a 3+1 schedule following primary or booster vaccination, but a significantly higher proportion of infants had an SBA titre ≥4 against strain NZ98/254 (porin A) at 1 month after primary vaccination using a 3+1 compared with a 2+1 schedule (3+1: 87% (95% CI 76 to 94%), 2+1: 70% (95% CI 56 to 81%), p=0.03).At 12 weeks of age those in the 3+1 group, who received a dose of 4CMenB, had significantly more episodes of fever >38.0°C than those in the 2+1 group who did not (group 2+1: 2% (n=1); 3+1: 14% (n=9); p=0.02)., Conclusions: Both schedules were immunogenic in preterm infants, although a lower response against strain NZ98/254 was seen in the 2+1 schedule; ongoing disease surveillance is important in understanding the clinical significance of this difference., Trial Registration Number: NCT03125616., Competing Interests: Competing interests: JL and RB perform contract research on behalf of UKHSA for GlaxoSmithKline (GSK), Pfizer and Sanofi. JC works for an institution which conducts meningococcal vaccine research on behalf of GSK; he receives no personal payment or inducement of any kind. MS was an employee of the University of Oxford and Oxford University Hospitals Foundation NHS trust up until September 2022, and in this role acted as an investigator for clinical research studies funded or otherwise supported by the vaccine manufacturers GSK, Janssen, AstraZeneca, Pfizer, Novavax and MCM vaccines. He received no personal financial benefit for this work. As of September 2022, MS has been an employee of Moderna UK and holds equity in this company; however, all study activities and data analysis were completed before this date., (© 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: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown., Methods: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%)., Results: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure., Conclusions: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.)., (Copyright © 2024 Massachusetts Medical Society.)