Gene Expression in Skeletal Muscle Biopsies from People with Type 2 Diabetes and Relatives: Differential Regulation of Insulin Signaling Pathways

BACKGROUND:Gene expression alterations have previously been associated with type 2 diabetes, however whether these changes are primary causes or secondary effects of type 2 diabetes is not known. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease. METHODS/PRINCIPAL FINDINGS:We determined gene expression profiles in skeletal muscle biopsies from Caucasian males with type 2 diabetes, healthy first degree relatives, and healthy controls. Gene expression was measured using Affymetrix Human Genome U133 Plus 2.0 Arrays covering the entire human genome. These arrays have not previously been used for this type of study. We show for the first time that genes involved in insulin signaling are significantly upregulated in first degree relatives and significantly downregulated in people with type 2 diabetes. On the individual gene level, 11 genes showed altered expression levels in first degree relatives compared to controls, among others KIF1B and GDF8 (myostatin). LDHB was found to have a decreased expression in both groups compared to controls. CONCLUSIONS/SIGNIFICANCE:We hypothesize that increased expression of insulin signaling molecules in first degree relatives of people with type 2 diabetes, work in concert with increased levels of insulin as a compensatory mechanism, counter-acting otherwise reduced insulin signaling activity, protecting these individuals from severe insulin resistance. This compensation is lost in people with type 2 diabetes where expression of insulin signaling molecules is reduced

A Research Strategy Case Study of Alcohol and Drug Prevention by Non-Governmental Organizations in Sweden 2003-2009

<p>Abstract</p> <p>Background</p> <p>Alcohol and drug prevention is high on the public health agenda in many countries. An increasing trend is the call for evidence-based practice. In Sweden in 2002 an innovative project portfolio including an integrated research and competence-building strategy for non-governmental organisations (NGOs) was designed by the National Board of Health and Welfare (NBHW). This research strategy case study is based on this initiative.</p> <p>Methods</p> <p>The embedded case study includes 135 projects in 69 organisations and 14 in-depth process or effect studies. The data in the case study has been compiled using multiple methods - administrative data; interviews and questionnaires to project leaders; focus group discussions and seminars; direct and participatory observations, interviews, and documentation of implementation; consultations with the NBHW and the NGOs; and a literature review. Annual reports have been submitted each year and three bi-national conferences Reflections on preventions have been held.</p> <p>Results</p> <p>A broad range of organisations have been included in the NBHW project portfolio. A minority of the project were run by Alcohol or drug organisations, while a majority has children or adolescents as target groups. In order to develop a trustful partnership between practitioners, national agencies and researchers a series of measures were developed and implemented: meeting with project leaders, project dialogues and consultations, competence strengthening, support to documentation, in-depth studies and national conferences. A common element was that the projects were program-driven and not research-driven interventions. The role of researchers-as-technical advisors was suitable for the fostering of a trustful partnership for research and development. The independence of the NGOs was regarded as important for the momentum in the project implementation. The research strategy also includes elements of participatory research.</p> <p>Conclusions</p> <p>This research strategy case study shows that it is possible to integrate research into alcohol and drug prevention programs run by NGOs, and thereby contribute to a more evidence-based practice. A core element is developing a trustful partnership between the researchers and the organisations. Moreover, the funding agency must acknowledge the importance of knowledge development and allocating resources to research groups that is capable of cooperating with practitioners and NGOs.</p

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Funder: Victorian Cancer AgencyFunder: NIHR Manchester Biomedical Research CentreFunder: Cancer Research UKFunder: Cancer Council TasmaniaFunder: Instituto de Salud Carlos IIIFunder: Cancer AustraliaFunder: NIHR Oxford Biomedical Research CentreFunder: Fundación Científica de la Asociación Española Contra el CáncerFunder: Cancer Council South AustraliaFunder: Swedish Cancer SocietyFunder: NIHR Cambridge Biomedical Research CentreFunder: Institut Català de la SalutFunder: Cancer Council VictoriaFunder: Prostate Cancer Foundation of AustraliaFunder: National Institutes of HealthBACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI &lt;18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For school&#x2;aged children and adolescents, we report thinness (BMI &lt;2 SD below the median of the WHO growth reference) and obesity (BMI &gt;2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Management of patients with advanced prostate cancer. Report from the 2024 advanced prostate cancer consensus conference (APCCC)

© in press The Authors. Published by Elsevier. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.eururo.2024.09.017BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.Published onlin

β-Lactoglobulin fouling and its removal upon rinsing and by SDS as influenced by surface characteristics, temperature and adsorption time

The extensive fouling common in the food industry puts high demands on equipment cleaning. The adsorption of β-lactoglobulin and its removal by the anionic surfactant sodium dodecyl sulphate (SDS) were followed at pH 6.0 using in situ ellipsometry. Hydrophilic chromium oxide and stainless steel together with hydrophobic methylated silica were studied at different temperatures. Differences between chromium oxide and steel were small, while hydrophobic silica showed significantly different initial adsorption kinetics and adsorbed amounts. Also, the temperature-dependence of the amount desorbed upon rinsing as well as of the overall cleanability differed greatly. At around the β-lactoglobulin denaturation temperature, multilayer build-up at the surface was seen, and the cleanability was very low. Of two protein adsorption times employed, the longer resulted, for metal oxide surfaces, in less desorption during rinsing

Some surface-related aspects of the cleaning of new and reused stainless-steel surfaces fouled by protein

The adsorption of β-lactoglobulin to stainless steel and its subsequent alkali-induced removal were followed using ellipsometry. New steel samples differing in bulk composition, surface finish or chemical pretreatment were used. All surfaces were precleaned in strongly alkaline solution, and some were subsequently passivated in nitric acid. Furthermore, on surfaces differing in pretreatment measurements were performed during repeated fouling and cleaning cycles. No correlation was found between the bulk composition or the surface finish and the fouling tendency or the cleanability. However, striking differences in cleanability between stainless-steel surfaces subjected to different chemical pretreatments were evident, particularly at low temperature. Still, only minor effects on the fouling tendency were observed. When subjecting surfaces to repeated fouling and cleaning without renewed pretreatment, the differences in cleaning performance decreased but were still significant. While the cleanability of non-passivated surfaces appeared to decrease somewhat when reused, changes seemed smaller for passivated surfaces

Time and temperature aspects of β-lactoglobulin removal from methylated silica surfaces by sodium dodecyl sulphate

The adsorption of β-lactoglobulin onto methylated silica surfaces and the subsequent protein removal by the anionic surfactant sodium dodecyl sulphate (SDS) were followed using in-situ ellipsometry. Experiments were performed at pH 6.0 in phosphate-buffered saline solution. Parameters varied include temperature, length of time for protein adsorption from solution and surface residence time of β-lactoglobulin. The temperature was kept constant throughout a trial, and the majority of experiments were carried out at a few degrees below the protein denaturation temperature as reported from differential scanning calorimetry studies. β-Lactoglobulin adsorption at high temperatures resulted in aggregation at the surface after a lag phase of several minutes. Varying the protein adsorption time and thus the amount adsorbed while keeping the protein surface residence time fixed did not seem to affect the amount desorbed upon rinsing or the amount eluted by surfactant. For short β-lactoglobulin adsorption times, the adsorbed amounts were comparable at all temperatures studied. The temperature hardly affected the amount desorbed during rinsing, but did however have a pronounced influence on the protein removed by surfactant. Up to around 60°C practically all β-lactoglobulin was eluted by the SDS. The fraction removed then decreased with temperature, with a sharp drop between 70 and 73°C, and a further decline at higher levels. SDS was seen to be highly inefficient at removing β-lactoglobulin adsorbed at temperatures above 70°C. The trend observed is attributed to temperature-dependent changes in the protein resident on the surface. The β-lactoglobulin surface residence time was seen to significantly affect the elutability. At short residence times the removal efficiency was comparably high, but decreased with time. However, no significant difference could be detected between two sufficiently long residence times. The behaviour is consistent with the assumption of multiple states of adsorbed proteins, together with slow conformational changes in the adsorbed protein layer