Life tables of annual life expectancy and risk factors for mortality in cats in the UK.

OBJECTIVES: The aims of the present study were to generate the first life tables for the UK companion cat population overall as well as broken down by sex and breed status, and to quantify associations between mortality and traits such as sex, neuter status, breed status and body weight in relation to mortality. METHODS: Life table construction and modelling included data on 7936 confirmed deaths in cats under primary veterinary care at clinics participating in the VetCompass Programme in 2019. The life tables were built for cats overall, female and male cats, and crossbred and purebred cats. Multivariable generalised linear regression models were generated to explore the risk factors for a shortened lifespan. RESULTS: Life expectancy at age 0 for UK companion cats overall was 11.74 years (95% confidence interval [CI] 11.61-11.87). The probability of death at each year interval increased with age from year interval 3-4, with the probability value not exceeding 0.05 before year 9. Female cats (12.51 years; 95% CI 12.32-12.69) had a 1.33-year longer life expectancy than male cats (11.18 years; 95% CI 11.01-11.38) at age 0. Among the 12 breeds (including crossbred) analysed, Burmese and Birman had the longest life expectancy at year 0, showing 14.42 years (95% CI 12.91-15.93) and 14.39 years (95% CI 12.87-15.91), respectively. Sphynx had the shortest life expectancy at year 0 among the analysed breeds at 6.68 years (95% CI 4.53-8.83). Being entire, purebred and with a non-ideal body weight were significantly linked to a decreased lifespan. CONCLUSIONS AND RELEVANCE: The life tables presented here for companion cats in the UK overall, by sex, and by crossbred and purebred cats can contribute to a better understanding of the life trajectory of cats, helping with evidence-based decision-making for cat owners and the veterinary profession. We have also provided an updated life expectancy at age 0 for various cat breeds for 2019 and showed evidence of the association between non-ideal weight and a decreased lifespan.

Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts.

BACKGROUND: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

Prediction of recurrence risk in endometrial cancer with multimodal deep learning.

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. Here we developed HECTOR (histopathology-based endometrial cancer tailored outcome risk), a multimodal deep learning prognostic model using hematoxylin and eosin-stained, whole-slide images and tumor stage as input, on 2,072 patients from eight EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal (n = 353) and two external (n = 160 and n = 151) test sets of 0.789, 0.828 and 0.815, respectively, outperforming the current gold standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low-, intermediate- and high-risk groups, respectively, by Kaplan-Meier analysis). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold standard and may help delivery of personalized treatment in EC.

Stimulation of muscle protein synthesis with low-dose amino acid composition in older individuals.

Essential amino acid (EAA)-based compositions have been shown to be effective stimulators of muscle protein synthesis, but the lower limit of effective dosage is not clear. We have used stable isotope tracer methodology to quantify the response of muscle protein fractional synthetic rate (FSR) to a dose of 3.6 g of a high-leucine composition of EAAs plus arginine in older subjects. Muscle protein FSR increased 0.058%/hour over 3 h following consumption. When account was taken of the total muscle mass, this increase in muscle protein FSR represented approximately 80% of ingested EAAs. We conclude that a low dose of an EAA-based composition can effectively stimulate muscle protein synthesis.

Target Trial Emulation: Does surgical versus non-surgical management of cranial cruciate ligament rupture in dogs cause different outcomes?

Target trial emulation applies design principles from randomised controlled trials to the analysis of observational data for causal inference and is increasingly used within human epidemiology. Using anonymised veterinary clinical data from the VetCompass Programme, this study applied the target trial emulation framework to determine whether surgical (compared to non-surgical) management for cranial cruciate ligament (CCL) rupture in dogs causes improved short- and long-term lameness and analgesia outcomes. The emulated target trial included dogs diagnosed with CCL rupture between January 1, 2019 and December 31, 2019 within the VetCompass database. Inclusion in the emulated trial required dogs aged ≥ 1.5 and < 12 years, first diagnosed with unilateral CCL rupture during 2019 and with no prior history of contralateral ligament rupture or stifle surgery. Dogs were retrospectively observed to have surgical or non-surgical management. Informed from a directed acyclic graph derived from expert opinion, data on the following variables were collected: age, breed, bodyweight, neuter status, insurance status, non-orthopaedic comorbidities, orthopaedic comorbidities and veterinary group. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding, with weights calculated based on a binary logistic regression exposure model. Censored dogs were accounted for in the IPTW analysis using inverse probability of censoring weighting (IPCW). The IPCWs were combined with IPTWs and used to weight each dog's contribution to binary logistic regression outcome models. Standardized mean differences (SMD) examined the balance of covariate distribution between treatment groups. The emulated trial included 615 surgical CCL rupture cases and 200 non-surgical cases. The risk difference for short-term lameness in surgically managed cases (compared with non-surgically managed cases) was -25.7% (95% confidence interval (CI) -36.7% to -15.9%) and the risk difference for long-term lameness -31.7% (95% CI -37.9% to -18.1%). The study demonstrated the application of the target trial framework to veterinary observational data. The findings show that surgical management causes a reduction in short- and long-term lameness compared with non-surgical management in dogs.

Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies.

PURPOSE: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. METHODS: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. RESULTS: IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], PINTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], PINTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status. CONCLUSION: IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.

Feline Comorbidities: Hypersomatotropism-induced diabetes in cats.

PRACTICAL RELEVANCE: Diabetes mellitus is the second-most common feline endocrinopathy, affecting an estimated 1/200 cats. While the underlying causes vary, around 15-25% of cats with diabetes mellitus develop the condition secondarily to progressive growth hormone (GH)-induced insulin resistance. This typically results in a form of diabetes that is challenging to manage, whereby the response to insulin is very variable or high doses are required to achieve even minimal diabetic control. CLINICAL CHALLENGES: Although uncontrolled chronic excessive GH may result in phenotypic changes that raise suspicion for acromegaly, many cats with hypersomatotropism (HST) do not have these changes. In these situations, a clinician's index of suspicion may be increased by the presence of less dramatic changes such as marked polyphagia, stertor or uncontrolled diabetes mellitus. The current diagnostic test of choice is demonstration of a markedly increased serum insulin-like growth factor 1 (IGF1) concentration, but some affected cats will have only a marginal increase; additionally, chronic insulin administration in cats results in an increase in serum IGF1, making the diagnosis less clear cut and requiring additional confirmatory tests. EVIDENCE BASE: Over the past two decades, HST has increasingly been recognised as an underlying cause of diabetes mellitus in cats. This review, which focuses on diagnosis and treatment, utilises data from observational studies, clinical trials and case series, as well as drawing on the experience of the authors in managing this condition.

Early Life Androgen Administration Attenuates Aging Related Declines in Muscle Protein Synthesis.

PURPOSE: This study examined the acute and long-term effects of nandrolone decanoate (ND) on fractional synthetic rates (FSR). METHODS: Male C57BL/6 mice were randomized into ND ( n = 20) or sham ( n = 20) groups. ND injections (10 g·kg -1 ·wk -1 ) started at 7 months of ages and continued for 6 wk. Ten animals from each group were randomly separated and examined 1 wk following drug cessation. The remaining animals were examined at 16 months of age. Animals were injected IP with 1.5 mL of deuterated water 24 h before euthanasia. The kidney, liver, heart, gastrocnemius, and soleus were extracted. Samples were analyzed for deuterated alanine enrichment in the bound protein and intracellular fraction by liquid chromatography tandem mass spectrometry to measure estimated FSR (fraction/day (F/D)) of mixed tissue. RESULTS: One-way ANOVA, with treatment and age as fixed factors, indicated that kidney FSR was greater ( P = 0.027) in ND (0.41 ± 0.02 F/D) than sham (0.36 ± 0.014F/D) and higher ( P = 0.003) in young (0.42 ± 0.2 F/D) than old (0.35 ± 0.01 F/D). Liver and heart FSR values were greater ( P ≤ 0.001) in young (0.79 ± 0.06 F/D and 0.13 ± 0.01 F/D, respectively) compared with old (0.40 ± 0.01 F/D and 0.09 ± 0.01 F/D, respectively), but not between ND and sham. Gastrocnemius FSR was ( P ≤ 0.001) greater in young (0.06 ± 0.01 F/D) compared with old (0.03 ± 0.002 F/D), and greater ( P = 0.006) in ND (0.05 ± 0.01 F/D) compared with sham (0.04 ± 0.003 F/D). Soleus FSR rates were greater ( P = 0.050) in young (0.13 ± 0.01 F/D) compared with old (0.11 ± 0.003 F/D), but not between ND (0.12 ± 0.01 F/D) and sham (0.12 ± 0.01 F/D). Old animals who had received ND displayed elevated FSR in the gastrocnemius ( P = 0.054) and soleus ( P = 0.024). CONCLUSIONS: ND use in young adult animals appeared to maintain long-term elevations in FSR in muscle during aging.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II-III colorectal cancer from the SCOT and QUASAR 2 trials: a retrospective analysis.

BACKGROUND: Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS: We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS: After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION: Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

Demography, common disorders and mortality of Shih Tzu dogs under primary veterinary care in the UK.

BACKGROUND: Shih Tzus are a popular dog breed in the UK although there is relatively little reported information on their health. This study aimed to characterise the demography, common disorders and mortality of Shih Tzus under primary veterinary care during 2016 in the UK using de-identified clinical records from the VetCompass™ Programme. RESULTS: The study population of 336,865 dogs under veterinary care during 2016 included 11,082 Shih Tzus (3.3%). The median age was 4.1 years (IQR: 2.1-7.1, range: 0.3-20.4) and mean adult bodyweight was 7.9 kg (SD: 1.9 kg). Annual proportional births increased from 2.2% of all dog births in 2005 to 3.8% in 2013, dropping to 3.3% by 2016. From a random subset of 2,423 Shih Tzus that had information extracted on disorders diagnosed during 2016, the most prevalent fine-level precision disorders were periodontal disease (n = 229, prevalence 9.5%, 95% CI: 8.4-10.7), anal sac impaction (180, 7.4%, 95% CI: 6.5-8.5) and ear disorders (134, 5.5%, 95% CI: 4.7-6.5). The most prevalent grouped-level precision disorders were cutaneous (n = 402, prevalence: 16.6%, 95% CI: 15.2-18.1), dental (322, 13.3%, 95% CI: 12.0-14.7), and ophthalmological (289, 11.9%, 95% CI: 10.7-13.3). Males were more likely than females to be diagnosed with skin disorders (P = 0.007) and musculoskeletal disorders (P = 0.010) while females were more likely than males to be diagnosed with hernias (P = 0.005). The median age of death was 12.7 years (IQR 8.7-14.3, range 2.0-19.9) and did not differ statistically between males and females. The most common grouped causes of death were enteropathy (7.9%, 95% CI: 3.9-15.4), heart disease (7.9%, 95% CI: 3.9-15.4) and poor quality of life (7.9%, 95% CI: 3.9-15.4). CONCLUSIONS: Periodontal disease, anal sac impaction and ear disorders were identified as common health issues. Shih Tzus had higher prevalence of anal sac impaction, umbilical hernias and eye problems than reported previously in dogs overall, suggesting potential predispositions. Shih Tzus appear to be relatively long-lived compared to previous reports of lifespan in dogs overall. The results can inform veterinarians and owners on priority disorders for monitoring to protect welfare. Oral hygiene was highlighted as a healthcare priority.

The Shih Tzu is a popular small breed of dog in the UK. However, there is little information on common health conditions affecting this breed. This study aimed to describe the demography, common disorders, and causes of death of Shih Tzus in the UK in 2016 using the VetCompass™ Programme, which holds a database of anonymized clinical records of dogs attending primary-care veterinary practices in the UK.The study included 11,082 Shih Tzus (3.3%) from 336,865 dogs under veterinary care in the UK in VetCompass™ in 2016. The popularity of the Shih Tzu increased slightly from 2005 to 2013 but showed signs of decline towards 2016. The average age of Shih Tzus in the study was 4.1 years and the average adult bodyweight was 7.9 kg. The most common disorders affecting Shih Tzus in the study were periodontal disease (inflammation of the gums and tissue around the teeth, affecting 9.5% of Shih Tzus), anal sac impaction (7.4%) and ear disorders (5.5%). Male Shih Tzus were more likely than females to have skin and musculoskeletal disorders (conditions affecting bones, muscles and joints), while female Shih Tzus were more likely be diagnosed with hernias (when internal tissues push out through weakened muscle tissues). Shih Tzus had higher prevalence of anal sac impaction, umbilical hernias and eye problems than previously reported in dogs overall, suggesting potential predispositions. The average age at death of Shih Tzus was 12.7 years of age and the most common causes of death were enteropathy (gastrointestinal diseases causing signs such as diarrhoea and vomiting, 7.9%), heart disease (7.9%) and poor quality of life (7.9%).This study demonstrated the value of analysis of veterinary clinical records to increase our understanding of common health problems affecting dogs in the UK. The results can help both current and prospective Shih Tzu owners, and veterinarians, in prioritising preventative healthcare for Shih Tzus. For example, the most common disorder in Shih Tzus was periodontal disease, suggesting that increased preventative dental checkups and toothbrushing could improve welfare, especially if implemented from an early age.

English Cocker Spaniels under primary veterinary care in the UK: disorder predispositions and protections.

BACKGROUND: The English Cocker Spaniel (ECS) is one of the most popular dog breeds in the UK but information on disorder predisposition and protection is limited. Using anonymised veterinary clinical data from the VetCompass™ Programme, this study aimed to compare disorder predisposition and protection between the ECS and the remaining dogs under primary veterinary care in the UK during 2016. Electronic patient records for random samples of ECS and non-ECS were reviewed. The most common disorders diagnosed during 2016 were extracted and compared using multivariable logistic regression, controlling for confounders. RESULTS: The analysis included random samples of 2510/10,313 (24.3%) ECS and 7813/326,552 (2.39%) non-ECS. After accounting for confounding by age, sex, bodyweight within breed-sex, insurance status and veterinary practice group, the ECS had increased odds of 21/43 (48.85%) disorders at fine-level precision, with highest odds for aural discharge (odds ratio (OR) 14.66, 95% confidence interval (CI): 7.73-30.90, P <  0.001) and keratoconjunctivitis sicca (OR 7.64, 95% CI: 4.33-14.14, P <  0.001) and lowest odds for atopic dermatitis (OR 0.14, 95% CI: 0.05-0.31, P <  0.001) and allergy (OR 0.14, 95% CI: 0.06-0.28, P <  0.001). CONCLUSIONS: This study provides evidence for strong predisposition to aural and ocular disorders and protection from hypersensitivity disorders in the ECS. These results can aid dog owners, breeders, and veterinarians to better monitor health in ECS, and promote earlier diagnosis with improved prognosis. Further, the results can help breeding organisations establish key priorities the health-based reforms of the ECS.

Fast food proximity and weight gain in childhood and adolescence: Evidence from Great Britain.

We study the relationship between proximity to fast food restaurants and weight gain from late childhood to early adolescence. We use the Millennium Cohort Study, a UK-wide nationally representative longitudinal study, linked with granular geocoded food outlet data to measure the presence of fast food outlets around children's homes and schools from ages 7 to 14. We find that proximity to fast food outlets is associated with increased weight (body mass index, overweight, obese, body fat, weight), but only among those with maternal education below degree level. Within this sample, those with lower levels of emotional regulation are at heightened risk of weight gain.

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/ß-catenin, mitogen-activated protein kinase, and TGF-ß receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Is it now time to iron out the wrinkles? Health of Shar Pei dogs under primary veterinary care in the UK.

BACKGROUND: The Shar Pei is a common dog breed with a distinctive appearance caused by hyaluronosis that has been linked with several health conditions. Anonymised primary-care veterinary clinical records were explored to extract data on the demography, common disorders and mortality of Shar Pei in the UK in 2013. RESULTS: The study population of 455,557 dogs included 1913 (0.42%) Shar Pei. The mean adult bodyweight was 22.26 kg. The most prevalent fine-level precision disorders were entropion (prevalence 17.88%, 95% CI: 16.16-19.59), otitis externa (16.36%, 95% CI: 14.70-18.02), ear disorders (6.69%, 95% CI: 5.57-7.81), aggression (5.23%, 95% CI: 4.23-6.22), and pyoderma (4.29%, 95% CI: 3.38-5.19). The most prevalent disorder groups were ophthalmologic (prevalence = 22.27%, 95% CI: 20.40-24.13), dermatological (21.01%, 95% CI: 19.19-22.84), aural (18.66%, 95% CI: 16.92-20.41), traumatic injury (7.53%, 95% CI: 6.35-8.71) and behavioural (7.21%, 95% CI: 6.05-8.37). The median longevity of 190 Shar Pei that died during the study period was 7.28 years (IQR 5.04-10.05, range 0.04-15.04). Of 184 deaths with a recorded method of death, 157 (85.33%) deaths involved euthanasia and 27 (14.67%) deaths were unassisted. Among 136 (71.58%) deaths with a recorded biomedical cause of death, the most common causes of death at group level precision were neoplasia (15.44%, 95% CI: 9.37-21.51), renal disorders (13.24%, 95% CI: 7.54-18.93), and behavioural disorders (11.03%, 95% CI: 5.76-16.29). CONCLUSIONS: Almost one fifth of Shar Pei receive veterinary care each year for entropion, a condition linked strongly with the extreme conformation of thickened and folded skin and bristly hair that characterises the Shar Pei breed. Several other common disorders are also linked to hyaluronosis. Current UK legislation can help support efforts to avoid breeding or acquiring animals with extreme conformations and to promote adequate veterinary care for already-owned animals with extreme conformations.

The Shar Pei dog breed is instantly recognisable by their copious loose folded skin and bristly coat, with Shar Pei translating from Chinese as 'sand paper skin'. Although originally a fighting, hunting and guarding dog in China, the Shar Pei breed was re-invented in the US as a companion animal in the late 1970s where a more wrinkled and heavy-set American 'meat mouth' variety replaced the traditional 'bone mouth' variety originally popular in China. However, the underlying disease of hyaluronosis that causes the characteristic extreme appearance of the Shar Pei has also been linked with several other health problems in the breed such as in-turned eyelids (entropion) and ear disease. Using anonymised veterinary clinical records collected within the VetCompass Programme at the Royal Veterinary College (RVC), Shar Pei made up 0.4% of all dogs in the UK in 2013 and had an average adult bodyweight of 22 kg. The most common specific disorders diagnosed in Shar Pei were in-turned eyelids (17.88%), ear infection (16.36%), ear problems (6.69%), aggression (5.23%), and skin infection (4.29%). Among the 30 most common specific disorders, females were more likely to show in-turned eyelids and conjunctivitis, while males were more likely to show aggression and infected paws. Once the disorders were grouped, the most common disorder groups were eye disorders (22.27%), skin (21.01%), ear (18.66%), traumatic injury (7.53%), and behavioural (7.21%). The average lifespan of Shar Pei was 7.28 years. The most common causes of death were cancer (15.44%,), kidney disorders (13.24%), and behavioural disorders (11.03%). This study highlights that almost one fifth of the breed receive veterinary care each year for in-turned eyelids that can lead to extreme pain and are linked to the thickened and folded skin that humans find so appealing in this breed. Current UK legislation can help support concerted efforts from all animal welfare stakeholders to avoid breeding or acquiring animals with these and other extreme conformations and to promote adequate veterinary care for already-owned animals with extreme conformations.

International Society of Sports Nutrition Position Stand: Effects of essential amino acid supplementation on exercise and performance.

Position Statement: The International Society of Sports Nutrition (ISSN) presents this position based on a critical examination of literature surrounding the effects of essential amino acid (EAA) supplementation on skeletal muscle maintenance and performance. This position stand is intended to provide a scientific foundation to athletes, dietitians, trainers, and other practitioners as to the benefits of supplemental EAA in both healthy and resistant (aging/clinical) populations. EAAs are crucial components of protein intake in humans, as the body cannot synthesize them. The daily recommended intake (DRI) for protein was established to prevent deficiencies due to inadequate EAA consumption. The following conclusions represent the official position of the Society: 1. Initial studies on EAAs' effects on skeletal muscle highlight their primary role in stimulating muscle protein synthesis (MPS) and turnover. Protein turnover is critical for replacing degraded or damaged muscle proteins, laying the metabolic foundation for enhanced functional performance. Consequently, research has shifted to examine the effects of EAA supplementation - with and without the benefits of exercise - on skeletal muscle maintenance and performance. 2. Supplementation with free-form EAAs leads to a quick rise in peripheral EAA concentrations, which in turn stimulates MPS. 3. The safe upper limit of EAA intake (amount), without inborn metabolic disease, can easily accommodate additional supplementation. 4. At rest, stimulation of MPS occurs at relatively small dosages (1.5-3.0 g) and seems to plateau at around 15-18 g. 5. The MPS stimulation by EAAs does not require non-essential amino acids. 6. Free-form EAA ingestion stimulates MPS more than an equivalent amount of intact protein. 7. Repeated EAA-induced MPS stimulation throughout the day does not diminish the anabolic effect of meal intake. 8. Although direct comparisons of various formulas have yet to be investigated, aging requires a greater proportion of leucine to overcome the reduced muscle sensitivity known as "anabolic resistance." 9. Without exercise, EAA supplementation can enhance functional outcomes in anabolic-resistant populations. 10. EAA requirements rise in the face of caloric deficits. During caloric deficit, it's essential to meet whole-body EAA requirements to preserve anabolic sensitivity in skeletal muscle.

Dietary protein recommendations to support healthy muscle ageing in the 21st century and beyond: considerations and future directions.

This review explores the evolution of dietary protein intake requirements and recommendations, with a focus on skeletal muscle remodelling to support healthy ageing based on presentations at the 2023 Nutrition Society summer conference. In this review, we describe the role of dietary protein for metabolic health and ageing muscle, explain the origins of protein and amino acid (AA) requirements and discuss current recommendations for dietary protein intake, which currently sits at about 0⋅8 g/kg/d. We also critique existing (e.g. nitrogen balance) and contemporary (e.g. indicator AA oxidation) methods to determine protein/AA intake requirements and suggest that existing methods may underestimate requirements, with more contemporary assessments indicating protein recommendations may need to be increased to >1⋅0 g/kg/d. One example of evolution in dietary protein guidance is the transition from protein requirements to recommendations. Hence, we discuss the refinement of protein/AA requirements for skeletal muscle maintenance with advanced age beyond simply the dose (e.g. source, type, quality, timing, pattern, nutrient co-ingestion) and explore the efficacy and sustainability of alternative protein sources beyond animal-based proteins to facilitate skeletal muscle remodelling in older age. We conclude that, whilst a growing body of research has demonstrated that animal-free protein sources can effectively stimulate and support muscle remodelling in a manner that is comparable to animal-based proteins, food systems need to sustainably provide a diversity of both plant and animal source foods, not least for their protein content but other vital nutrients. Finally, we propose some priority research directions for the field of protein nutrition and healthy ageing.

Resolution of dysglycaemia after treatment of monoclonal gammopathy of endocrine significance.

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Target trial emulation applies design principles from randomised controlled trials to the analysis of observational data for causal inference and is increasingly used within human epidemiology. Veterinary electronic clinical records represent a potentially valuable source of information to estimate real-world causal effects for companion animal species. This study employed the target trial framework to evaluate the usefulness on veterinary observational data. Acute diarrhoea in dogs was used as a clinical exemplar. Inclusion required dogs aged ≥ 3 months and < 10 years, presenting for veterinary primary care with acute diarrhoea during 2019. Treatment strategies were: 1. antimicrobial prescription compared to no antimicrobial prescription and 2. gastrointestinal nutraceutical prescription compared to no gastrointestinal nutraceutical prescription. The primary outcome was clinical resolution (defined as no revisit with ongoing diarrhoea within 30 days from the date of first presentation). Informed from a directed acyclic graph, data on the following covariates were collected: age, breed, bodyweight, insurance status, comorbidities, vomiting, reduced appetite, haematochezia, pyrexia, duration, additional treatment prescription and veterinary group. Inverse probability of treatment weighting was used to balance covariates between the treatment groups for each of the two target trials. The risk difference (RD) of 0.4% (95% CI -4.5% to 5.3%) was non-significant for clinical resolution in dogs treated with antimicrobials compared with dogs not treated with antimicrobials. The risk difference (RD) of 0.3% (95% CI -4.5% to 5.0%) was non-significant for clinical resolution in dogs treated with gastrointestinal nutraceuticals compared with dogs not treated with gastrointestinal nutraceuticals. This study successfully applied the target trial framework to veterinary observational data. The findings show that antimicrobial or gastrointestinal prescription at first presentation of acute diarrhoea in dogs causes no difference in clinical resolution. The findings support the recommendation for veterinary professionals to limit antimicrobial use for acute diarrhoea in dogs.