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BACKGROUND: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. OBJECTIVE: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. PATIENTS AND METHODS: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. RESULTS: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3-134.2, and 74.8-126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. CONCLUSIONS: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).

OBJECTIVES: There is little evidence guiding the management of grade I-II traumatic splenic injuries with contrast blush (CB). We aimed to analyze the failure rate of nonoperative management (NOM) of grade I-II splenic injuries with CB in hemodynamically stable patients. METHODS: A multicenter, retrospective cohort study examining all grade I-II splenic injuries with CB was performed at 21 institutions from January 1, 2014, to October 31, 2019. Patients >18 years old with grade I or II splenic injury due to blunt trauma with CB on CT were included. The primary outcome was the failure of NOM requiring angioembolization/operation. We determined the failure rate of NOM for grade I versus grade II splenic injuries. We then performed bivariate comparisons of patients who failed NOM with those who did not. RESULTS: A total of 145 patients were included. Median Injury Severity Score was 17. The combined rate of failure for grade I-II injuries was 20.0%. There was no statistical difference in failure of NOM between grade I and II injuries with CB (18.2% vs 21.1%, p>0.05). Patients who failed NOM had an increased median hospital length of stay (p=0.024) and increased need for blood transfusion (p=0.004) and massive transfusion (p=0.030). Five patients (3.4%) died and 96 (66.2%) were discharged home, with no differences between those who failed and those who did not fail NOM (both p>0.05). CONCLUSION: NOM of grade I-II splenic injuries with CB fails in 20% of patients. LEVEL OF EVIDENCE: IV.

Abstract Background In England, the number of takeaway food outlets (‘takeaways’) has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated. Methods To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaways (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we estimated changes in body mass index (BMI) from changes in takeaway exposure, from 2018 to 2040. We used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25–64 years), on incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs), and healthcare costs saved by 2040 in six local authorities (LAs) across the rural–urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland). Results By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to mean per person reductions in BMI of 0.08 and 0.68 kg/m2, respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (e.g. 964 (95% UI: 1565, 870) fewer cases/100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers, and low back pain. Savings in healthcare costs (millions) ranged from £1.65 (95% UI: £1.17, £2.25)/100,000 population in North Somerset to £2.02 (95% UI: £1.39, £2.83)/100,000 population in Wandsworth. Gains in QALYs/100,000 person were broadly similar across LAs. Conclusions Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, at the local level and across the rural–urban spectrum.

Abstract Background Neighbourhood exposure to takeaways can contribute negatively to diet and diet-related health outcomes. Urban planners within local authorities (LAs) in England can modify takeaway exposure through denying planning permission to new outlets in management zones around schools. LAs sometimes refer to these as takeaway “exclusion zones”. Understanding the long-term impacts of this intervention on the takeaway retail environment and health, an important policy question, requires methods to forecast future takeaway growth and subsequent population-level exposure to takeaways. In this paper we describe a novel two-stage method to achieve this. Methods We used historic data on locations of takeaways and a time-series auto-regressive integrated moving average (ARIMA) model, to forecast numbers of outlets within management zones to 2031, based on historical trends, in six LAs with different urban/rural characteristics across England. Forecast performance was evaluated based on root mean squared error (RMSE) and mean absolute scaled error (MASE) scores in time-series cross-validation. Using travel-to-work data from the 2011 UK census, we then translated these forecasts of the number of takeaways within management zones into population-level exposures across home, work and commuting domains. Results Our ARIMA models outperformed exponential smoothing equivalents according to RMSE and MASE. The model was able to forecast growth in the count of takeaways up to 2031 across all six LAs, with variable growth rates by RUC (min–max: 39.4-79.3%). Manchester (classified as a non-London urban with major conurbation LA) exhibited the highest forecast growth rate (79.3%, 95% CI 61.6, 96.9) and estimated population-level takeaway exposure within management zones, increasing by 65.5 outlets per capita to 148.2 (95% CI 133.6, 162.7) outlets. Overall, urban (vs. rural) LAs were forecast stronger growth and higher population exposures. Conclusions Our two-stage forecasting approach provides a novel way to estimate long-term future takeaway growth and population-level takeaway exposure. While Manchester exhibited the strongest growth, all six LAs were forecast marked growth that might be considered a risk to public health. Our methods can be used to model future growth in other types of retail outlets and in other areas.

Abstract The Staphylococcus aureus (S. aureus) one of the important food borne pathogen from milk, which was investigated in this study. The isolates were screened for antimicrobial resistance, enterotoxin genes, biofilm formation, spa typing, coagulase gene polymorphism and accessory gene regulator types. The prevalence of S. aureus in milk samples was 34.4% (89/259). Methicillin resistant S. aureus (MRSA) was found at 27% (24/89) of the isolates, were classified as community acquired based on SCCmec typing. The 24.71% (22/89) isolates demonstrated multiple antimicrobial resistance (MAR) pattern. However, none of the isolates carried vancomycin and mupirocin resistance genes. The isolates were positive for sea and sed enterotoxin genes and exhibited high frequency of biofilm formation. The High-Resolution Melting and conventional spa typing revealed that the isolates had both animal and community-associated S. aureus clustered origins. Coagulase gene polymorphism and agr typing demonstrated variable genotypic patterns. The finding of this study establishes the prevalence of community associated, enterotoxigenic, biofilm forming and antimicrobial resistance among S. aureus from milk in Chennai city. This emphasizing a potential threat to public health which needs a continuous monitoring system and strategies to mitigate their spread across the food chain and achieve food safety.

Objective: To determine differences in glucose control and cardiovascular disease risk factors following three weeks of added soda, 100% fruit juice, or water in apparently healthy, college-aged adults. Participants: Thirty-six adults (18 males; 18 females) between the ages of 18 and 30 years of age. Methods: A 3-arm randomized controlled parallel-arm trial; at baseline and after three weeks consuming the assigned beverage, participants completed glucose control and cardiovascular disease risk factor assessments. Results: There were no significant differences between beverage conditions for glucose control or cardiovascular disease risk factors (ps > 0.05). There were no significant changes in caloric intake or differences in caloric intake between conditions, p = 0.17. p Conclusions: In healthy, young adults, under free-living conditions, short-term consumption of two commercially packaged servings of SBs did not lead to significant glucose control or cardiovascular disease risk factor changes, indicating potential compensation and/or resilience to negative short-term effects.

Background: The American Academy of Orthopaedic Surgeons (AAOS) has been recommending a weight loss of 5% of body weight or more as a treatment for those who have osteoarthritis (OA). However, the AAOS does not recommend or guide clinicians in the best weight loss strategies, leaving the clinician and the patients on their own to navigate the weight loss process. Aim: This scoping review addresses the most effective ways to reach the recommended weight loss and achieve symptomatic improvement through various methods, including diet, exercise, meal replacements and specific diet types, with or without the help of a trained professional. Methods: In a scoping literature review, this author investigated medication use, diet, exercise or a combination of diet and exercise as an effective method for weight loss to treat hip and knee osteoarthritis and whether the delivery method (i.e., telehealth or application-based versus in-person) played a role in the effectiveness of weight loss. Results: A loss of body weight between 10% and 20% results in more significant symptomatic improvement and is safe and effective with the help of a trained health care professional and meal replacement foods. Conclusion: A clear dose response exists between the amount of weight lost and symptomatic improvement, with better symptomatic improvement seen in patients losing more than the typically recommended 5% body weight. Contribution: This review shows that a weight loss of 10–20% of body weight through a low carbohydrate diet combined with exercise can effectively be used as symptomatic management of hip or knee osteoarthritis.

Local and national policymakers are seeking innovative solutions to create healthier food environments around the world. Between 2009 and 2017, 35 local authorities across England (UK) adopted planning guidance designed to limit the proliferation of hot food takeaways near schools. Whilst these policies are intended to improve population health, they are also likely to have economic impacts. Often a decision to introduce such policies comes down to consideration of whether the short-term economic imperatives of allowing new takeaway outlets to open outweighs the potential long-term public health implications and associated economic consequences. These potential negative and positive economic impacts have not previously been clearly described and are summarised here. The aim of this paper is to provide an overview of the potential economic impacts of takeaway management zones. In particular, we present a Causal Loop Diagram (CLD) that outlines the possible economic impacts of takeaway management zones based on researcher knowledge of the interventions and the industry. Potential negative impacts fall across sectors and may include a loss of employment opportunities and reductions in local and national tax receipts, and may impact the economic vitality of local communities. In the longer term, there is the potential for positive impacts such as reductions in healthcare resource utilisation, social care expenditure and sickness-related absence from work. Part of a robust case would a better economic understanding, that would enable local authorities to improve understanding of the trade-offs associated with the policy, such as short-versus long-term, and business-related versus society-related health benefits and costs.

IntroductionAntimicrobial resistance (AMR) in Brucella melitensis, the causative agent of brucellosis, is of growing concern, particularly in low and middle-income countries. This study aimed to explore the genetic basis of AMR in B. melitensis strains from India.MethodsTwenty-four isolates from humans and animals were subjected to antimicrobial susceptibility testing and whole-genome sequencing.ResultsResistance to doxycycline (20.80%), ciprofloxacin (16.67%), cotrimoxazole (4.17%), and rifampicin (16.67%) was observed. Genome analysis revealed efflux-related genes like mprF, bepG, bepF, bepC, bepE, and bepD across all isolates, however, classical AMR genes were not detected. Mutations in key AMR-associated genes such as rpoB, gyrA, and folP were identified, intriguingly present in both resistant and susceptible isolates, suggesting a complex genotype–phenotype relationship in AMR among Brucella spp. Additionally, mutations in efflux genes were noted in resistant and some susceptible isolates, indicating their potential role in resistance mechanisms. However, mutations in AMR-associated genes did not consistently align with phenotypic resistance, suggesting a multifactorial basis for resistance.DiscussionThe study underscores the complexity of AMR in B. melitensis and advocates for a holistic multi-omics approach to fully understand resistance mechanisms. These findings offer valuable insights into genetic markers associated with AMR, guiding future research and treatment strategies.