A pilot study investigating plasma pharmacokinetics and tolerance of oral capecitabine in carcinoma-bearing dogs.

BACKGROUND: Capecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks. RESULTS: Capecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m[Formula: see text] by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC[Formula: see text] was 890 h[Formula: see text]ng/ml (range 750-1100 h[Formula: see text]ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose. CONCLUSIONS: Capecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.

Changing socioeconomic and geographic gradients in cardiovascular disease risk factors among Indians aged 15-49 years - evidence from nationally representative household surveys.

Background: Cardiovascular diseases (CVDs) are the leading cause of death in most low- and middle-income countries (LMICs). CVDs and their metabolic risk factors have historically been concentrated among urban residents with higher socioeconomic status (SES) in LMICs such as India. However, as India develops, it is unclear whether these socioeconomic and geographic gradients will persist or change. Understanding these social dynamics in CVD risk is essential for mitigating the rising burden of CVDs and to reach those with the greatest needs. Methods: Using nationally representative data with biomarker measurements from the fourth (2015-16) and fifth (2019-21) Indian National Family and Health Surveys, we investigated trends in the prevalence of four CVD risk factors: smoking (self-reported), unhealthy weight (BMI ≥25 kgm2), diabetes (random plasma glucose concentration ≥200 mg/dL or self-reported diabetes), and hypertension (one of: average systolic blood pressure ≥140 mmHg, average diastolic blood pressure ≥90 mmHg, self-reported past diagnosis, or self-reported current antihypertensive medication use) among adults aged 15-49 years. We first described changes at the national level and then trends stratified by place of residence (urban versus rural), geographic region (northern, northeastern, central, eastern, western, southern), regional level of development (Empowered Action Group member state or not), and two measures of socioeconomic status: level of education (no education, primary incomplete, primary complete, secondary incomplete, secondary complete, higher) and wealth (quintiles). Findings: Unhealthy weight increased among all social and geographic groups but both the absolute and the relative changes were substantially higher among people with low SES (as measured by education or wealth) and in rural areas. For diabetes and hypertension, the prevalence increased for those from disadvantaged groups while staying constant or even decreasing among the wealthier and more educated. In contrast, smoking consumption declined for all social and geographic groups. Interpretation: In 2015-16, CVD risk factors were higher among more advantaged subpopulations in India. However, between 2015-16 and 2019-21, the prevalence of these risk factors grew more rapidly for less wealthy and less educated subpopulations and those living in rural areas. These trends have resulted in CVD risk becoming far more widespread throughout the population; CVD can no longer be characterized as a wealthy urban phenomenon. Funding: This work was supported by the Alexander von Humboldt Foundation (grant received by NS); the Stanford Diabetes Research Center [grant received by PG] and the Chan Zuckerberg Biohub [grant received by PG].

Rapidly Rising Diabetes and Increasing Body Weight: A Counterfactual Analysis in Repeated Cross-sectional Nationally Representative Data from Bangladesh.

BACKGROUND: Diabetes is a growing concern in South Asia but few nationally representative studies identify factors behind this rising disease burden. We studied the nationwide change in diabetes prevalence in Bangladesh, subpopulations disproportionately affected, and the contribution of rising unhealthy weight to the change in diabetes prevalence. METHODS: Based on a sample of 13,959 adults aged 35 years and older with biomarker measurements from the 2011 and 2017/2018 Bangladesh Demographic and Health Surveys, we estimated how the prevalence of diabetes changed nationally and across socioeconomic/geographic groups. Using counterfactual decomposition, we assessed how much the prevalence of diabetes would have grown if body mass index (BMI) had not changed between 2011 and 2017. RESULTS: Diabetes prevalence increased from 12.1% (11.1, 13.1) to 14.4% (13.3, 15.5) between 2011 and 2017/2018. Diabetes grew disproportionately quickly among population groups with higher household wealth, and more education, and in three regions. Over this same period, mean BMI increased from 20.9 (20.8, 21.1) to 22.5 kg/m 2 (22.4, 22.7) and overweight from 25.8 (24.4, 27.3) to 42.1% (40.4, 43.7). Under the counterfactual scenario of constant BMI, diabetes would have risen by only 1.0 (-0.4, 2.4) instead of 2.3 percentage points (0.8, 3.7) nationally, corresponding to a contribution of 58% (-106.3, 221.7). Similarly, group-specific trends were largely attributable to increasing BMI. CONCLUSIONS: Diabetes prevalence in Bangladesh has increased rapidly between 2011 and 2017/2018. Decomposition analysis estimates have wide confidence intervals but are consistent with the hypothesis that this change was driven by the dramatic rise in body weights.

Multimodal Blockade of the Renin-Angiotensin System Is Safe and Is a Potential Cancer Treatment for Cats.

The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats.

Know-do gaps for cardiovascular disease care in Cambodia: Evidence on clinician knowledge and delivery of evidence-based prevention actions.

Cardiovascular diseases (CVD) are the leading cause of death in Cambodia. However, it is unknown whether clinicians in Cambodia provide evidence-based CVD preventive care actions. We address this important gap and provide one of the first assessments of clinical care for CVD prevention in an LMIC context. We determined the proportion of primary care visits by adult patients that resulted in evidence-based CVD preventive care actions, identified which care actions were most frequently missed, and estimated the know-do gap for each clinical action. We used data on 190 direct clinician-patient observations and 337 clinician responses to patient vignettes from 114 public primary care health facilities. Our main outcomes were the proportion of patient consultations and responses to care vignettes where clinicians measured blood pressure, blood glucose, body mass index, and asked questions regarding alcohol, tobacco, physical activity, and diet. There were very large clinical care shortfalls for all CVD care actions. Just 6.4% (95% CI: 3.0%, 13.0%) of patients had their BMI measured, 8.0% (4.6%, 13.6%) their blood pressure measured at least twice, only 4.7% (1.9%, 11.2%) their blood glucose measured. Less than 21% of patients were asked about their physical activity (11.7% [7.0%, 18.9%]), smoking (18.0% [11.8%, 26.5%]), and alcohol-related behaviors (20.2% [13.7%, 28.9%]). We observed the largest know-do gaps for blood glucose and BMI measurements with smaller but important know-do gaps for the other clinical actions. CVD care did not vary across clinician cadre or by years of experience. We find large CVD care delivery gaps in primary-care facilities across Cambodia. Our results suggest that diabetes is being substantially underdiagnosed and that clinicians are losing CVD prevention potential by not identifying individuals who would benefit from behavioral changes. The large overall and know-do gaps suggest that interventions for improving preventive care need to target both clinical knowledge and the bottlenecks between knowledge and care behavior.

The association between the risk of developing type 2 diabetes mellitus and health-related quality of life: baseline results from the Dimini lifestyle intervention.

PURPOSE: The aim of the study was to analyse health-related quality of life (HRQoL) and its determinants in individuals with an increased risk of developing type 2 diabetes mellitus (T2D). METHODS: We used pseudonymized baseline data collected between 2018 and 2020 as part of the Dimini project in Hesse and Schleswig-Holstein. HRQoL was measured by the mental and the physical component score of the validated instrument Short Form 12 and descriptively analysed followed by multiple linear regression analysis. RESULTS: The Dimini population (n = 662) showed an average physical component score of 42.12 (SD 10.56) and a mental component score of 47.12 (SD 11.13). While men demonstrated both significantly higher physical and mental component scores than women, differences based on migration background were not observed. Younger age was associated with a higher level of the physical component score, whereas mental component scores linearly increased with age. Regarding indicators of T2D-risk, a significant influence of HbA1c on HRQoL was not confirmed. However, physical component scores are negatively related to Findrisk scores and BMI. Finally, study participants living alone and those with a handicap reported lower levels of HRQoL. CONCLUSION: Compared with a representative sample of the general German population (DEGS1), Dimini participants were characterized by a lower average HRQoL. The analysis showed a higher vulnerability to an impaired HRQoL within certain subgroups of the population and among participants with relatively higher levels of T2D-risk. As a result, tailored healthcare interventions are required to reach these target groups. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID NCT03482674.

Retrospective evaluation of toceranib phosphate (Palladia) use in cats with mast cell neoplasia.

Objectives The purpose of this study was to solicit and compile data from practicing veterinary specialists regarding their use of toceranib in cats with mast cell neoplasia and to provide initial assessment of possible clinical benefit and adverse events. Methods The American College of Veterinary Internal Medicine and Oncology listservs were used to solicit data pertaining to cases in which toceranib was used in the treatment of feline mast cell neoplasia. Cases were included if the following data were received: signalment (age, sex, breed), diagnosis of mast cell neoplasia by either cytology or histopathology, anatomic classification of disease (cutaneous, splenic/hepatic, gastrointestinal, other), previous and concurrent treatment, toceranib dose (mg/kg) and schedule, duration of therapy, best response and documentation of adverse events. Results Case data from 50 cats with cutaneous (n = 22), splenic/hepatic (visceral) (n = 10), gastrointestinal (n = 17) or other (n = 1) mast cell neoplasia were received. Clinical benefit was seen in 80% (40/50), including 86% (19/22) with cutaneous, 80% (8/10) with visceral and 76% (13/17) with gastrointestinal involvement. A majority of cats (n = 35) received glucocorticoids during toceranib treatment. Median duration of treatment in cats experiencing clinical benefit was 36 weeks (range 4-106 weeks), 48 weeks (range 12-199 weeks) and 23 weeks (range 13-81 weeks) for cutaneous, visceral and gastrointestinal cases, respectively. Toceranib was administered at a median dose of 2.5 mg/kg (range 1.6-3.5 mg/kg); in 90% (45/50) the drug was given three times per week. Treatment was generally well tolerated with 60% (30/50) of cats experiencing adverse events. The majority of these events were low-grade (grade 1 or 2) gastrointestinal or hematologic events that resolved with treatment break and/or dose adjustment. Conclusions and relevance Toceranib appears to be well tolerated in feline patients with mast cell neoplasia. Biologic activity of this drug is evident in the studied cats; however, further prospective studies are needed to elucidate fully its role in treatment of this disease.