Changes in weight status of caregivers of children and adolescents enrolled in a community-based healthy lifestyle programme: Five-year follow-up.

Whanau Pakari is a family-centred healthy lifestyle programme for children/adolescents with overweight/obesity in New Zealand. This secondary analysis from our randomised trial within the clinical service assessed 5-year BMI changes in accompanying caregivers (n = 23), mostly mothers. Overall, baseline and 5-year caregivers' BMI were similar (32.50 vs 31.42 kg/m2, respectively; p = 0.31) but two-thirds (65%) experienced BMI reductions. Five-year BMI change was similar in High-intensity and Low-intensity randomisation groups [-1.37 kg/m2 (-4.95, 2.21); p = 0.44]. Caregiver's BMI change was not associated with child's BMI change. Despite no overall BMI reduction, our findings contrast with upward BMI trajectories predicted for NZ adults with overweight/obesity.

Associations between changes in caregiver's and child's weight status in a community-based obesity intervention programme.

OBJECTIVES: We examined whether caregivers of children/adolescents enroled in a randomised controlled trial (RCT) of a family-centred intervention indirectly achieved reductions in body mass index (BMI), and if these were associated with changes in their children's BMI. METHODS: RCT participants were New Zealand children/adolescents aged 4.8-16.8 years with BMI ≥ 98th percentile or >91st with weight-related comorbidities. Participants and accompanying caregivers were assessed at baseline, 12, and 24 months. RESULTS: Overall, caregivers' BMI was unchanged at 12 or 24 months. Among Maori participants, reductions in caregivers' BMI at 12 months were associated with reductions in their children's BMI SDS at 12 (r = 0.30; p = 0.038) and 24 months (r = 0.39; p = 0.009). Further, children identifying as Maori whose caregivers' BMI decreased at 12 months had greater BMI SDS reductions at 12 months [-0.30 (95% CI -0.49, -0.10); p = 0.004] and 24 months [-0.39 (95% CI -0.61, -0.16); p = 0.001] than children of caregivers with increased/unchanged BMI. CONCLUSIONS: This intervention programme for children/adolescents with obesity did not indirectly reduce caregiver weight status. However, reductions in caregivers' BMI were key to BMI SDS reductions among Maori participants. Given the intergenerational nature of obesity, our findings highlight the importance of culturally relevant, family-focused programmes to achieve clinically meaningful improvements in weight status across the family.

US-Focused Conceptual Health Care Decision-Analytic Models Examining the Value of Pivmecillinam Relative to Current Standard-of-Care Agents Among Adult Patients With Uncomplicated Urinary Tract Infections due to Enterobacterales.

BACKGROUND: Pivmecillinam is approved for the treatment of adults with uncomplicated urinary tract infection (uUTI) in Canada and Europe and is pending United States (US) Food and Drug Administration submission for consideration for approval. US-focused health care decision-analytics were developed to define the value of an agent like pivmecillinam relative to current standard-of-care (SOC) agents among adult patients with Enterobacterales uUTIs based on its improved microbiologic activity against common Enterobacterales. METHODS: The model population was 100 theoretical adult outpatients with Enterobacterales uUTIs under 4 different uUTI first-line empiric treatment scenarios (ie, pivmecillinam, nitrofurantoin, trimethoprim-sulfamethoxazole [SXT], or fluoroquinolones). The total mean uUTI-related 30-day costs, including inappropriate treatment costs, were calculated for each regimen. The range of pivmecillinam regimen costs that conferred cost savings relative to the current SOC agents based on its potentially improved microbiologic activity against common Enterobacterales was determined. RESULTS: The 30-day uUTI-related costs associated with nitrofurantoin, SXT, and fluoroquinolones were $655.61, $687.57, and $659.69, respectively. The pivmecillinam neutral regimen cost thresholds that resulted in the same uUTI-related 30-day per-patient costs for nitrofurantoin, SXT, and fluoroquinolones were $83.50, $115.45, and $87.58, respectively. The overall antimicrobial susceptibility improvement required with pivmecillinam fixed at $200/regimen, for it to be cost savings relative to SOC agents, was 28%. CONCLUSIONS: The analyses suggests that an agent like pivmecillinam, if approved in the US, has the potential to reduce the economic burden associated with inappropriate treatment of adult outpatients with uUTIs, especially in patients at high risk for an Enterobacterales uUTI that is resistant to SOC agents.

TGF-ß signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves.

AIMS: Myxomatous mitral valve disease (MMVD) is associated with leaflet thickening, fibrosis, matrix remodelling, and leaflet prolapse. Molecular mechanisms contributing to MMVD, however, remain poorly understood. We tested the hypothesis that increased transforming growth factor-ß (TGF-ß) signalling and reactive oxygen species (ROS) are major contributors to pro-fibrotic gene expression in human and mouse mitral valves. METHODS AND RESULTS: Using qRT-PCR, we found that increased expression of TGF-ß1 in mitral valves from humans with MMVD (n = 24) was associated with increased expression of connective tissue growth factor (CTGF) and matrix metalloproteinase 2 (MMP2). Increased levels of phospho-SMAD2/3 (western blotting) and expression of SMAD-specific E3 ubiquitin-protein ligases (SMURF) 1 and 2 (qRT-PCR) suggested that TGF-ß1 signalling occurred through canonical signalling cascades. Oxidative stress (dihydroethidium staining) was increased in human MMVD tissue and associated with increases in NAD(P)H oxidase catalytic subunits (Nox) 2 and 4, occurring despite increases in superoxide dismutase 1 (SOD1). In mitral valves from SOD1-deficient mice, expression of CTGF, MMP2, Nox2, and Nox4 was significantly increased, suggesting that ROS can independently activate pro-fibrotic and matrix remodelling gene expression patterns. Furthermore, treatment of mouse mitral valve interstitial cells with cell permeable antioxidants attenuated TGF-ß1-induced pro-fibrotic and matrix remodelling gene expression in vitro. CONCLUSION: Activation of canonical TGF-ß signalling is a major contributor to fibrosis and matrix remodelling in MMVD, and is amplified by increases in oxidative stress. Treatments aimed at reducing TGF-ß activation and oxidative stress in early MMVD may slow progression of MMVD.