Health gains from achieving optimal body mass index in Australia: a simulation study.

Background: We estimated the health gains and health inequality impacts for the Australian population alive in 2021 (n = 25.0 million) in the next 20 years and over their remaining lifespan, from shifting everyone above a BMI of 25 kg/m2 to 25 kg/m2 compared to the BMI distribution in 2021 persisting into the future. Methods: National Health Survey 2017-2018 was used to estimate BMI distributions by sex, age and, socio-economic status (Socio-Economic Indexes for Areas; SEIFA). A proportional multistate life table linking BMI to 19 associated diseases and allowing for time lags and competing morbidity and mortality, was used to estimate the future stream of health adjusted life years (HALYs) gained from eradicating high BMI. Findings: Undiscounted health gains in the first 20 years and lifetime of the population were, respectively, 2.00 million (95% uncertainty interval 1.70-2.32) and 20.4 million (17.0-24.2) (at a 3% annual discount rate, HALY gains were 1.37 and 5.77 million, respectively). Reductions in the incidence of cardio metabolic diseases contributed 61% (95% UI: 54%-68%) of the undiscounted health gains in the first 20 years, musculoskeletal diseases contributed 26% (20%-32%) and cancer 5% (3%-8%). HALY gains in the first 20 years and lifetime, per person alive in 2021, were 2.5 (2.4-2.5) and 1.9 (1.9-2.0) times higher for the most compared to the least deprived SEIFA quintile. Interpretation: The total theoretical envelope of health gains, and health inequality reductions, through eradication of BMI is substantial. Our modeling infrastructure can be used to estimate the health impacts and cost effectiveness of many actual interventions. Funding: No funding was received for the study.

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

Assessing the potential of portable X-ray fluorescence (XRF) as a rapid, onsite screening tool in the assessment of cadmium surface decontamination effectiveness.

Portable X-ray fluorescence has successfully been used to effectively evaluate occupational exposure to airborne and surface metal contaminants nondestructively. Traditional methods of assessing metal surface contamination involve the costly, time-consuming collection and laboratory analysis of wipe samples, making portable X-ray fluorescence an attractive alternative method for screening worksites by reducing delays in risk assessment decision-making. Existing research into this use of portable X-ray fluorescence has primarily been centered on the analysis of airborne and surface lead contamination. The extant literature is sparse on the use of portable X-ray fluorescence with other metals for surface contamination with respect to occupational exposure. The present study evaluated the use of portable X-ray fluorescence in the screening of cadmium surface contamination to determine if the effectiveness of decontamination measures can be ascertained by this technique. Wipe samples were collected and screened with portable X-ray fluorescence before being sent to the laboratory for definitive analysis to assess the correlation between portable X-ray fluorescence readings in percent mass with laboratory results in µg/ft2. Portable X-ray fluorescence readings demonstrated a strong linear correlation with laboratory results, as indicated by the R2 value of 0.993. Therefore, this technique may be further developed and deployed as a screening tool for wipe samples used for evaluating contamination and decontamination of metal-contaminated areas.

Economic effects for citizens and the government of a country-level tobacco endgame strategy: a modelling study.

BACKGROUND: Aotearoa-New Zealand (A/NZ) was the first country to pass a comprehensive commercial tobacco endgame strategy into law. Key components include the denicotinisation of smoked tobacco products and a major reduction in tobacco retail outlets. Understanding the potential long-term economic impacts of such measures is important for government planning. DESIGN: A tobacco policy simulation model that evaluated the health impacts of the A/NZ Smokefree Action Plan was extended to evaluate the economic effects from both government and citizen perspectives. Estimates were presented in 2021 US$, discounted at 3% per annum. RESULTS: The modelled endgame policy package generates considerable growth in income for the A/NZ population with a total cumulative gain of US$31 billion by 2050. From a government perspective, increased superannuation payments and reduced tobacco excise tax revenue result in a negative net financial position and a cumulative shortfall of US$11.5 billion by 2050. In a sensitivity analysis considering future labour force changes, the government's cumulative net position remained negative by 2050, but only by US$1.9 billion. CONCLUSIONS: A policy such as the A/NZ Smokefree Action Plan is likely to produce substantial economic benefits for citizens, and modest impacts on government finances related to reduced tobacco tax and increases in aged pensions due to increased life expectancy. Such costs can be anticipated and planned for and might be largely offset by future increases in the size of the labour force and the proportion of people 65+ years old working in the formal economy.

Tobacco endgame intervention impacts on health gains and Maori:non-Maori health inequity: a simulation study of the Aotearoa/New Zealand Tobacco Action Plan.

BACKGROUND: The Aotearoa/New Zealand Government is aiming to end the tobacco epidemic and markedly reduce Maori:non-Maori health inequalities by legislating: (1) denicotinisation of retail tobacco, (2) 95% reduction in retail outlets and (c) a tobacco free-generation whereby people born after 2005 are unable to legally purchase tobacco. This paper estimates future smoking prevalence, mortality inequality and health-adjusted life year (HALY) impacts of these strategies. METHODS: We used a Markov model to estimate future yearly smoking and vaping prevalence, linked to a proportional multistate life table model to estimate future mortality and HALYs. RESULTS: The combined package of strategies (plus media promotion) reduced adult smoking prevalence from 31.8% in 2022 to 7.3% in 2025 for Maori, and 11.8% to 2.7% for non-Maori. The 5% smoking prevalence target was forecast to be achieved in 2026 and 2027 for Maori males and females, respectively.The HALY gains for the combined package over the population's remaining lifespan were estimated to be 594 000 (95% uncertainty interval (UI): 443 000 to 738 000; 3% discount rate). Denicotinisation alone achieved 97% of these HALYs, the retail strategy 19% and tobacco-free generation 12%.By 2040, the combined package was forcat to reduce the gap in Maori:non-Maori all-cause mortality rates for people 45+ years old by 22.9% (95% UI: 19.9% to 26.2%) for females and 9.6% (8.4% to 11.0%) for males. CONCLUSION: A tobacco endgame strategy, especially denicotinisation, could deliver large health benefits and dramatically reduce health inequities between Maori and non-Maori in Aotearoa/New Zealand.

Surgeon preference for treatment allocation in older people facing major gastrointestinal surgery: an application of the discrete choice experiment methodology.

AIM: Variation in major gastrointestinal surgery rates in the older population suggests heterogeneity in surgical management. A higher prevalence of comorbidities, frailty and cognitive impairments in the older population may account for some variation. The aim of this study was to determine surgeon preference for major surgery versus conservative management in hypothetical patient scenarios based on key attributes. METHOD: A survey was designed according to the discrete choice methodology guided by a separate qualitative study. Questions were designed to test for associations between key attributes (age, comorbidity, urgency of presentation, pathology, functional and cognitive status) and treatment preference for major gastrointestinal surgery versus conservative management. The survey consisting of 18 hypothetical scenarios was disseminated electronically to UK gastrointestinal surgeons. Binomial logistic regression was used to identify associations between the attributes and treatment preference. RESULTS: In total, 103 responses were received after 256 visits to the questionnaire site (response rate 40.2%). Participants answered 1847 out of the 1854 scenarios (99.6%). There was a preference for major surgery in 1112/1847 (60.2%) of all scenarios. Severe comorbidities (OR 0.001, 95% CI 0.000-0.030; P = 0.000), severe cognitive impairment (OR 0.001, 95% CI 0.000-0.033; P = 0.000) and age 85 years and above (OR 0.028, 95% CI 0.005-0.168; P = 0.000) were all significant in the decision not to offer major gastrointestinal surgery. CONCLUSION: This study has demonstrated variation in surgical treatment preference according to key attributes in hypothetical scenarios. The development of fitness-stratified guidelines may help to reduce variation in surgical practice in the older population.

Healthcare professional preferences in the health and fitness assessment and optimization of older patients facing colorectal cancer surgery.

AIM: There are few age- and fitness-specific, evidence-based guidelines for colorectal cancer surgery. The uptake of different assessment and optimization strategies is variable. The aim of this study was to explore healthcare professional opinion about these issues using a mixed methods design. METHODS: Semi-structured qualitative interviews were undertaken with healthcare professionals from a single UK region involved in the treatment, assessment and optimization of colorectal surgery patients. Interviews were analysed using the framework approach. An online questionnaire survey was subsequently designed and disseminated to UK surgeons to quantitatively assess the importance of interview themes. Descriptive statistics were used to analyse questionnaire data. RESULTS: Thirty-seven healthcare professionals out of 42 approached (response rate 88%) were interviewed across five hospitals in the south Yorkshire region. Three broad themes were developed: attitudes towards treatment of the older patient, methods of assessment of suitability and optimization strategies. The questionnaire was completed by 103 out of an estimated 256 surgeons (estimated response rate 40.2%). There was a difference in opinion regarding the role of major surgery in older patients, particularly when there is coexisting dementia. Assessment was not standardized. Access to optimization strategies was limited, particularly in the emergency setting. CONCLUSION: There is wide variation in the process of assessment and provision of optimization strategies in UK practice. Lack of evidence-based guidelines, cost and time constraints restrict the development of services and pathways. Differences in opinion between surgeons towards patients with frailty or dementia may account for some of the variation in colorectal cancer outcomes.

Protocol for a multi-centre observational and mixed methods pilot study to identify factors predictive of poor functional recovery after major gastrointestinal surgery and strategies to enhance uptake of perioperative optimization: Optimizing the care and treatment pathways for older patients facing major gastrointestinal surgery (OCTAGON).

INTRODUCTION: National datasets report large variations in outcomes from older people (≥65 years) between different UK surgical units. This implies that not all patients receive the same level of care or access to resources, such as rehabilitation or allied health professional input. This might impact functional decline. AIMS: Our aim is to evaluate the baseline status of older patients facing major gastrointestinal surgery and the impact of variation in perioperative assessment and provision of perioperative support on functional outcomes. Patients' experiences and views of assessment and optimization will be explored via integrated qualitative semi-structured interviews. METHODS AND ANALYSIS: This multi-centre, pilot cohort study will include patients ≥65 years presenting via both elective and emergency pathways at three to five South Yorkshire NHS hospitals (Clinical Trials registration NCT04545125). The primary outcome is functional recovery measured using the World Health Organization Disability Assessment Schedule 2.0 at 6 weeks post-operation. Secondary outcomes include feasibility, quality of life, length of stay and complication rate. An opportunistic sample size of 120 has been estimated and will inform the design of a future, adequately powered study. For the qualitative study, 20-30 semi-structured patient interviews will be undertaken with patients from the cohort study to explore experiences of assessment and optimization. Interviews will be digitally recorded, transcribed verbatim and analysed according to the framework approach. ETHICS AND DISSEMINATION: This study has been approved by the National Health Service Research Ethics Committee and is registered centrally with Health Research Authority. It has been adopted by the National Institute for Health Research Portfolio scheme. Dissemination will be via international and national surgical and geriatric conferences.

Long-term retention of a 3-dimensional educational computer model of the larynx: a follow-up study.

OBJECTIVES: To determine the long-term retention of a 3-dimentional (3-D) educational computer model of the larynx to teach laryngeal anatomy and to compare it with standard written instruction (SWI). DESIGN: Prospective randomized controlled trial. SETTING: University education program. PARTICIPANTS: One hundred health care students. INTERVENTIONS: For short-term assessment, 50 students were randomized to the 3-D model and 50 to SWI and were tested using a 20-question laryngeal test. Six months later, the same students were invited to retake the laryngeal anatomy test to examine long-term retention. MAIN OUTCOME MEASURE: The score on a 20-item Web-based test that assessed the students' level of knowledge of laryngeal anatomy approximately 6 months after their initial exposure to the laryngeal anatomy teaching intervention. RESULTS: Sixty-two students retook the test: 3-D (n = 30) and SWI (n = 32). No significant difference was noted in mean scores (P = .54) and change in scores (P = .59) between short- and long-term retention on the laryngeal anatomy test. There was a trend toward an increase in 3-D scores in both groups (P = .07) and a significant increase in 3-D scores in the 3-D group only (P = .049). CONCLUSIONS: A low-fidelity model (SWI) is just as effective as a high-fidelity model (3-D) in teaching laryngeal anatomy. The acquired knowledge from either educational intervention may last up to 6 months for long-term retention. This study is one of the few in medical education to examine long-term retention.

Introduction of a novel teaching paradigm for head and neck anatomy.

INTRODUCTION: Didactic head and neck anatomy teaching has been replaced by a novel self-directed, multimodal, and multidisciplinary approach at the Schulich School of Medicine and Dentistry (SSMD). OBJECTIVES: To describe the use of a novel teaching paradigm at SSMD and to enable readers to determine how this methodology may benefit medical students at other academic institutions and disciplines. DESIGN: Prospective cohort study. METHODS: The paradigm consists of multimedia learning modules to guide independent anatomy learning. Students received a case-based assignment based on the content of the learning modules to guide them through cadaveric dissections facilitated by a multidisciplinary team of surgeons and anatomists. PRIMARY OUTCOME: Postcourse survey and mean scores comparison. The survey collected data, including demographics and previous anatomic and computer-assisted learning (CAL) experiences, and focused on measuring student perception of the proposed paradigm. Secondary outcome: Correlation of demographics. RESULTS: The paradigm was successfully implemented and warmly received, but it still requires further development. Although CAL allows increased individual engagement, students still enjoy and value lectures. In addition, students view instruction by surgeons in laboratories as the most valuable component of their anatomy teaching as it not only deepened the students' understanding of anatomic structures but also provided them with the clinical relevance. Technological innovations were welcomed by the students but have not replaced their appreciation of dissection and lecures.

Evaluation of a three-dimensional educational computer model of the larynx: voicing a new direction.

OBJECTIVE: To evaluate a novel method of teaching laryngeal anatomy. DESIGN: Prospective, randomized, controlled trial. SETTING: University educational program. METHODS: Computer model development: A three-dimensional (3D) educational computer model of the larynx was created from high-resolution computed tomography and magnetic resonance images of cadaveric necks using segmentation software (Amira) (Visage Imaging, Inc., Carlsbad, CA). E-learning authoring software (Articulate, Articulate Global, Inc, New York, NY) then was used to make the model interactive and multimedia. The model was launched on a Web-based platform. Model evaluation: One hundred students (age 23.8 +/- 2.2 years; 55% male) were randomized to either the 3D computer model group (3D group) (n = 50) or the standard written instruction group (SWI group) (n = 50). MAIN OUTCOME MEASURES: The primary outcome measure was the score on a 20-question laryngeal anatomy test; the secondary outcome measure was a student opinion questionnaire. RESULTS: The mean score on the laryngeal anatomy test was 14.2 +/- 2.8 (72.0 +/- 15.1%). The mean score for the 3D group was 13.6 +/- 3.0 (67.0 +/- 16.1%) versus 14.8 +/- 2.5 (76.0 +/- 12.7%) for the SWI group (t = 2.194, df = 98, p < .031). A majority of students felt that the 3D model was effective, clear, user-friendly, and a preferred supplement to traditional methods of instruction. The 3D group rated the computer model more enjoyable than the SWI group. CONCLUSIONS: A 3D educational computer model of the larynx was not shown to be superior to written lecture notes in its efficacy in teaching anatomy; however, it was judged to be a preferred and valuable supplement to traditional teaching methods.

Three-dimensional educational computer model of the larynx: voicing a new direction.

OBJECTIVES: To create a 3-dimensional (3D) educational computer model of the larynx, to assess the feasibility of this learning module on a Web-based platform, and to obtain student feedback on the module. DESIGN: Male and female adult cadaveric necks were scanned with microcomputed tomographic and magnetic resonance imaging scanners. Key structures were identified on each slice of the computed tomogram and/or magnetic resonance image and analyzed with a segmentation software package. Then, the images were exported into Microsoft Powerpoint. Visual text and audio commentary were added. Real cases of a child's larynx, an adult with a tracheostomy, and a patient with laryngeal carcinoma were included. The computer module was launched on a password-protected, Web-based platform. PARTICIPANTS: Fifty-eight first-year medical students (38% male; mean [SD] age, 23 [1.8] years) were invited to evaluate the module and to complete a survey. RESULTS: Most students thought that the 3D computer module was effective (60%), clear (66%), and user friendly (72%); most students (81%) thought that it was easier to understand laryngeal anatomy when they could visualize it in 3D; and most students (83%) said that they would like lectures better if they were supplemented with 3D computer modules. CONCLUSION: A 3D educational computer model of the larynx has been successfully created and warmly received by medical students.

Long-term results of laparoscopic totally extraperitoneal inguinal herniorrhaphy.

BACKGROUND: The short-term advantages of laparoscopic totally extraperitoneal mesh herniorrhaphy (TEP) are well documented, but the long-term results remain unclear. The purpose of the present paper is to clarify this issue with particular reference to hernia recurrence and chronic pain. METHODS: A retrospective case series of 100 consecutive patients undergoing TEP 5 years ago by a single surgeon were followed up prospectively with a focused physical examination and interview. Data collected included recurrence, chronic groin pain, tenderness, sensory disturbance, activity or occupational limitation, and personal satisfaction. RESULTS: During the period between 1997 and 1999, 100 consecutive patients underwent 110 TEP hernia repairs. The mean age was 56 years. Two patients were excluded from the study because they had had open repairs for technical reasons. Median follow up was 64 months. Follow up was complete (interview and physical examination) in 88% and partial (telephone interview only) in a further 5%. There was no major morbidity or mortality. Hernia recurrence rate was 1%. Chronic pain occurred in 14 patients (14%), which was mild in 13 patients and moderate in one. Ninety-eight per cent of patients were satisfied with their repair and would or had recommended TEP to others. CONCLUSIONS: Long-term results of TEP demonstrate it to be an effective and safe procedure with a low recurrence and low prevalence of chronic pain that is generally of a mild, infrequent nature.

Benign retroperitoneal cyst of Mullerian type.

Retroperitoneal cysts are rare, usually asymptomatic, lesions. We present the case of a 42-year-old woman with an asymptomatic abdominal mass. The mass excised at our district hospital was found in the retroperitoneum. Histologically, the cyst was lined with benign Mullerian-type epithelium. The classification, aetiology and clinical manifestations of retroperitoneal cysts are discussed. Retroperitoneal cysts present as an acute abdomen in only a minority of cases. Ultrasound is the most reliable test for their detection, usually followed by computed tomography and/or an upper gastrointestinal series. Optimally, these cysts should be completely excised.

Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue.

The phosphoinositide 3-kinase (PI3K) catalytic subunit p110 delta is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110 delta is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor alpha (TNF alpha). Specifically, administration of the selective inhibitor of PI3K delta, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110 delta. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K delta in TNF alpha-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110 delta expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K delta may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium.