Assessing unknown potential-quality and limitations of different large language models in the field of otorhinolaryngology.

BACKGROUND: Large Language Models (LLMs) might offer a solution for the lack of trained health personnel, particularly in low- and middle-income countries. However, their strengths and weaknesses remain unclear. AIMS/OBJECTIVES: Here we benchmark different LLMs (Bard 2023.07.13, Claude 2, ChatGPT 4) against six consultants in otorhinolaryngology (ORL). MATERIAL AND METHODS: Case-based questions were extracted from literature and German state examinations. Answers from Bard 2023.07.13, Claude 2, ChatGPT 4, and six ORL consultants were rated blindly on a 6-point Likert-scale for medical adequacy, comprehensibility, coherence, and conciseness. Given answers were compared to validated answers and evaluated for hazards. A modified Turing test was performed and character counts were compared. RESULTS: LLMs answers ranked inferior to consultants in all categories. Yet, the difference between consultants and LLMs was marginal, with the clearest disparity in conciseness and the smallest in comprehensibility. Among LLMs Claude 2 was rated best in medical adequacy and conciseness. Consultants' answers matched the validated solution in 93% (228/246), ChatGPT 4 in 85% (35/41), Claude 2 in 78% (32/41), and Bard 2023.07.13 in 59% (24/41). Answers were rated as potentially hazardous in 10% (24/246) for ChatGPT 4, 14% (34/246) for Claude 2, 19% (46/264) for Bard 2023.07.13, and 6% (71/1230) for consultants. CONCLUSIONS AND SIGNIFICANCE: Despite consultants superior performance, LLMs show potential for clinical application in ORL. Future studies should assess their performance on larger scale.

Characterising 24-h skeletal muscle gene expression alongside metabolic & endocrine responses under diurnal conditions.

CONTEXT: Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism. OBJECTIVE: To characterise temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol. METHODS: Ten healthy adults (9M/1F, mean ± SD: age: 30 ± 10 y; BMI: 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours of this period (i.e., 0800-0800 h). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 2200-0700 h. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 h from 1200 h to 0800 h the following day to quantify gene expression. RESULTS: Plasma insulin displayed diurnal rhythmicity peaking at 1804 h. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name - Acrophase; GLUT4 - 1440 h; PPARGC1A -1613 h; HK2 - 1824 h) and lipid metabolism (FABP3 - 1237 h; PDK4 - 0530 h; CPT1B - 1258 h) displayed 24 h rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (0019 h), NEFA (0456 h), glycerol (0432 h), triglyceride (2314 h), urea (0046 h), CTX (0507 h) and cortisol concentrations (2250 h) also all displayed diurnal rhythmicity. CONCLUSION: Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.

Myths and Methodologies: Standardisation in human physiology research-should we control the controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Myths and Methodologies: Standardisation in Human Physiology Research-Should We Control the Controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Pulmonary artery sarcoma affecting the pulmonary valve mistaken as pulmonary vasculitis: a case report and comparative literature review.

Pulmonary arterial sarcomas (PAS) are rare aggressive tumours occurring mainly in the pulmonary trunk. We report a case of PAS involving the pulmonary trunk wall and valve, with uniform wall thickening which represents an atypical imaging manifestation of this tumour. A 63-year-old male presented with vague respiratory symptoms with rapid progression. CTPA showed low density filling defects in both pulmonary arteries and PET scan showed increased uptake in the pulmonary trunk, which along with raised ESR suggested Pulmonary Vasculitis. Echo imaging showed Right ventricular hypertrophy and pulmonary stenosis. Response to steroid therapy was minimal and his symptoms worsened. A referral for second opinion was made and he was diagnosed with PAS. He underwent Pulmonary thromboendarterectomy with Pulmonary valve replacement. Post-operative histopathology confirmed the diagnosis. PAS is rare and frequently misdiagnosed. Surgical resection is not curative, but together with chemotherapy can prolong survival.

Substituting carbohydrate at lunch for added protein increases fat oxidation during subsequent exercise in healthy males.

CONTEXT: How pre-exercise meal composition influences metabolic and health responses to exercise later in the day is currently unclear. OBJECTIVE: Examine the effects of substituting carbohydrate for protein at lunch on subsequent exercise metabolism, appetite, and energy intake. METHODS: Twelve healthy males completed three trials in randomized, counterbalanced order. Following a standardized breakfast (779 ± 66 kcal; ∼08:15), participants consumed a lunch (1186 ± 140 kcal; ∼13:15) containing either 0.2 g·kg-1 carbohydrate and ∼2 g·kg-1 protein (LO-CARB), 2 g·kg-1 carbohydrate and ∼0.4 g·kg-1 protein (HI-CARB), or fasted (FAST). Participants later cycled at ∼60% V̇O2peak for 1 h (∼16:15) and post-exercise ad-libitum energy intake was measured (∼18:30). Substrate oxidation, subjective appetite, and plasma concentrations of glucose, insulin, non-esterified fatty acids (NEFA), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and acylated ghrelin (AG) were measured for 5 h post-lunch. RESULTS: Fat oxidation was greater during FAST (+11.66 ± 6.63 g) and LO-CARB (+8.00 ± 3.83 g) than HI-CARB (p < 0.001), with FAST greater than LO-CARB (+3.67 ± 5.07 g; p < 0.05). NEFA were lowest in HI-CARB and highest in FAST, with insulin demonstrating the inverse response (all p < 0.01). PYY and GLP-1 demonstrated a stepwise pattern, with LO-CARB greatest and FAST lowest (all p < 0.01). AG was lower during HI-CARB and LO-CARB versus FAST (p < 0.01). Energy intake in LO-CARB was lower than FAST (-383 ± 233 kcal; p < 0.001) and HI-CARB (-313 ± 284 kcal; p < 0.001). CONCLUSION: Substituting carbohydrate for protein in a pre-exercise lunch increased fat oxidation, suppressed subjective and hormonal appetite, and reduced post-exercise energy intake.

Don't keep me waiting: estimating the lifetime impact of reduced vein-to-vein time for CAR-T treated patients with LBCL.

Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of hematological cancers. Production requires a complex logistical process from leukapheresis to patient infusion, the vein-to-vein time (V2VT), during which a patients clinical condition may deteriorate. This study was designed to estimate the benefits of reduced V2VT for third-line+ (3L+) relapsed/refractory large B-cell lymphoma (r/r LBCL) patients treated with CAR T. A mathematical model was developed to estimate the lifetime outcomes of a hypothetical cohort of patients who had either a 'long' or 'short' V2VT. Life-years (LYs), quality-adjusted life years (QALYs), and costs were estimated. Scenario analyses were performed to assess the robustness of results to key assumptions.  The results of the model show that reducing V2VT from 54 days (tisa-cel median V2VT; JULIET) to 24 days (axi-cel median V2VT; ZUMA-1) led to a 3.2-year gain in life expectancy (4.2 vs 7.7 LYs), and 2.4 additional QALYs (3.2 vs 5.6) per patient. Furthermore, a shorter V2VT was shown to be cost-effective under conventional willingness-to-pay thresholds in the United States. Results are driven by a higher infusion rate and and a better efficacy of CAR T-cell therapy for those infused. Scenario analyses using a smaller difference in V2VT (24 vs 36 days) produced consistent results. Our study is the first to quantify lifetime V2VT-related outcomes for 3L+ r/r LBCL patients treated with CAR T utilizing currently available evidence. Shorter V2VTs led to improved outcomes, demonstrating the importance of timely infusion achievable by faster manufacturing times and optimization of hospital delivery.

Oral Cannabis consumption and intraperitoneal THC:CBD dosing results in changes in brain and plasma neurochemicals and endocannabinoids in mice.

BACKGROUND: While the use of orally consumed Cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC) containing products, i.e. "edibles", has expanded, the health consequences are still largely unknown. This study examines the effects of oral consumption of whole Cannabis and a complex Cannabis extract on neurochemicals, endocannabinoids (eCB), and physiological parameters (body temperature, heart rate) in mice. METHODS: In this pilot study, C57BL/6 J mice were treated with one of the following every other day for 2 weeks: a complex Cannabis extract by gavage, whole Cannabis mixed with nutritional gel through free feeding, or purified THC/CBD by intraperitoneal (i.p.) injection. Treatments were conducted at 4 doses ranging from 0-100 mg/kg/day of CBD with THC levels of ≤ 1.2 mg/kg/day for free feeding and gavage and 10 mg/kg/day for i.p. Body temperature and heart rate were monitored using surgically implanted telemetry devices. Levels of neurochemicals, eCB, THC, CBD, and 11-OH-THC were measured using mass spectrometry 48 h after the final treatment. Statistical comparisons were conducted using ANOVA and t-tests. RESULTS: Differences were found between neurochemicals in the brains and plasma of mice treated by i.p. (e.g. dopamine, p < 0.01), gavage (e.g., phenylalanine, p < 0.05) and in mice receiving whole Cannabis (e.g., 3,4-dihydroxyphenylacetic DOPAC p < 0.05). Tryptophan trended downward or was significantly decreased in the brain and/or plasma of all mice receiving Cannabis or purified CBD/THC, regardless of dose, compared to controls. Levels of the eCB, arachidonoyl glycerol (2-AG) were decreased in mice receiving lowest doses of a complex Cannabis extract by gavage, but were higher in mice receiving highest doses compared to controls (p < 0.05). Plasma and brain levels of THC and 11-OH-THC were higher in mice receiving 1:1 THC:CBD by i.p. compared to those receiving 1:5 or 1:10 THC:CBD. Nominal changes in body temperature and heart rate following acute and repeated exposures were seen to some degree in all treatments. CONCLUSIONS: Changes to neurochemicals and eCBs were apparent at all doses regardless of treatment type. Levels of neurochemicals seemed to vary based on the presence of a complex Cannabis extract, suggesting a non-linear response between THC and neurochemicals following repeated oral dosing.

Effects of physical form of ß-lactoglobulin and calcium ingestion on GLP-1 secretion, gastric emptying and energy intake in humans: a randomised crossover trial.

The aim of this study was to assess whether adding Ca2+ to aggregate or native forms of ß-lactoglobulin alters gut hormone secretion, gastric emptying rates and energy intake in healthy men and women. Fifteen healthy adults (mean ± sd: 9M/6F, age: 24 ± 5 years) completed four trials in a randomised, double-blind, crossover design. Participants consumed test drinks consisting of 30 g of ß-lactoglobulin in a native form with (NATIVE + MINERALS) and without (NATIVE) a Ca2+-rich mineral supplement and in an aggregated form both with (AGGREG + MINERALS) and without the mineral supplement (AGGREG). Arterialised blood was sampled for 120 min postprandially to determine gut hormone concentrations. Gastric emptying was determined using 13C-acetate and 13C-octanoate, and energy intake was assessed with an ad libitum meal at 120 min. A protein × mineral interaction effect was observed for total glucagon-like peptide-1 (GLP-1TOTAL) incremental AUC (iAUC; P < 0·01), whereby MINERALS + AGGREG increased GLP-1TOTAL iAUC to a greater extent than AGGREG (1882 ± 603 v. 1550 ± 456 pmol·l-1·120 min, P < 0·01), but MINERALS + NATIVE did not meaningfully alter the GLP-1 iAUC compared with NATIVE (1669 ± 547 v. 1844 ± 550 pmol·l-1·120 min, P = 0·09). A protein × minerals interaction effect was also observed for gastric emptying half-life (P < 0·01) whereby MINERALS + NATIVE increased gastric emptying half-life compared with NATIVE (83 ± 14 v. 71 ± 8 min, P < 0·01), whereas no meaningful differences were observed between MINERALS + AGGREG v. AGGREG (P = 0·70). These did not result in any meaningful changes in energy intake (protein × minerals interaction, P = 0·06). These data suggest that the potential for Ca2+ to stimulate GLP-1 secretion at moderate protein doses may depend on protein form. This study was registered at clinicaltrials.gov (NCT04659902).

Thyroid Cancer Polygenic Risk Score Improves Classification of Thyroid Nodules as Benign or Malignant.

CONTEXT: Thyroid nodule ultrasound-based risk stratification schemas rely on the presence of high-risk sonographic features. However, some malignant thyroid nodules have benign appearance on thyroid ultrasound. New methods for thyroid nodule risk assessment are needed. OBJECTIVE: We investigated polygenic risk score (PRS) accounting for inherited thyroid cancer risk combined with ultrasound-based analysis for improved thyroid nodule risk assessment. METHODS: The convolutional neural network classifier was trained on thyroid ultrasound still images and cine clips from 621 thyroid nodules. Phenome-wide association study (PheWAS) and PRS PheWAS were used to optimize PRS for distinguishing benign and malignant nodules. PRS was evaluated in 73 346 participants in the Colorado Center for Personalized Medicine Biobank. RESULTS: When the deep learning model output was combined with thyroid cancer PRS and genetic ancestry estimates, the area under the receiver operating characteristic curve (AUROC) of the benign vs malignant thyroid nodule classifier increased from 0.83 to 0.89 (DeLong, P value = .007). The combined deep learning and genetic classifier achieved a clinically relevant sensitivity of 0.95, 95% CI [0.88-0.99], specificity of 0.63 [0.55-0.70], and positive and negative predictive values of 0.47 [0.41-0.58] and 0.97 [0.92-0.99], respectively. AUROC improvement was consistent in European ancestry-stratified analysis (0.83 and 0.87 for deep learning and deep learning combined with PRS classifiers, respectively). Elevated PRS was associated with a greater risk of thyroid cancer structural disease recurrence (ordinal logistic regression, P value = .002). CONCLUSION: Augmenting ultrasound-based risk assessment with PRS improves diagnostic accuracy.

ChatGPT Versus Consultants: Blinded Evaluation on Answering Otorhinolaryngology Case-Based Questions.

BACKGROUND: Large language models (LLMs), such as ChatGPT (Open AI), are increasingly used in medicine and supplement standard search engines as information sources. This leads to more "consultations" of LLMs about personal medical symptoms. OBJECTIVE: This study aims to evaluate ChatGPT's performance in answering clinical case-based questions in otorhinolaryngology (ORL) in comparison to ORL consultants' answers. METHODS: We used 41 case-based questions from established ORL study books and past German state examinations for doctors. The questions were answered by both ORL consultants and ChatGPT 3. ORL consultants rated all responses, except their own, on medical adequacy, conciseness, coherence, and comprehensibility using a 6-point Likert scale. They also identified (in a blinded setting) if the answer was created by an ORL consultant or ChatGPT. Additionally, the character count was compared. Due to the rapidly evolving pace of technology, a comparison between responses generated by ChatGPT 3 and ChatGPT 4 was included to give an insight into the evolving potential of LLMs. RESULTS: Ratings in all categories were significantly higher for ORL consultants (P<.001). Although inferior to the scores of the ORL consultants, ChatGPT's scores were relatively higher in semantic categories (conciseness, coherence, and comprehensibility) compared to medical adequacy. ORL consultants identified ChatGPT as the source correctly in 98.4% (121/123) of cases. ChatGPT's answers had a significantly higher character count compared to ORL consultants (P<.001). Comparison between responses generated by ChatGPT 3 and ChatGPT 4 showed a slight improvement in medical accuracy as well as a better coherence of the answers provided. Contrarily, neither the conciseness (P=.06) nor the comprehensibility (P=.08) improved significantly despite the significant increase in the mean amount of characters by 52.5% (n= (1470-964)/964; P<.001). CONCLUSIONS: While ChatGPT provided longer answers to medical problems, medical adequacy and conciseness were significantly lower compared to ORL consultants' answers. LLMs have potential as augmentative tools for medical care, but their "consultation" for medical problems carries a high risk of misinformation as their high semantic quality may mask contextual deficits.

Glycaemic variability, assessed with continuous glucose monitors, is associated with diet, lifestyle and health in people without diabetes.

Background: Continuous glucose monitors (CGMs) provide high-frequency information regarding daily glucose variation and are recognised as effective for improving glycaemic control in individuals living with diabetes. Despite increased use in individuals with non-diabetic blood glucose concentrations (euglycemia), their utility as a health tool in this population remains unclear. Objectives: To characterise variation in time in range (TIR) and glycaemic variability in large populations without diabetes or impaired glucose tolerance; describe associations between CGM-derived glycaemic metrics and metabolic and cardiometabolic health traits; identify key diet and lifestyle factors associated with TIR and glycaemic variability. Design: Glycaemic variability (coefficient of variation) and time spent in both the ADA secondary target range (TIRADA; 3.9-7.8 mmol/L) and a more stringent range (TIR3.9-5.6; 3.9-5.6 mmol/L) were calculated during free-living in PREDICT 1, PREDICT 2, and PREDICT 3 euglycaemic community-based volunteer cohorts. Associations between CGM derived glycaemic metrics, markers of cardiometabolic health, diet (food frequency questionnaire and logged diet records), diet-habits, and lifestyle were explored. Results: Data from N=4135 participants (Mean SD; Age: 47 12 y; Sex: 83% Female, BMI: 27 6 kg/m2). Median glycaemic variability was 14.8% (IQR 12.6-17.6%), median TIRADA was 95.8% (IQR 89.6-98.6%) and TIR3.9-5.6 was 75.0% (IQR 64.6-82.8%). Greater TIR3.9-5.6 was associated with lower HbA1c, ASCVD 10y risk and HOMA-IR (all p < 0.05). Lower glycaemic variability was associated with lower % energy derived from carbohydrate (rs: 0.17, p < 0.01), ultra-processed foods (NOVA 4, % EI; rs: 0.12, p = 0.01) and a longer overnight fasting duration (rs: -0.10, p = 0.01). Conclusions: A stringent TIR target provides sensitivity to detect changes in HOMA-IR, ASCVD 10 y risk and HbA1c that were not detected using ADA secondary targets. Associations among TIR, glycaemic variability, dietary intake (e.g. carbohydrate and protein) and habits (e.g. nocturnal fasting duration) highlight potential strategic targets to improve glycaemic metrics derived from continuous glucose monitors.

Whey Protein-Enriched and Carbohydrate-Rich Breakfasts Attenuate Insulinemic Responses to an ad libitum Lunch Relative to Extended Morning Fasting: A Randomized Crossover Trial.

BACKGROUND: Typical breakfast foods are rich in carbohydrate, so they not only elevate blood glucose during the morning, but also elicit a second-meal effect that can attenuate blood glucose responses in the afternoon. OBJECTIVES: To determine whether a reduced-carbohydrate protein-enriched breakfast can elicit similar effects on glucose control later in the day but without hyperglycemia in the morning. METHODS: In a randomized crossover design, 12 healthy men and women (age 22 ± 2 y, BMI 24.1 ± 3.6 kg·m-2; Mean ± SD) completed 3 experimental conditions. In all conditions, participants consumed an ad libitum lunch at 1200 ± 1 h but differed in terms of whether they had fasted all morning (control) or had consumed a standardized porridge breakfast at 0900 ± 1 h (320 ± 50 kcal; prescribed relative to resting metabolic rate) that was either carbohydrate-rich (50 ± 10 g CHO) or protein-enriched (that is, isoenergetic substitution of carbohydrate for 15 g whey protein isolate). RESULTS: The protein-enriched breakfast reduced the morning glycemic response (iAUC 87 ± 36 mmol·L-1·180 min) relative to the carbohydrate-rich breakfast (119 ± 37 mmol·L-1·180 min; P = 0.03). Despite similar energy intake at lunch in all 3 conditions (protein-enriched 769 ± 278 kcal; carbohydrate-rich 753 ± 223 kcal; fasting 790 ± 227 kcal), postlunch insulinemic responses were markedly attenuated when breakfasts had been consumed that were either protein-enriched (18.0 ± 8.0 nmol·L-1·120 min; P = 0.05) or carbohydrate-rich (16.0 ± 7.7 nmol·L-1·120 min; P = 0.005), relative to when lunch was consumed in an overnight fasted state (26.9 ± 13.5 nmol·L-1·120 min). CONCLUSIONS: Breakfast consumption attenuates insulinemic responses to a subsequent meal, achieved with consumption of energy-matched breakfasts typically high in carbohydrates or enriched with whey protein isolate relative to extended morning fasting. TRIAL REGISTRATION NUMBER: NCT03866720 (clinicaltrials.gov).

Adipocyte hypertrophy in mesenchymal stem cells from infants of mothers with obesity.

OBJECTIVE: Fat content of adipocytes derived from infant umbilical cord mesenchymal stem cells (MSCs) predicts adiposity in children through 4 to 6 years of age. This study tested the hypothesis that MSCs from infants born to mothers with obesity (Ob-MSCs) exhibit adipocyte hypertrophy and perturbations in genes regulating adipogenesis compared with MSCs from infants of mothers with normal weight (NW-MSCs). METHODS: Adipogenesis was induced in MSCs embedded in three-dimensional hydrogel structures, and cell size and number were measured by three-dimensional imaging. Proliferation and protein markers of proliferation and adipogenesis in undifferentiated and adipocyte differentiating cells were measured. RNA sequencing was performed to determine pathways linked to adipogenesis phenotype. RESULTS: In undifferentiated MSCs, greater zinc finger protein (Zfp)423 protein content was observed in Ob- versus NW-MSCs. Adipocytes from Ob-MSCs were larger but fewer than adipocytes from NW-MSCs. RNA sequencing analysis showed that Zfp423 protein correlated with mRNA expression of genes enriched for cell cycle, MSC lineage specification, inflammation, and metabolism pathways. MSC proliferation was not different before differentiation but declined faster in Ob-MSCs upon adipogenic induction. CONCLUSIONS: Ob-MSCs have an intrinsic propensity for adipocyte hypertrophy and reduced hyperplasia during adipogenesis in vitro, perhaps linked to greater Zfp423 content and changes in cell cycle pathway gene expression.

Changing estimates of leadership ability before a programme: retrospective self-assessments and response-shift bias.

BACKGROUND: Most evaluations of clinical leadership development programmes rely on self-assessments. Self-assessments are vulnerable to response-shift bias. Using retrospective then-tests may help to avoid this bias.In this study, we investigate whether post-programme then-tests (retrospective self-assessments) are more sensitive to change in clinical leadership development programme participants than traditional pre-programme pre-tests when paired with post-test self-assessments. METHODS: 17 healthcare professionals participated in an 8-month single-centre multidisciplinary leadership development programme. Participants completed prospective pre-test, retrospective then-test and traditional post-test self-assessments using the Primary Colours Questionnaire (PCQ) and Medical Leadership Competency Framework Self-Assessment Tool (MLCFQ). Pre-post pairs and then-post pairs were analysed for changes using Wilcoxon signed-rank tests and compared with a parallel multimethod evaluation organised by Kirkpatrick levels. RESULTS: A greater number of significant changes were detected using then-test pairs than pre-test pairs for both the PCQ (11 of 12 vs 4 of 12 items) and MLCFQ (7 of 7 vs 3 of 7 domains). The multimethods data showed positive outcomes at all Kirkpatrick levels. CONCLUSIONS: In ideal circumstances, both pre-test and then-test evaluations should be conducted. We cautiously suggest that if only one post-programme evaluation can be conducted, then-tests may be appropriate means of detecting change.

Next Generation Leaders Programme: A Multi-Methods Evaluation of a Leadership Development Programme for Biomedical Researchers.

Background: Biomedical scientists have become de facto leaders for their research teams. Theories of expert leadership suggest that the specialist knowledge and credibility these researcher-leaders bring to their roles can lead to improved performance. Formal leadership development for biomedical researchers remains uncommon, and it is unclear whether existing leadership development programmes achieve improved individual and organisational outcomes. Our study evaluates the effectiveness of a single centre leadership development programme for biomedical researchers using a mixed-methods approach. Methods: 26 biomedical researchers participated in an 8 month single centre multidisciplinary leadership development programme. Participants completed prospective pre-test, retrospective then-test and traditional post-test self-assessments using the Primary Colours Questionnaire (PCQ) and Medical Leadership Competency Framework Self-Assessment Tool (MLCFQ). Pre-post pairs and then-post pairs were analysed for changes using Wilcoxon signed-rank tests and compared with a parallel mixed-methods evaluation organised by Kirkpatrick levels. Results: There were significant increases in 3/7 domains and 1/5 tasks of leadership in the PCQ, in both pre-post and then-post paired assessments. There were statistically significant but small increases in 2/7 domains of the MLCFQ. The mixed-methods data showed positive outcomes at all Kirkpatrick levels. Participants said the programme was relevant, interesting and well-organised, with 63% reporting increased confidence and motivation. Participants had a significant change in behaviour, spending 1-2 hours per week on group projects, which were successfully implemented locally. 42% of participants expected these projects to continue beyond the programme. Discussion: This study demonstrates a local leadership programme can have positive impact within a biomedical research centre despite time and financial constraints. We encourage future studies to utilise a mixed-methods approach to evaluating the impact of leadership development programmes.

A salutogenic urban design framework: the case of UK local high streets and older people.

The article provides a novel look at the links between salutogenesis, health promotion, and urban design supported by the findings of recent research on local high streets and their benefits for the well-being of older people. Salutogenesis and the related explanatory concept of sense of coherence (SOC) have provided a theoretical framework for developing healthy settings interventions, shifting the focus from exploring barriers and deficits to assets and resources in promoting people's health and well-being. While these concepts have informed policies and programmes at the level of regions and cities, no attempt has been made to establish more direct links with the disciplines devoted to the organization and design of the built environment at the scale of public spaces and streets. This article advances the idea that the main categories of SOC-comprehensibility, manageability and meaningfulness-have found application in urban design theory. Linking these categories with urban design concepts in a comprehensive framework, it is possible to guide interventions aimed at strenghtening well-being resources available in the public realm. This is corroborated by the findings resulting from a study of the well-being experiences of older people (n = 84) across a range of local high streets in the city of Edinburgh (UK) applying an innovative multi-methods approach. The discussion establishes the links between well-being benefits, SOC constructs and urban design concepts, and underscores the potential of the proposed framework to guide a design-oriented salutogenic approach to the built environment.

In this article, we propose a novel conceptual framework that links health promotion and the theory of salutogenesis with key concepts commonly used in the urban design. The framework is articulated in relation to the findings of recent research on main neighbourhood commercial streets in Edinburgh (UK)­local high streets­and their benefits for the well-being of older people. Salutogenesis theory and related concepts have emphasized the role that everyday environments can have in promoting people's health and well-being, through the opportunities for social interaction and access to material resources they provide. They have informed policies and programmes at city-wide level but not at the scale of streets and public spaces, which is the spatial domain of urban design. The proposed framework establishes the links for a design-oriented salutogenic approach to the built environment and suggests a range of interventions in local high streets that can benefit an ageing population.

Beyond Genes: Inclusion of Alternative Splicing and Alternative Polyadenylation to Assess the Genetic Architecture of Predisposition to Voluntary Alcohol Consumption in Brain of the HXB/BXH Recombinant Inbred Rat Panel.

Post transcriptional modifications of RNA are powerful mechanisms by which eukaryotes expand their genetic diversity. For instance, researchers estimate that most transcripts in humans undergo alternative splicing and alternative polyadenylation. These splicing events produce distinct RNA molecules, which in turn yield distinct protein isoforms and/or influence RNA stability, translation, nuclear export, and RNA/protein cellular localization. Due to their pervasiveness and impact, we hypothesized that alternative splicing and alternative polyadenylation in brain can contribute to a predisposition for voluntary alcohol consumption. Using the HXB/BXH recombinant inbred rat panel (a subset of the Hybrid Rat Diversity Panel), we generated over one terabyte of brain RNA sequencing data (total RNA) and identified novel splice variants (via StringTie) and alternative polyadenylation sites (via aptardi) to determine the transcriptional landscape in the brains of these animals. After establishing an analysis pipeline to ascertain high quality transcripts, we quantitated transcripts and integrated genotype data to identify candidate transcript coexpression networks and individual candidate transcripts associated with predisposition to voluntary alcohol consumption in the two-bottle choice paradigm. For genes that were previously associated with this trait (e.g., Lrap, Ift81, and P2rx4) (Saba et al., Febs. J., 282, 3556-3578, Saba et al., Genes. Brain. Behav., 20, e12698), we were able to distinguish between transcript variants to provide further information about the specific isoforms related to the trait. We also identified additional candidate transcripts associated with the trait of voluntary alcohol consumption (i.e., isoforms of Mapkapk5, Aldh1a7, and Map3k7). Consistent with our previous work, our results indicate that transcripts and networks related to inflammation and the immune system in brain can be linked to voluntary alcohol consumption. Overall, we have established a pipeline for including the quantitation of alternative splicing and alternative polyadenylation variants in the transcriptome in the analysis of the relationship between the transcriptome and complex traits.

Nutrient timing and metabolic regulation.

Daily (circadian) rhythms coordinate our physiology and behaviour with regular environmental changes. Molecular clocks in peripheral tissues (e.g. liver, skeletal muscle and adipose) give rise to rhythms in macronutrient metabolism, appetite regulation and the components of energy balance such that our bodies can align the periodic delivery of nutrients with ongoing metabolic requirements. The timing of meals both in absolute terms (i.e. relative to clock time) and in relative terms (i.e. relative to other daily events) is therefore relevant to metabolism and health. Experimental manipulation of feeding-fasting cycles can advance understanding of the effect of absolute and relative timing of meals on metabolism and health. Such studies have extended the overnight fast by regular breakfast omission and revealed that morning fasting can alter the metabolic response to subsequent meals later in the day, whilst also eliciting compensatory behavioural responses (i.e. reduced physical activity). Similarly, restricting energy intake via alternate-day fasting also has the potential to elicit a compensatory reduction in physical activity, and so can undermine weight-loss efforts (i.e. to preserve body fat stores). Interrupting the usual overnight fast (and therefore also the usual sleep cycle) by nocturnal feeding has also been examined and further research is needed to understand the importance of this period for either nutritional intervention or nutritional withdrawal. In summary, it is important for dietary guidelines for human health to consider nutrient timing (i.e. when we eat) alongside the conventional focus on nutrient quantity and nutrient quality (i.e. how much we eat and what we eat).