Modus Therapeutics (Sweden)

Hepcidin is an essential regulator of systemic iron availability mediating both iron uptake from the diet and its release from body stores. Abnormally high hepcidin levels resulting from inflammation in chronic diseases cause iron restriction with the onset of anemia. Restoring physiological levels of hepcidin could contribute to ameliorating anemia in these patients. Heparin derivatives are known to suppress hepcidin expression acting on the BMP/SMAD pathway. The novel heparin derivative sevuparin, modified to markedly reduce its anticoagulant activity, is proposed as a promising hepcidin antagonizing strategy. Sevuparin was tested for its anti-hepcidin properties in vitro in HepG2 cells, in vivo in mice, and in healthy volunteers. Sevuparin strongly suppressed basal, BMP6-, and IL6-dependent hepcidin expression in HepG2 cells in a dose- and time-dependent manner, modulating the essential BMP6/SMAD cascade. These effects were evident in C57BL/6J mice after intravenous injection of a single dose of sevuparin (20 mg/kg) with a 70% reduction of hepcidin mRNA. Remarkably, similar effects were observed in healthy volunteers following single subcutaneous doses at 3, 6, and 9 mg/kg with 40%-50% suppression at 3 and 6 mg/kg and 72% at 9 mg/kg. Moreover, sevuparin was able to reduce hepcidin upregulation in a mouse model of acute inflammation induced by LPS, also showing an amelioration of the inflammatory markers. Combined with its excellent safety profile, these data suggest a role for sevuparin in treating high-hepcidin disorders.

Abstract Introduction The cardiovascular disease (CVD) risk score DiCAVA was developed in 2021 using UK Biobank data with the aim to be used for population health screening by deriving its predictions only from variables readily available to every individual, omitting difficult-to-obtain measurements such as blood pressure and invasive blood tests for metrics like cholesterol or HbA1c, which are commonly used in clinical CVD risk assessment tools. The original set of variables was reduced to 30 in the DiCAVA Lite score to further improve usability in a digital solution accessible to the general population, while maintaining its discrimination ability. Purpose Like many countries, the US has a large burden of CVD and would benefit from easily accessible screening tools. However, to ensure generalisability of the UK-developed score, it is necessary to evaluate its performance in a population where the score is intended to be used. Methods Data from a large real-world modern observational study in the US, All of Us, was used to evaluate discrimination and calibration metrics of the risk score. Participants with pre-existing CVD and without available electronic health records were excluded from the study. Variables from the All of Us dataset were matched to the original variables and any missing values were imputed using multiple imputation. Results 216,985 participants with a median follow-up time of 3.44 years were included in the study. The median age was 51 years and 63% of the population were female. Discrimination ability in the All of Us dataset (C-index 0.76) slightly surpassed the discrimination achieved at training with UK Biobank (C-index 0.73), and that of Framingham risk score calculated for the All of Us population (C-index 0.72), demonstrating the score’s usability in the US. The score showed very good discrimination in both males (C-index 0.74) and females (C-index 0.77), all ethnic groups and age groups, with the exception of the population over 65 years of age, where the C-index dropped to 0.65 as expected (similar to that observed in the UK Biobank). Calibration of the original model was assessed at 3 years and showed under-estimation of the predicted risk (calibration-in-the-large of 2.37%). Following re-calibration, the algorithm demonstrated excellent results with the average predicted 3-year risk showing 0.59% difference from the observed CVD rate (calibration plot in Figure). Conclusions Overall, the DiCAVA Lite score has shown very good discrimination in the US, showing its generalisability in different demographic populations. Its re-calibrated form is now validated for use in the US population and because of its ability to be utilised outside clinical settings, it can be deployed widely in the general population as an initial screening tool and potentially boost awareness of cardiovascular health in an effort to drive preventative care of CVD.Re-calibration of the DiCAVA Lite score

Global year against visceral painThe Brazilian Society for the Study of Pain, as a member of the International Association for the Study of Pain, is committed to the global campaign against visceral pain, which has started in mid October 2012 and will end in October 2013.The objective is to join worldwide forces to elucidate health professionals and patients about VISCERAL PAIN, disease which surreptitiously torments the lives of millions of people, disabling them for social and labor life.Visceral pain is one of the commonest reasons for looking for outpatient or hospital assistance and is associated to different types of chronic pain, especially chest and abdominal pain, and health system costs related to visceral pain, especially abdominal pain, are high.Its prevalence is high since approximately 25% of the population report some visceral pain during their lives.Let's unite in this campaign to spread information about visceral pain pathophysiology and management throughout our country; educating health professionals to observe visceral pain-related issues in their interactions with patients, increasing the awareness about the need to control visceral pain among governmental authorities, media professionals and the general population.

Preventing the occurrence of accidents in drilling and well servicing operations is a constant and major concern for any company or contractor acting in the upstream business. Analysis of accidents often identifies a number of contributing factors and/or anomalies, among which the equipment related items play a significant role. This article concentrates on the rig inspection process as a consistent method of detecting equipment related anomalies before operations commence. These inspections enable the necessary corrections to be made in due time, thereby limiting the occurrence of accidents once the rig is in operation.When in-depth and systematic rig inspections are carried out, it is that the percentage of accidents where equipment failure is the major cause remains very low. However, equipment condition factors contributing to the accidents still remain present in a large number of cases.Introduction. Rig Inspection activities are normally an important part of the drilling safety programme. The inspection objective is both to prevent the occurrence of accidents, to limit their consequences and to minimise non-productive time linked to equipment failure. Analysis of the accidents occurring during rig operations indicates that equipment is often involved as a contributory factor. As rig equipment maintenance standards have, in general, suffered from depressed rig rates during the past ten years, the need for detailed inspection has become more important.Rig inspections normally consist of an independent and thorough survey of the rig drilling, mechanical, electrical, well control, marine and safety equipment. This allows specialised expertise to be targeted at the equipment maintenance standards, including full testing of equipment safety devices, to determine the level of equipment maintenance and safe working condition.The objective of this paper is to present the conclusions and lessons learnt from these inspections, based on the survey of 75 rigs carried out since 1991. This paper also demonstrates the benefits of this integrated philosophy, which includes a better safety approach, a worldwide standard, the rapid inclusion and verification of relevant safety bulletins and alerts, plus appropriate examples of the system achievements, and confirms the old saying that