Suchergebnisse

Background: Liberia is a West African country that needs substantial investment to strengthen its National Malaria Control Programme (NMCP), which was disrupted during the 2014–2016 Ebola epidemic. As elsewhere, Liberian pregnant women are especially vulnerable to malaria. Understanding prevention and treatment-seeking behaviours among the population is crucial to strategize context-specifc and women-centred actions, including locally-led malaria research, to improve women's demand, access and use of NMCP strategies against malaria in pregnancy. Methods: In 2016, after the Ebola crisis, a qualitative inquiry was conducted in Monrovia to explore populations' insights on the aetiology, prevention and therapeutics of malaria, as well as the community and health workers' perceptions on the utility of malaria research for pregnant women. In-depth interviews and focus group discussions were conducted among pregnant women, traditional community representatives and hospital staf (n=38), using a feminist interpretation of grounded theory. Results: The narratives indicate that some Liberians believed in elements other than mosquito bites as causes of malaria; many had a low malaria risk perception and disliked current efective prevention methods, such as insecticide-treated nets; and some would resort to traditional medicine and spiritual care to cure malaria. Access to clinic-based malaria care for pregnant women was reportedly hindered by lack of fnancial means, by unofcial user fees requested by healthcare workers, and by male partners' preference for traditional medicine. The participants suggested that malaria research in Liberia could help to design evidence-based education to change current malaria prevention, diagnostic and treatment-seeking attitudes, and to develop more acceptable prevention technologies. Conclusion: Poverty, insufcient education on malaria, corruption, and poor trust in healthcare establishment are structural factors that may play a greater role than local traditional beliefs in deterring Liberians from seeking, access‑ ing and using government-endorsed malaria control strategies. To increase access to and uptake of preventive and biomedical care by pregnant women, future malaria research must be informed by people's expressed needs and constructed meanings and values on health, ill health and healthcare.

AbstractOchratoxin A (OTA) is a well-known mycotoxin that adversely affects different human cells. Inhalational exposure to OTA and subsequent pulmonary diseases have been previously reported, yet its potential carcinogenicity and underlying molecular mechanisms have not been fully elucidated. This study aimed to evaluate the OTA-induced cytotoxicity and the epigenetic changes underlying its potential carcinogenicity in fetal lung fibroblast (WI-38) cells. OTA cytotoxicity was assessed by MTT assay; RT-qPCR was used to determine the expression of BAX, BCL-2, TP53, and miR-155, while ELISA was used for measuring 5-methyl cytosine percentage to assess global DNA methylation in OTA-treated versus control cells. WI-38 cells demonstrated sensitivity to OTA with IC50 at 22.38 μM. Though BAX and Bcl-2 were downregulated, with low BAX/BCL-2 ratio, and TP53 was upregulated, their fold changes showed decline trend with increasing OTA concentration. A significant dose-dependent miR-155 upregulation was observed, with dynamic time-related decline. Using subtoxic OTA concentrations, a significant global DNA hypermethylation with significant dose-dependent and dynamic alterations was identified. Global DNA hypermethylation and miR-155 upregulation are epigenetic mechanisms that mediate OTA toxicity on WI-38 cells. BAX downregulation, reduced BAX/BCL-2 ratio together with miR-155 upregulation indicated either the inhibition of TP53-dependent apoptosis or a tissue specific response to OTA exposure. The aforementioned OTA-induced variations present a new molecular evidence of OTA cytotoxicity and possible carcinogenicity in lung fibroblast cells.
Graphical Abstract

Highly productive fast-growing Eucalyptus plantations cover more than 5 million hectares in Brazil and exhibit very dynamic carbon fluxes throughout their 6-7 year rotations. These plantations quickly shift from C sources at the beginning of the rotation to large C sinks until harvest. In order to get a model simulating carbon pool and fluxes for both Eucalyptus plantations and other crops, we integrated several sub-models of the Eucalyptus-dedicated Generic Decomposition And Yield Model (G'DAY) into the large scale and multi-cover model Agro-IBIS (Integrated Biosphere Simulator). The G'DAY model was previously parametrized and validated using large experimental datasets obtained in commercial eucalypt plantations in the state of Sao Paulo. Implementing an Eucalyptus plantation cover type within AgroIBIS. which had no Plant Functional Type dedicated to fast-growing forest plantations, required important changes in the carbon allocation turnover sub-models. This study included three phases: (1) the computational modification of AgrolBIS; (2) the model parametrization, calibration and validation using data from intensively monitored sites or inventories datasets; and (3) model application at regional scale using sets of parameters which were considered to be constant in space and/or time based on data from the local experiments, and other sets of parameters which could vary spatially. Carbon fluxes of Eucalyptus plantations were simulated at the regional scale, and their inter-annual and spatial variabilities were analysed. Such spatial and multiannual quantification of carbon fluxes at large scales brings a better understanding of these forest ecosystems on global carbon cycling, which is a prerequisite to support policy decisions.

IMPORTANCE: Angiosarcoma is a rare sarcoma subtype with a poor outcome. Carotuximab plus pazopanib produced a median progression-free survival (PFS) of 7.8 months in pazopanib-naive patients with chemotherapy-refractory angiosarcoma in a phase 1/2 trial. OBJECTIVE: To determine whether carotuximab plus pazopanib improves PFS compared with pazopanib alone in patients with advanced angiosarcoma. DESIGN, SETTING, AND PARTICIPANTS: The TAPPAS Trial: An Adaptive Enrichment Phase 3 Trial of TRC105 and Pazopanib vs Pazopanib Alone in Patients With Advanced Angiosarcoma was a multinational, multicenter, open-label, parallel-group, phase 3 randomized clinical trial of 123 patients 18 years or older with advanced angiosarcoma that was conducted between February 16, 2017, and April 12, 2019, at 31 sites in the US and the European Union. Patients were randomized 1:1 to receive pazopanib alone or carotuximab plus pazopanib. The trial incorporated an adaptive enrichment design. Inclusion criteria were no more than 2 prior lines of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. The efficacy analysis used the intent-to-treat population; the safety analysis included all patients who received a dose of either study drug. EXPOSURES: Oral pazopanib, 800 mg/d, or intravenous carotuximab, 10 mg/kg, administered weekly, plus oral pazopanib, 800 mg/d, with dose modification allowed per patient tolerance or until disease progression. MAIN OUTCOMES AND MEASURES: The primary end point was PFS, assessed by blinded independent radiographic and cutaneous photographic review per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Secondary end points included the objective response rate and overall survival. An interim analysis to determine the final sample size was conducted after enrollment of 123 patients. PFS in the group receiving pazopanib alone was compared with PFS in the group receiving carotuximab plus pazopanib using the log rank test. RESULTS: Of 114 patients ...

AbstractObjectiveThe aim was to assess the reported family relationships during the COVID‐19 pandemic and the association between these relationships and individual, interpersonal, and country‐level income in eight Middle East and North Africa (MENA) countries.BackgroundCOVID‐19 causes fear of infection, loss of loved ones, and economic problems that may affect family relationships.MethodsData were collected from eight MENA countries using an online survey (July–August 2020). The dependent variable was change in family relationship during COVID‐19, and the independent variables were individual, interpersonal, and country‐level factors represented by sociodemographic factors, COVID‐19 status, financial impact (whether participants lost or had reduced wages) and country income. Multilevel logistic regression analysis was conducted.ResultsThere were 1854 responses, mean (SD) age of 30.6 (9.9) years, 65.8% were female, 3.4% tested COVID‐19 positive, and 20.8% reported lost/reduced wages. Family relationships were more likely to improve or remain unchanged (84.3%) for participants who had a history of COVID‐19 (adjusted odds ratio [AOR] = 3.54, 95% confidence interval [CI]: [1.25, 10.01]). However, family relationships were more likely to not improve for those who knew someone who died of COVID‐19 (AOR = 0.76, 95% CI [0.58, 0.99]) and those with lost/reduced wages (AOR = 0.69, 95% CI [0.52, 0.94]).ConclusionFamily relationship improved or remained unchanged for those who tested positive for COVID‐19 and did not improve for those who lost wages or lost someone due to COVID‐19.ImplicationsPolicy makers should develop strategies to provide social and financial support to employees to reduce the losses and adverse social impact caused by the pandemic.

BACKGROUND: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. METHODS: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants. RESULTS: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)). CONCLUSION: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. ; This study was supported by MRC grant MC_UU_12015/1 and by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372 (contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies). ANECS recruitment was supported by project grants from the National Health and Medical Research Council of Australia (ID#339435), The Cancer Council Queensland (ID#4196615) and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK [C490/A10124]. Case genotyping was supported by the National Health and Medical Research Council (ID#552402). Control data was generated by the Wellcome Trust Case Control Consortium (WTCCC), and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Funding for this project was provided by the Wellcome Trust under award 085475. Recruitment of the QIMR controls was supported by the National Health and Medical Research Council of Australia (NHMRC). The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed towards the costs of establishing the Hunter Community Study. K.T.N. was supported by the Gates Cambridge Trust. R.K.S. is supported by the Wellcome Trust (grant number WT098498). A.B.S. is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. D.F.E. is a Principal Research Fellow of Cancer Research UK. A.M.D is supported by the Joseph Mitchell Trust. ; This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/jnci/djv178

AbstractIntroductionLiver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low‐ and middle‐income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV.MethodsWe conducted a cross‐sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA‐Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration‐controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula.ResultsOverall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45−56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1−8.4) and 28.4% (95% CI 26.5−30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10−2.40), overweight/obesity (OR = 2.50, 95% CI 1.69−3.75), T2DM (OR 2.26, 95% CI 1.46−3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46−6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti‐HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29−5.51), T2DM (OR 2.06, 95% CI 1.47−2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27−2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31−2.16).ConclusionsMetabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page ; Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. ; HHSN268201100009C/HL/NHLBI NIH HHS/United States K12 RR023250/RR/NCRR NIH HHS/United States P30 DK072488/DK/NIDDK NIH HHS/United States R01 AG018728/AG/NIA NIH HHS/United States R01 AG033193/AG/NIA NIH HHS/United States R01 DK058845/DK/NIDDK NIH HHS/United States R01 DK066574/DK/NIDDK NIH HHS/United States R01 DK075787/DK/NIDDK NIH HHS/United States R01 DK084350/DK/NIDDK NIH HHS/United States R01 DK089256/DK/NIDDK NIH HHS/United States R01 HL087641/HL/NHLBI NIH HHS/United States R01 HL087660/HL/NHLBI NIH HHS/United States R01 HL088119/HL/NHLBI NIH HHS/United States R01 HL117078/HL/NHLBI NIH HHS/United States R01DK090311/DK/NIDDK NIH HHS/United States R24OD017870/OD/NIH HHS/United States T32 HL007024/HL/NHLBI NIH HHS/United States U01 GM074518/GM/NIGMS NIH HHS/United States U01 HG004399/HG/NHGRI NIH HHS/United States U01 ...

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. ; This research has been conducted using the UK Biobank Resource. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129.