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.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Epidemiology of heat-related illness in dogs under UK emergency veterinary care in 2022.

BACKGROUND: Dogs are exposed to increasing environmental risk for developing heat-related illness (HRI), with 2022 recorded as the hottest year to date in the UK and most of Europe. METHODS: This study used VetCompass data to report the incidence risk, event fatality rate and canine risk factors for HRI in dogs presenting to Vets Now emergency care practices in the UK during 2022. RESULTS: From the clinical records of 167,751 dogs under care at Vets Now emergency clinics in 2022, 384 HRI events were identified. The 2022 incidence risk of HRI within the Vets Now caseload was 0.23% (95% confidence interval [CI]: 0.21%‒0.25%), with an event fatality rate of 26.56% (95% CI: 21.66%-32.25%). Multivariable analysis identified breed, age and sex/neuter status as risk factors for HRI. Brachycephalic dogs had 4.21 times the odds of HRI compared to mesocephalic dogs (95% CI: 3.22‒5.49, p < 0.001). LIMITATIONS: The clinical data used in this study were not primarily recorded for research and had some substantial levels of missing data (especially patient bodyweight). CONCLUSION: In order to protect canine welfare, improved long-term mitigation strategies are urgently needed to minimise HRI risk and associated fatality in UK dogs.

Researcher, research thyself? Mapping the landscape of canine health and welfare research funding provided by UK not-for-profit organisations from 2012-2022.

BACKGROUND: Research into canine health and welfare is supported by Government, charitable and private UK funding organisations. However, there is no current overall visibility or coordination of these funding activities, potentially compromising optimal distribution of limited resources. This study aimed to survey UK canine health and welfare funding by not-for-profit funders between 2012 and 2022, providing a novel baseline analysis to inform future sector stakeholder priorities. RESULTS: Funding data were collected from 10 wide-scope funders (UK Government funding councils and medical charities), 18 animal-directed funders (organisations specifically concerned with animal health and welfare) and 81 breed community groups. These 109 UK funders together provided traceable canine-relevant funding of £57.8 million during the surveyed period, comprising 684 individual grant awards supporting over 500 separate research projects. Wide-scope funders contributed £41.2 million (71.2% of total funding); animal-directed organisations, £16.3 million (28.1% of total funding); and breed-specific groups, £370K (0.6% of total funding). Individual grants ranged from £2.3 million to £300. Funding patterns varied between sectors. Animal-directed funders provided £14.7 million of canine-relevant research funding that foregrounded the dog, 73% of all such funding; wide-scope funders provided £17.5 million of canine-relevant One Health research funding, 97% of all such funding. Customised metrics developed for this study assessed the 'benefit to the dog' and 'pathway to impact' of individual research projects. Overall, studies supported by animal-directed funders achieved significantly higher 'benefit to the dog' scores (Mann-Whitney U = 45235, p<0.001) and 'pathway to impact' scores (Mann-Whitney U = 43506.5, p<0.001) than those supported by wide-scope funders. CONCLUSION: The landscape of UK not-for-profit funding of canine health and welfare research is complex, with considerable variation between providers. Although wide-scope funders provide the majority of overall canine-relevant research funding, animal-directed funders provide the majority of canine-focused funding and support research with greater direct impact on canine welfare. Visibility of past funding patterns will enable stakeholders in this sector to make more informed decisions about future research. DEFINITIONS: To increase clarity, certain words and phrases are used in specific ways within the context of this paper. Animal-directed funders-Charities and other funding organisations whose remit primarily concerns animals or veterinary work Canine-focused research-Investigations where the primary purpose is to advance understandings of canine health and/or welfare Canine-relevant research-All research that is framed as advancing understandings of canine health and/or welfare as a primary or subsidiary purpose Institution-Refers to universities and other centres where research is carried out Organisation-Refers to funding bodies, including research councils, charities and other groups Research grant-A single funding event originating from one or more funders Research project-A cohesive piece of research concerning a particular topic; may involve multiple researchers and/or multiple research grants, in series or in parallel Wide-scope funders-Large organisations whose remit does not primarily concern animals, i.e. (in this dataset) UKRI councils and the Wellcome Trust.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs, an effective treatment for lymphomas, has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Histoplasma seropositivity and environmental risk factors for exposure in a general population in Upper River Region, The Gambia: A cross-sectional study.

Robust surveillance of Histoplasma species is warranted in endemic regions, including investigation of community-level transmission dynamics. This cross-sectional study explored anti-Histoplasma antibody seroprevalence and risk factors for exposure in a general population in Upper River Region (URR), The Gambia. Study participants were recruited (December 2022-March 2023) by random household sampling across 12 Enumeration Areas (EAs) of URR. A questionnaire and clinical examination were performed; exploring demographic, clinical and environmental risk factors for Histoplasma exposure. One venous blood sample per participant was subject to IMMY Latex Agglutination Histoplasma test to determine presence of a recent IgM response to Histoplasma. Seropositivity risk factors were explored by multi-level, multivariable logistic regression analysis. The study population (n = 298) aged 5-83 years, demonstrated a positively skewed age distribution and comprised 55.4% females. An apparent seroprevalence of 18.8% (n = 56/298, 95% CI 14.5-23.7%) was measured using the LAT. A multivariable model demonstrated increased odds of Histoplasma seropositivity amongst female participants (OR = 2.41 95% CI 1.14-5.10); and participants reporting involvement in animal manure management (OR = 4.21 95% CI 1.38-12.90), and management of domestic animals inside the compound at night during the dry season (OR = 10.72 95% CI 2.02-56.83). Increasing age (OR = 0.96 95% CI 0.93-0.98) was associated with decreased odds of seropositivity. Clustering at EA level was responsible for 17.2% of seropositivity variance. The study indicates frequent recent Histoplasma exposure and presents plausible demographic and environmental risk factors for seropositivity. Histoplasma spp. characterisation at this human-animal-environment interface is warranted, to determine public health implications of environmental reservoirs in The Gambia. The study was supported by Wellcome Trust (206,638/Z/17/Z to CES) and a University of Liverpool-funded PhD studentship (to TRC).

Post-exercise management of exertional hyperthermia in dogs participating in dog sport (canicross) events in the UK.

Exercise is a common trigger of heat-related illness (HRI) events in dogs, accounting for 74% of canine HRI cases treated under primary veterinary care in the United Kingdom. However, few empirical studies have evaluated the effectiveness of differing cooling methods for dogs with exertional hyperthermia or HRI. This study aimed to prospectively evaluate effects of ambient conditions and post-exercise management practices (cooling methods and vehicular confinement) on the post-exercise temperature change of dogs participating in UK canicross events. Canine temperature was recorded at three intervals post-exercise: as close as possible to 0- (immediately post-exercise), 5-, and 15-min post-exercise. Ambient conditions and post-exercise management were recorded for 115 cooling profiles from 52 dogs. In 28/115 (24.4%) profiles, the dog's temperature increased during the first 5-min post-exercise. Overall, 68/115 (59.1%) profiles included passive cooling (stood or walked outside), 35 (30.4%) active cooling (cold-water immersion or application of a cooling coat), and 12 (10.4%) involved no cooling and were immediately housed in vehicles. No dogs developed hypothermia during the study and no adverse effects were observed from any cooling method. In hyperthermic dogs, overall post-exercise body temperature change was significantly negatively associated (i.e. the dogs cooled more) with 0-min post-exercise body temperature (ß = -0.93, p < 0.001), and not being housed in a vehicle (ß = -0.43, p = 0.013). This study provides evidence cold-water immersion (in water at 0.1-15.0 °C) can be used to effectively and safely cool dogs with exertional hyperthermia. Progressive temperature increases in many dogs - even after exercise has terminated - supports the message to "cool first, transport second" when managing dogs with HRI. When transporting dogs post-exercise or with HRI even after active cooling, care should be taken to cool the vehicle before entry and promote air movement around the dog during transport to facilitate ongoing cooling and prevent worsening of hyperthermia during travel.

Surgical outcomes of patients with inferior vena cava leiomyosarcoma.

INTRODUCTION: Primary vascular leiomyosarcomas are incredibly rare and have a poor prognosis. The purpose of this study was to analyze the surgical outcomes of patients with primary inferior vena cava (IVC) leiomyosarcoma. METHODS: We performed a retrospective review of IVC leiomyosarcoma resections performed at a single tertiary care hospital from 2014 to 2023. A total of 13 cases were analyzed, including 10 women and 3 men. The presenting symptoms, tumor characteristics, operative management, postoperative complications, and survival rates were assessed for each patient. RESULTS: The median patient age was 59 years (quartile [Q]1, 52 years; Q3, 68 years). The median tumor size was 7.0 cm (Q1, 6 cm; Q3, 12 cm). The median mitotic rate was 6 per 10 high-power fields (Q1, 2.5; Q3, 15.5). All 13 patients underwent grossly negative tumor resection, with 9 (69%) having microscopically negative margins (R0). No patient had lymph node involvement. The IVCs were managed with ligation in four patients for tumors already occluding the IVC and bovine pericardial patch angioplasty in seven patients or primary repair in two patients for patent IVCs. Concomitant right nephrectomy was performed in seven patients. Left renal vein ligation was performed in three patients, but no left nephrectomies were performed. Significant postoperative complications included one patient with lower extremity compartment syndrome, two patients with severe leg swelling, and one patient with arm swelling. The 30-day mortality rate was zero. Using the Kaplan-Meier product limit method, disease-specific survival was estimated to be 93%. CONCLUSIONS: Surgical resection is a feasible and effective oncologic treatment option for patients with IVC leiomyosarcoma. The IVC can be safely managed by ligation, primary repair, or patch angioplasty, depending on the prior patency of the IVC.

Dental disease in companion rabbits under UK primary veterinary care: Frequency and risk factors.

BACKGROUND: Some prior evidence has suggested that lop-eared rabbits and those with brachycephalic skull conformations have a higher dental disease risk. This retrospective cohort study reports the frequency and conformational risk factors for primary-care veterinary diagnosis with dental disease in companion rabbits in the UK. METHODS: Anonymised VetCompass clinical records were manually reviewed to confirm dental disease cases. Risk factor analysis used multivariable binary logistic regression modelling. RESULTS: From 161,979 rabbits under primary veterinary care in 2019, the 1-year period prevalence of overall dental disease was 15.36% (95% confidence interval [CI]: 14.78-15.96). The prevalence of dental disease affecting incisors was 3.14% (95% CI: 2.87-3.44), and for cheek teeth it was 13.72% (95% CI: 13.17-14.29). Neither lop-eared conformation nor brachycephalic skull conformation was significantly associated with increased odds of dental disease. Dental disease odds increased as age increased and decreased as bodyweight increased. LIMITATIONS: This study retrospectively accessed clinical records, so breed names may sometimes be imprecise. CONCLUSION: The high overall prevalence of dental disease represents a major welfare concern for all companion rabbits, regardless of conformation. This information can be used to encourage regular routine dental assessment of rabbits of all conformations to promote earlier diagnosis, paying particular attention to older rabbits and those with low bodyweight.

Defining the learning curve for robotic pancreaticoduodenectomy for a single surgeon following experience with laparoscopic pancreaticoduodenectomy.

Robotic pancreaticoduodenectomy (RPD) has a learning curve of approximately 30-250 cases to reach proficiency. The learning curve for laparoscopic pancreaticoduodenectomy (LPD) at Duke University was previously defined as 50 cases. This study describes the RPD learning curve for a single surgeon following experience with LPD. LPD and RPD were retrospectively analyzed. Continuous pathologic and perioperative metrics were compared and learning curve were defined with respect to operative time using CUSUM analysis. Seventeen LPD and 69 RPD were analyzed LPD had an inverted learning curve possibly accounting for proficiency attained during the surgeon's fellowship and acquisition of new skills coinciding with more complex patient selection. The learning curve for RPD had three phases: accelerated early experience (cases 1-10), skill consolidation (cases 11-40), and improvement (cases 41-69), marked by reduction in operative time. Compared to LPD, RPD had shorter operative time (379 vs 479 min, p < 0.005), less EBL (250 vs 500, p < 0.02), and similar R0 resection. RPD also had improved LOS (7 vs 10 days, p < 0.007), and lower rates of surgical site infection (10% vs 47%, p < 0.002), DGE (19% vs 47%, p < 0.03), and readmission (13% vs 41%, p < 0.02). Experience in LPD may shorten the learning curve for RPD. The gap in surgical quality and perioperative outcomes between LPD and RPD will likely widen as exposure to robotics in General Surgery, Hepatopancreaticobiliary, and Surgical Oncology training programs increase.

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.

Plasma Growth Hormone as a Prognostic Biomarker to Durvalumab and Tremelimumab in Patients with Advanced Hepatocellular Carcinoma.

Introduction: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 16 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023 and had plasma GH measurements recorded before treatment. Plasma GH levels were measured from prospectively collected blood samples and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 µg/L and ≤0.9 µg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Sixteen patients were included in this analysis, two female and fourteen male, with a median age of 65.5 years. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusion: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Demography, commonly diagnosed disorders and mortality of guinea pigs under primary veterinary care in the UK in 2019-A VetCompass study.

INTRODUCTION: Guinea pigs are popular as domestic pets but there is limited information on the health of the wider pet population. This study aimed to report demography, commonly diagnosed disorders and mortality of guinea pigs under UK primary veterinary care. METHODS: Diagnosis and mortality information on guinea pigs was extracted from anonymised UK primary-care clinical records in VetCompass. RESULTS: From 51,622 guinea pigs under primary veterinary care during 2019, a specific breed was not recorded in 50,098 (97.05%). Of guinea pigs with information recorded, 23,206 (47.33%) were female and 25,828 (52.67%) were male. There were 1,020 (2.08%) neutered and 48,014 (97.92%) entire. Median adult bodyweight overall was 1.05kg (interquartile range [IQR] 0.90-1.19, range 0.40-2.66). From a random sample of 3,785/51,622 (7.33%) guinea pigs, the most prevalent disorders were overgrown nail(s) (n = 1,005, 26.55%, 95% confidence interval [CI] 25.15-27.99), dermatophytosis (228, 6.02%, 95% CI 5.29-6.83) and corneal ulceration (189, 4.99%, 95% CI 4.32-5.74). Among the 30 most common disorders, females showed predisposition for 3 disorders and males showed predisposition for 5 disorders. The disorder with the youngest age of affected animals was dermatophytosis (1.11 years) while weight loss had the oldest age of affected animals (4.64 years). From 757 recorded deaths, the median age at death overall was 4.03 years (IQR 2.56-5.44, range 0.17-10.00). Among deaths with a recorded cause, the most common causes of death were anorexia (n = 82, 13.87%, 95% CI 11.19-16.93), collapsed (58, 9.81%, 95% CI 7.54-12.50) and peri-anaesthetic death (20, 3.38%, 95% CI 2.08-5.18). CONCLUSIONS: These results can assist veterinarians and owners by providing demographic, disorder and mortality benchmarks that support improved clinical care and welfare outcomes in guinea pigs. Many common disorders in guinea pigs were husbandry related.

Simple versus radical cholecystectomy and survival for pathologic stage T1B gallbladder cancer.

BACKGROUND: Radical cholecystectomy is recommended for T1B and greater gallbladder cancer, however, there are conflicting reports on the utility of extended resection for T1B disease. Herein, we characterize outcomes following simple and radical cholecystectomy for pathologic stage T1B gallbladder cancer. METHODS: The National Cancer Database (NCDB) was queried for patients with pathologic T1B gallbladder cancer diagnosed from 2004 to 2018. Patients were stratified by surgical management. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Altogether, 950 patients were identified with pathologic T1B gallbladder cancer: 187 (19.7 %) receiving simple and 763 (80.3 %) radical cholecystectomy. Median OS was 89.5 (95 % CI 62.5-137) and 91.4 (95 % CI 75.9-112) months for simple and radical cholecystectomy, respectively (log-rank p = 0.55). Receipt of simple cholecystectomy was not associated with greater hazard of mortality compared to radical cholecystectomy (HR 1.23, 95 % CI 0.95-1.59, p = 0.12). DISCUSSION: In this analysis, we report comparable outcomes with simple cholecystectomy among patients with pathologic T1B gallbladder cancer. These findings suggest that highly selected patients, such as those with R0 resection and imaging at low risk for residual disease and/or nodal metastasis, may not benefit from extended resection; however, radical cholecystectomy remains standard of care until prospective validation can be achieved.

Impacts of Puppy Early Life Experiences, Puppy-Purchasing Practices, and Owner Characteristics on Owner-Reported Problem Behaviours in a UK Pandemic Puppies Cohort at 21 Months of Age.

Problem behaviours are a leading cause of relinquishment and euthanasia of young dogs. Previous research has identified associations between owner-reported problem behaviours and risk factors, including how dogs were acquired as puppies, early socialisation experiences, and owners' experience levels. Puppies acquired during the 2020 phase of the UK COVID-19 pandemic ("Pandemic Puppies") were more likely to be exposed to many of these risk factors compared to puppies acquired in 2019; however, consequences for their adult behaviour are, as yet, unexplored. This study aimed to investigate the impact of these early-life and provenance-based risk factors, in addition to owner management strategies (including training methods) into early adulthood, upon adult dog behaviour aged 21 months. An online longitudinal cohort study of n = 985 Pandemic Puppies was conducted, recruited from a cohort of n = 4369 puppies originally surveyed in November-December 2020, which included data on how and why they were acquired and their socialisation/habituation experiences <16 weeks of age. Nearly all owners (96.7%) reported that their dog had exhibited at least one problem behaviour up to 21 months of age (median: 5; IQR: 3-7). Almost one third of dogs (30.9%) were reported to have displayed separation-related behaviours. Multivariable linear regression modelling revealed that owners reporting more problem behaviours were more likely to use multiple aversive training techniques (e.g., physical punishment), the use of which was notably high in this population (82.3%) compared to previous studies. Attendance at online puppy classes was the sole protective factor against owner use of aversive training methods. Almost one third of owners had underestimated how hard training their dog would be; this view was more likely among first-time owners. Urgent efforts are required to support this vulnerable population of dogs, including providing owner education regarding humane training techniques, to improve canine emotional health and avoid future relinquishment and/or behavioural euthanasia.

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.

The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer.

BACKGROUND & PURPOSE: Radium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models. MATERIALS & METHODS: We conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models-orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice-we tested the efficacy of combining Ra223 with ICI. RESULTS: Above-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue. CONCLUSION: The inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8+ T cell infiltration and proliferation and could improve OS when combined with anti-PD-1 ICI.

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.