Evaluation of the ‘Live Life Better Service’, a community-based weight management service, for morbidly obese patients

Background There is a limited evidence on the effectiveness of lifestyle interventions in achieving and maintaining a significant level of weight loss in morbidly obese patients. This study evaluated the impact on weight loss and psychological well-being of a community-based weight management service for morbidly obese patients [body mass index (BMI) ≥35 with related co-morbidities or BMI >40] in Derbyshire county. Methods Five hundred and fifty-one participants entered the service since 2010, and 238 participants were still active within the service or had completed the 2-year intervention in April 2013. A one-group pre–post design was used to determine average weight loss (kg) and impact on mental health and well-being [using the validated clinical outcomes of routine evaluation-outcome measure (CORE-OM) questionnaire] among participants. Measurements were recorded at baseline, 12 weeks, 24 weeks, 1 year, 18 months and 2 years, and significance (P [less than] 0.05) was determined using the paired sample t-test. Results Statistically significant weight loss was recorded at each measurement point for those participants who remained engaged with the service (4.9 kg weight loss at 12 weeks to 18.2 kg at 2 years). There was a significant positive impact on psychological well-being demonstrated by CORE-OM score. Conclusions Findings show clinically and statistically significant weight loss among participants with improvements in physical and mental health

RISK OF INJURY IN TRAIL RUNNING: A PRELIMINARY STUDY

To evaluate the biomechanical differences between 10 trained trail and matched 9 trained road runners during barefoot (BF) and shod running trials. To determine whether trail runners possess characteristics that are favourable in reducing the risk of running-related injury (RRI) when compared to their road running counterparts kinematic and kinetic data were collected during overground running. Road running controls exhibited greater mean peak knee flexion and footstrike angle while shod compared to shod trail runners. Both groups presented with greater mean vertical loading rate, mean foot pronation (velocity and magnitude) when BF, compared to shod conditions. This paper suggests that road runners may be at greater risk for RRI in comparison to trail runners. Consistent with current evidence, habitually shod runners who engage in BF running may be at greater risk of RRI

An acto-myosin II constricting ring initiates the fission of activity-dependent bulk endosomes in neurosecretory cells

Activity-dependent bulk endocytosis allows neurons to internalize large portions of the plasma membrane in response to stimulation. However, whether this critical type of compensatory endocytosis is unique to neurons or also occurs in other excitable cells is currently unknown. Here we used fluorescent 70 kDa dextran to demonstrate that secretagogue-induced bulk endocytosis also occurs in bovine chromaffin cells. The relatively large size of the bulk endosomes found in this model allowed us to investigate how the neck of the budding endosomes constricts to allow efficient recruitment of the fission machinery. Using time-lapse imaging of Lifeact–GFP-transfected chromaffin cells in combination with fluorescent 70 kDa dextran, we detected acto-myosin II rings surrounding dextran-positive budding endosomes. Importantly, these rings were transient and contracted before disappearing, suggesting that they might be involved in restricting the size of the budding endosome neck. Based on the complete recovery of dextran fluorescence after photobleaching, we demonstrated that the actin ring-associated budding endosomes were still connected with the extracellular fluid. In contrast, no such recovery was observed following the constriction and disappearance of the actin rings, suggesting that these structures were pinched-off endosomes. Finally, we showed that the rings were initiated by a circular array of phosphatidylinositol(4,5)bisphosphate microdomains, and that their constriction was sensitive to both myosin II and dynamin inhibition. The acto-myosin II rings therefore play a key role in constricting the neck of budding bulk endosomes before dynamin-dependent fission from the plasma membrane of neurosecretory cells

The concentration of ethanol affects its penetration rate in bovine cardiac and hepatic tissues

  Introduction. Ethanol is a commonly used fixative. Fixation of the inner layers of the tissue depends on the ability of the fixative to diffuse into the tissue. It is unknown whether the concentration of ethanol affects its penetration into tissues. This study aimed to compare the penetration rates of 50% and 100% ethanol into bovine heart and liver tissues. Materials and methods. The penetration distance and tissue shrinkage or expansion were measured by analysing the digital images of the heart and liver tissues before and after immersion in ethanol at 20°C for 2, 6, 24 or 30 hours. The penetration coefficients were calculated as the slope of the regression line using the linear regres­sion function between the penetration distance and square root of fixation time. Differences in tissue shrinkage or expansion and penetration distance at various time points between the two concentrations of ethanol were analysed using a mixed design ANOVA followed by Bonferroni’s post-hoc test. Results. The penetration distance of 100% ethanol was significantly greater in both heart and liver tissues com­pared with that of 50% ethanol (n = 4, p < 0.05 for both). 100% ethanol shrank immersed liver tissue signifi­cantly more than 50% ethanol (p = 0.002), but the shrinkage of the heart tissue caused by two concentrations of ethanol did not significantly differ (p = 0.054). The greater penetration distance of 100% over 50% ethanol remained unchanged after normalising the penetration distance to the individual tissue’s shrinkage (n = 4, p < 0.001). The mean penetration coefficient of 100% ethanol was significantly greater than 50% ethanol in the heart tissue (0.906 vs. 0.442, p = 0.003) and in the liver tissue (0.988 vs. 0.622, p = 0.028). Conclusions. It was proven that in two types of tissue that substantially differ in histological structures, 100% ethanol penetrated tissue significantly faster than 50% ethanol

The first recorded outbreak of cryptosporidiosis due to Cryptosporidium cuniculus (formerly rabbit genotype), following a water quality incident

Background: We report the first identified outbreak of cryptosporidiosis with Cryptosporidium cuniculus following a water quality incident in Northamptonshire, UK. Methods: A standardised, enhanced Cryptosporidium exposure questionnaire was administered to all cases of cryptosporidiosis after the incident. Stool samples, water testing, microscopy slides and rabbit gut contents positive for Cryptosporidium were typed at the Cryptosporidium Reference Unit, Singleton Hospital, Swansea. Results: Twenty-three people were microbiologically linked to the incident although other evidence suggests an excess of 422 cases of cryptosporidiosis above baseline. Most were adult females; unusually for cryptosporidiosis there were no affected children identified under the age of 5 years. Water consumption was possibly higher than in national drinking water consumption patterns. Diarrhoea duration was negatively correlated to distance from the water treatment works where the contamination occurred. Oocyst counts were highest in water storage facilities. Conclusions: This outbreak is the first caused by C. cuniculus infection to have been noted and it has conclusively demonstrated that this species can be a human pathogen. Although symptomatically similar to cryptosporidiosis from C. parvum or C. hominis, this outbreak has revealed some differences, in particular no children under 5 were identified and females were over-represented. These dissimilarities are unexplained although we postulate possible explanations

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials

The concentration of ethanol affects its penetration rate in bovine cardiac and hepatic tissues

Introduction. Ethanol is a commonly used fixative. Fixation of the inner layers of the tissue depends on the ability of the fixative to diffuse into the tissue. It is unknown whether the concentration of ethanol affects its penetration into tissues. This study aimed to compare the penetration rates of 50% and 100% ethanol into bovine heart and liver tissues. Materials and methods. The penetration distance and tissue shrinkage or expansion were measured by analysing the digital images of the heart and liver tissues before and after immersion in ethanol at 20°C for 2, 6, 24 or 30 hours. The penetration coefficients were calculated as the slope of the regression line using the linear regression function between the penetration distance and square root of fixation time. Differences in tissue shrinkage or expansion and penetration distance at various time points between the two concentrations of ethanol were analysed using a mixed design ANOVA followed by Bonferroni’s post-hoc test. Results. The penetration distance of 100% ethanol was significantly greater in both heart and liver tissues compared with that of 50% ethanol (n = 4, p < 0.05 for both). 100% ethanol shrank immersed liver tissue significantly more than 50% ethanol (p = 0.002), but the shrinkage of the heart tissue caused by two concentrations of ethanol did not significantly differ (p = 0.054). The greater penetration distance of 100% over 50% ethanol remained unchanged after normalising the penetration distance to the individual tissue’s shrinkage (n = 4, p < 0.001). The mean penetration coefficient of 100% ethanol was significantly greater than 50% ethanol in the heart tissue (0.906 vs. 0.442, p = 0.003) and in the liver tissue (0.988 vs. 0.622, p = 0.028). Conclusions. It was proven that in two types of tissue that substantially differ in histological structures, 100% ethanol penetrated tissue significantly faster than 50% ethanol

Elevating the role of carers in rheumatoid arthritis management in the Asia-Pacific region

Aim: Carers may offer valuable insight into the true health status of patients with rheumatoid arthritis (RA). This multinational, multi-stakeholder, exploratory study in Australia, China and Japan aimed to enrich our understanding of the role and potential impact of carers on RA management. Method: This study used a 2-phase sequential mixed methods approach involving 3 key stakeholder groups: rheumatologists, RA patients and carers. The first phase involved an in-depth qualitative exploratory survey (n = 30), which informed the development of the subsequent quantitative validation survey (n = 908). In both phases, patients and carers provided self-assessments of disease and support parameters. Results: In the qualitative phase, patients usually understated the amount of physical support required, compared to carers. Rheumatologists underestimated the amount of physical and emotional care required, compared to carers and patients; however, in the quantitative phase, rheumatologists overestimated the level of support provided by carers. Levels of support provided by carers increased as disease severity increased. Active participation of carers in clinical consultations and treatment decision-making was deemed important by 55% of all patients and 82% of all carers. All stakeholders believed carers’ insights into the physical and emotional conditions of patients were useful and should be considered in clinical decision-making. Over 95% of rheumatologists reported soliciting input from the carer. Conclusion: Carers provide valuable input that can give clinicians greater insight into the patients’ physical and emotional states, and treatment adherence. Development of standardized carer-reported outcomes that correlate with patient-reported outcomes and clinical parameters will ensure clinical meaningfulness and external validity

Nivolumab With or Without Ipilimumab in Pediatric Patients With High-Grade CNS Malignancies: Safety, Efficacy, Biomarker, and Pharmacokinetics: CheckMate 908

BACKGROUND: Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. METHODS: Patients (N=166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg+IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. RESULTS: As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. CONCLUSIONS: NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals