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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin.

The cardio-renal benefits of sodium glucose-like transporter 2 inhibitor (SGLT2i) therapies have been demonstrated in patients with and without type 2 diabetes. However, no studies have explored the long-term metabolic effects of SGLT2i, combined with dietary carbohydrate restriction. Our primary objective was to describe long-term changes in weight, energy expenditure, appetite and body composition after 12 months of Dapagliflozin therapy, with carbohydrate restriction, in people with type 2 diabetes and obesity. Our secondary objective was to assess changes in adiponectin and leptin.This was a 12-month cohort study in a secondary care setting. Participants (n = 18) with type 2 diabetes (T2D) and class 3 obesity underwent baseline indirect calorimetry for determination of 24-h energy expenditure, body composition, fasting serum leptin and adiponectin levels, and appetitive assessments. Following initiation of Dapagliflozin (and dietary carbohydrate restriction), measurements were repeated at monthly intervals up to 12 months.Mean starting weight of participants was 129.4 kg (SD 25.9), mean BMI 46.1 kg/mIn this study, combined Dapagliflozin therapy and carbohydrate restriction in patients with T2D and obesity resulted in a significant reduction of body weight and fat mass at 12 months without any discernible changes in energy expenditure or appetite. These results offer a scientific and clinical rationale to conduct an exploratory trial investigating the effects of a low carbohydrate diet combined with SGLT2 inhibitors in patients with T2D.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin. Medicinska Forskningsrådet; Spanish Ministerio de Ciencia e Innovacion/ Agencia Estatal de Investigacion (AEI), Grant/Award Number: PID2019-108489RB-I00; Asociación Progeria Alexandra Peraut; Fundació la Marató TV3; European Regional Development Fund, Grant/Award Number: 202033; Swedish Medical Research Council; Progeria Research Foundation, Grant/Award Number: PRF 2019-77. Sí

Gastrinoma; Insulinoma; Pancreatic neuroendocrine tumour Gastrinoma; Insulinoma; Tumor neuroendocrino pancreático Gastrinoma; Insulinoma; Tumor neuroendocrí pancreàtic Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1–3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Prisoners in most countries have a higher prevalence of HCV than the general population, but their access to treatment is very limited. Our aim was to evaluate a pilot programme using the ECHO model to enhance linkage to care in patients with HCV in 3 Argentinean prisons between October 2018 and January 2020. All inmates were invited to participate, and data were collected through a personal interview. We then estimated HCV prevalence with dried blood spot and performed a logistic regression analysis to identify risk behaviours associated with HCV infection. Finally, HCV management was assessed and monitored through ECHO. Overall, 1141 inmates agreed to participate, representing 39.7% of the total prison population. Anti-HCV prevalence was estimated at 1.58% (CI 0.93; 2.48), being significantly higher in women 2.98% (CI 1.4;5.6) than in men 1.07% (CI 0.5; 2.0); P = .03. Patients with anti-HCV were significantly older than those who tested negative, 42.3 years (CI 37.6;47.1) vs 30.1 years (CI 30.6;31.2), P < .001, respectively. Multiple logistic regression analysis, identified age OR 1.07 (CI 1.03;1.12, P = .001), history of sexually transmitted disease OR 3.08 (CI 0.97;9.82, P = .057) and intravenous drug use OR 12.6 (CI 3.31;48.53, P < .001) as risk factors associated with anti-HCV. Treatment was initiated in all the patients with specialist physician support utilizing ECHO model. In conclusion, our pilot study reported a low prevalence of anti-HCV in the studied population. Incarceration provides an ideal opportunity for testing and treating HCV. ECHO model arises as a useful tool to support assessment and treatment for inmates with chronic HCV.

Objective To estimate the prevalence and types of sexual dysfunction in pregnancy. Methods A cross-sectional facility-based descriptive study among pregnant women attending the prenatal clinic of the Greater Accra Regional Hospital, a large tertiary health facility in Accra, Ghana, from May to June 2018. The inclusion criteria were 18 years or older, singleton pregnancy of 8 gestational weeks or more, and residing with their partner for at least 4 weeks before the study. Face-to-face interviews were conducted among consecutively enrolled women by using the Female Sexual Function Index (FSFI) tool. Results Overall, 425 women were enrolled. The mean age was 30.8 ± 4.8 years. The mean gestational age was 32.3 ± 7.1weeks (range 9.7-42.0 weeks). The prevalence of sexual dysfunction in pregnancy was 64.9% (95% confidence interval [CI], 60.3%-69.4%) but only 32 (7.5%) women self-reported sexual problems. The predominant types of sexual disorder were desire disorder (377 [88.7%; 95% CI, 85.3%-91.4%] women) and arousal disorder (320 [75.3%; 95% CI, 71.0%-79.2%]). Conclusion Sexual dysfunction in pregnancy was found to be common, but most pregnant women were not aware that they had it.

Certain patient populations are unable to achieve the recommended low‐density lipoprotein cholesterol goals with statin monotherapy alone. Such patients may benefit from concomitant therapy with ezetimibe (EZE) 10 mg added on to a statin. To this end, fixed‐dose combination (FDC) tablets containing EZE 10 mg and rosuvastatin (ROS) 2.5 mg (EZE/ROS2.5) and EZE 10 mg and ROS 5 mg (EZE/ROS5) have been developed for treatment of hypercholesterolemia. The purpose of the series of clinical studies reported herein was to evaluate the potential food effect (MK‐0653H, protocol 836 (P836)) and the bioequivalence between FDC and co‐administration of EZE and ROS in healthy Japanese subjects under fasted and fed conditions (MK‐0653H, protocol 835 (P835) and MK‐0653H, protocol 846 (P846), respectively). These studies show there is no clinically relevant food effect on EZE exposure following single oral administration of the FDC EZE/ROS5 in healthy Japanese subjects; however, ROS exposure was decreased in the fed state under conditions used to evaluate the maximum food effect. Following single oral administration of individual ROS tablets under the same conditions, the magnitude of decrease in ROS exposure was comparable to that seen with FDC, suggesting that the effect of food on ROS exposure was similar between the FDC tablet and co‐administration of individual EZE and ROS tablets. The FDC EZE/ROS5 was generally well tolerated in healthy Japanese subjects under fasted and fed conditions.

The organization of extraocular muscles (EOMs) and their motor nuclei was investigated in the mouse due to the increased importance of this model for oculomotor research. Mice showed a standard EOM organization pattern, although their eyes are set at the side of the head. They do have more prominent oblique muscles, whose insertion points differ from those of frontal-eyed species. Retrograde tracers revealed that the motoneuron layout aligns with the general vertebrate plan with respect to nuclei and laterality. The mouse departed in some significant respects from previously studied species. First, more overlap between the distributions of muscle-specific motoneuronal pools was present in the oculomotor nucleus (III). Furthermore, motoneuron dendrites for each pool filled the entire III and extended beyond the edge of the abducens nucleus (VI). This suggests mouse extraocular motoneuron afferents must target specific pools based on features other than dendritic distribution and nuclear borders. Second, abducens internuclear neurons are located outside the VI. We concluded this because no unlabeled abducens internuclear neurons were observed following lateral rectus muscle injections and because retrograde tracer injections into the III labeled cells immediately ventral and ventrolateral to the VI, not within it. This may provide an anatomical substrate for differential input to motoneurons and internuclear neurons that allows rodents to move their eyes more independently. Finally, while soma size measurements suggested motoneuron subpopulations supplying multiply and singly innervated muscle fibers are present, markers for neurofilaments and perineuronal nets indicated overlap in the size distributions of the two populations. Anat Rec, 302:1865-1885, 2019. © 2019 American Association for Anatomy.

Proton Magnetic Resonance Spectroscopy ((1)H MRS) provides non-invasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Whilst most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges towards obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the popular point resolved spectroscopy (PRESS) localization sequence was found to be unacceptably high at 3T, and the use of the semi-adiabatic localization by adiabatic selective refocusing (semi-LASER) sequence is a recommended solution. The incorporation of simulated metabolite basis-sets into analysis routines is recommended for reliably capturing the full spectral detail available from short echo time acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B(0)) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. We anticipate the implementation of these recommendations will strengthen current clinical applications and advance progress towards developing and validating new MRS biomarkers for clinical use.

Subsurface engineering applications, such as the development of enhanced geothermal systems and unconventional oil and gas reservoirs, and the geologic disposal of CO 2 and waste water, involve flu...

BACKGROUND: The current coronavirus disease 2019 (COVID-19) pandemic has a huge impact on society and the economy and represents one of the biggest challenges for healthcare systems all over the world. Reports from healthcare institutions in different countries show a variety of crisis exit strategies. METHODS: The following is a review and update of the situation and crisis management in Zurich and Switzerland with a special focus on the impact on the cardiac surgery program and extracorporeal membrane oxygenation (ECMO)-therapy in COVID-19. RESULTS: Regional and national measures had avoided the collapse of the health system in Switzerland. There was a reduction of over 50% of the surgical and transcatheter caseload during the first wave of the pandemic. Twenty-three ECMO devices, 150 oxygenators, and more than 300 different cannulas were at our disposal. Between March and May 2020, nine COVID-19 patients were treated by us with ECMO-therapy. Three patients were transported by us from distant institutions. Median age at ECMO implantation was 59 years. Two patients died on support. CONCLUSIONS: Measures to prevent a collapse of the healthcare system were effective. Our local ECMO-Program on the ongoing COVID-19 pandemic has proven to be a useful tool to control mortality and organ failure in critically ill patients.

© 2020. American Geophysical Union. All Rights Reserved. Formation dry-out in fracture-dominated geological reservoirs may alter the fracture space, impair rock absolute permeability, and cause a significant decrease in well injectivity. In this study, we numerically model the dry-out processes occurring during supercritical CO2 (scCO2) injection into single brine-filled fractures and evaluate the potential for salt precipitation under increasing effective normal stresses in the evaporative regime. We use an open-source, parallel finite-element framework to numerically model two-phase flow through 2-D fracture planes with aperture fields taken from naturally fractured granite cores at the Grimsel Test Site in Switzerland. Our results reveal a displacement front and a subsequent dry-out front in all simulated scenarios, where higher effective stresses caused more flow channeling, higher rates of water evaporation, and larger volumes of salt precipitates. However, despite the larger salt volumes, the permeability impairment was lower at higher effective normal stresses. We conclude that the spatial distribution of the salt, precipitated in fractures with heterogeneous aperture fields, strongly affects the absolute permeability impairment caused by formation dry-out. The numerical simulations assist in understanding the behavior of the injectivity in fractures and fracture networks during subsurface applications that involve scCO2 injection into brine. ISSN:0043-1397 ISSN:1944-7973

Aims The Optimal Fibre Trial investigated metabolic effects of insoluble cereal fibre in subjects with high-risk prediabetes. As the study shows dose-dependent moderate glycemic and anti-inflammatory benefits, especially in subjects with an obesity-related phenotype, the putative mechanism of action of this particular food component warrants clarification. A sub-group of the OptiFiT cohort received detailed body imaging throughout the study, permitting the analysis of effects on body fat distribution by fibre supplementation. Methods 180 Caucasian participants with impaired glucose tolerance (IGT) received a blinded, randomized supplementation with insoluble cereal fibre or placebo for two years. Once a year, all subjects underwent fasting blood sampling, oGTT and full anthropometric measurements. A subgroup of 47 subjects additionally provided data from magnetic resonance imaging and spectroscopy for quantification of adipose tissue distribution and liver fat content. We compare these outcomes between fibre and placebo group and assess mechanistic connections to improvements in glucose metabolism and inflammation. Results MR-assessed visceral and non-visceral body fat volume, fasting glucose, HbA1c, fasting insulin, insulin resistance and uric acid decreased in the fibre group, only. However, after adjustment for weight loss, there are no significant differences in changes of MR-derived measurements of body fat distribution between the intervention groups. There is a statistical trend for fibre-driven liver fat reduction in subjects with confirmed non-alcoholic fatty liver disease (NAFLD; n = 19). The entire MR subgroup shows the same pattern in metabolic improvements as the entire cohort. Conclusions Data and evidence on beneficial effects of insoluble cereal fibre on visceral and hepatic fat storage is limited, but warrants further research. Targetted trials assessing the usefulness of fibre in visceral obesity and NAFLD are required. This article is protected by copyright. All rights reserved.