Fast versus slow weight loss: development process and rationale behind the dietary interventions for the TEMPO diet trial

OBJECTIVE AND METHODS: Finding effective solutions to curb the obesity epidemic is a great global public health challenge. The need for long‐term follow‐up necessitates weight loss trials conducted in real‐world settings, outside the confines of tightly controlled laboratory or clinic conditions. Given the complexity of eating behaviour and the food supply, this makes the process of designing a practical dietary intervention that stands up to scientific rigor difficult. Detailed information about the dietary intervention itself, as well as the process of developing the final intervention and its underlying rationale, is rarely reported in scientific weight management publications but is valuable and essential for translating research into practice. Thus, this paper describes the design process and underlying rationale behind the dietary interventions in an exemplar weight loss trial – the TEMPO Diet Trial (Type of Energy Manipulation for Promoting optimal metabolic health and body composition in Obesity). This trial assesses the long‐term effects of fast versus slow weight loss on adiposity, fat free mass, muscle strength and bone density in women with obesity (body mass index 30–40 kg m(−2)) that are 45–65 years of age, postmenopausal and sedentary. RESULTS AND CONCLUSIONS: This paper is intended as a resource for researchers and/or clinicians to illustrate how theoretical values based on a hypothesis can be translated into a dietary weight loss intervention to be used in free‐living women of varying sizes

A systematic review on the clustering and co-occurrence of multiple risk behaviours.

BACKGROUND: Risk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK. METHODS: Key databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses. RESULTS: Thirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse. The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications). CONCLUSIONS: Among general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours. This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

Drug delivery to pancreatic tumors is impaired by a unique desmoplastic response and poor tumor vascularization. A drug delivery device capable of overcoming these barriers could provide substantial benefit for patients with pancreatic cancer. In this study, we show that local iontophoretic delivery of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in better tumor response and tolerability compared with i.v. FOLFIRINOX. Given the low systemic exposure of FOLFIRINOX using iontophoretic delivery, it may be possible to use in combination with systemic delivery to treat micrometastatic disease. Local iontophoretic delivery of cytotoxic agents should be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer

Longitudinal evaluation of proton magnetic resonance spectroscopy metabolites as biomarkers in Huntington’s disease

Proton Magnetic resonance spectroscopy (1H-MRS) is a non-invasive method of exploring cerebral metabolism. In Huntington’s disease, altered 1H-MRS-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. 1H-MRS metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardised collection of CSF, blood, phenotypic and volumetric imaging data, we used 3T 1H-MRS in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington’s disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington’s disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between 1H-MRS metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline 1H-MRS values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed effects models revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that 1H-MRS metabolites have limited potential as Huntington’s disease biomarkers

Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer

Novel treatment strategies, including nanomedicine, are needed for improving management of triple-negative breast cancer. Patients with triple-negative breast cancer, when considered as a group, have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, a finding that reflects the intrinsically adverse prognosis associated with the disease. The aim of this study was to improve the efficacy of docetaxel by incorporation into a novel nanoparticle platform for the treatment of taxane-resistant triple-negative breast cancer. Rod-shaped nanoparticles encapsulating docetaxel were fabricated using an imprint lithography based technique referred to as Particle Replication in Nonwetting Templates (PRINT). These rod-shaped PLGA-docetaxel nanoparticles were tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represents the basal-like subtype of triple-negative breast cancer and is resistant to therapeutics from the taxane family. Thi..

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR 0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001). INTERPRETATION: We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact. FUNDING: Wellcome Trust, CHDI Foundation

Severe 2010 Cold-Water Event Caused Unprecedented Mortality to Corals of the Florida Reef Tract and Reversed Previous Survivorship Patterns

Background Coral reefs are facing increasing pressure from natural and anthropogenic stressors that have already caused significant worldwide declines. In January 2010, coral reefs of Florida, United States, were impacted by an extreme cold-water anomaly that exposed corals to temperatures well below their reported thresholds (16°C), causing rapid coral mortality unprecedented in spatial extent and severity. Methodology/Principal Findings Reef surveys were conducted from Martin County to the Lower Florida Keys within weeks of the anomaly. The impacts recorded were catastrophic and exceeded those of any previous disturbances in the region. Coral mortality patterns were directly correlated to in-situ and satellite-derived cold-temperature metrics. These impacts rival, in spatial extent and intensity, the impacts of the well-publicized warm-water bleaching events around the globe. The mean percent coral mortality recorded for all species and subregions was 11.5% in the 2010 winter, compared to 0.5% recorded in the previous five summers, including years like 2005 where warm-water bleaching was prevalent. Highest mean mortality (15%–39%) was documented for inshore habitats where temperatures were \u3c11°C for prolonged periods. Increases in mortality from previous years were significant for 21 of 25 coral species, and were 1–2 orders of magnitude higher for most species. Conclusions/Significance The cold-water anomaly of January 2010 caused the worst coral mortality on record for the Florida Reef Tract, highlighting the potential catastrophic impacts that unusual but extreme climatic events can have on the persistence of coral reefs. Moreover, habitats and species most severely affected were those found in high-coral cover, inshore, shallow reef habitats previously considered the “oases” of the region, having escaped declining patterns observed for more offshore habitats. Thus, the 2010 cold-water anomaly not only caused widespread coral mortality but also reversed prior resistance and resilience patterns that will take decades to recover

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Validation of remote collection and quantification of blood Neurofilament light in neurological diseases

Promising blood-based biomarkers of neuropathology have emerged with potential for therapeutic development and disease monitoring. However, these tools will require specialist tertiary services for integration into clinical management. Remote sampling for biomarker assessment could ease the burden of in-person clinical visits for such tests and allow for frequent sampling. Here we evaluated a capillary finger-prick collection for remote quantification of blood neurofilament light (NfL), a common blood-based biomarker evident in various neurological disorders, and other exploratory markers of neuronal injury and neuroinflammation (GFAP, tau). Matched samples from venepuncture and finger-prick were collected and processed into plasma and/or serum to directly compare NfL levels across four different neurological conditions (HD, MS, ALS, PD). Two delayed processing conditions were compared, three- and seven-day delay, simulating ambient shipment. Capillary NfL and GFAP concentrations were equivalent to those in venous blood serum and plasma. Only NfL remained stable after seven-day processing delay. Capillary NfL replicated disease group differences displayed in venous blood. This data supports our finger-prick method for remote collection and quantification of NfL. With the widespread applications for NfL across the spectrum of neurological disorders, this has the potential to transform disease monitoring, prognosis, and therapeutic development within clinical practice and research

Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition

PurposeThe incidence of small intestinal cancer (SIC) is increasing, however, its aetiology remains unclear due to a lack of data from large-scale prospective cohorts. We examined modifiable risk factors in relation to SIC overall and by histological subtype.MethodsWe analysed 450,107 participants enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. Cox proportional hazards models were used to estimate univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring an average of 14.1 years of follow-up, 160 incident SICs (62 carcinoids, 51 adenocarcinomas) were identified. Whilst univariable models revealed a positive association for current versus never smokers and SIC (HR, 95% CI: 1.77, 1.21-2.60), this association attenuated in multivariable models. In energy-adjusted models, there was an inverse association across vegetable intake tertiles for SIC overall (HRT3vsT1, 95% CI: 0.48, 0.32-0.71, p-trend: < 0.001) and for carcinoids (HRT3vsT1, 95% CI: 0.44, 0.24-0.82, p-trend: 0.01); however, these attenuated in multivariable models. Total fat was also inversely associated with total SIC and both subtypes but only in the second tertile (SIC univariable HRT2vsT1, 95% CI: 0.57, 0.38-0.84; SIC multivariable HRT2vsT1, 95% CI: 0.55, 0.37-0.81). Physical activity, intake of alcohol, red or processed meat, dairy products, or fibre were not associated with SIC.ConclusionThese exploratory analyses found limited evidence for a role of modifiable risk factors in SIC aetiology. However, sample size was limited, particularly for histologic subtypes; therefore, larger studies are needed to delineate these associations and robustly identify risk factors for SIC