Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Refugees and underdevelopment in Africa

Using an empirical study of the Barundi refugee settlements of Ulyankulu, Mishamo, and particularly Katumba in Western Tanzania, this study argues that the causes and consequences of the African refugee problem must be examined outside the normative humanitarian framework. It postulates that the refugee problem can be understood only in the historical context of the integration of African communities into the capitalist system and their resultant underdevelopment. Furthermore, that the neo-colonial state, its class character, and ethnic divisions, aggravated by economic crisis, fosters a climate of repression - prompting forced migration. The unequal relationship between western capital and Tanzania is exemplified in the microcosm of the refugee phenomenon, where international/ regional policy, legislation, security considerations, and aid not only demobilize a potential political force, but usurp the authority of the national and local state. Donor/state/refugee relationships are further discussed in the context of the settlements. The schemes, located in remote areas and with tight restrictions on mobility, while providing a humanitarian solution, act as mechanisms for the control of the Barundi refugees. Utilization of their labour is intentionally part of Tanzania's development strategy. Settlement and integration are discussed in relation to the contribution of Barundi people to the development of commodity production in Tanzania both historically and with regard to their current potential. While dismissing the notion of an undifferentiated mass of refugees, this study reveals how donor activities and the objective material conditions of the rural areas contribute to commodity production and mercantilist activities with increasing inequalities. It concludes that large groups of refugees in rural areas will inevitably heighten local tensions, and that only through greater x political liberalization' - removal of restrictions on mobility and political representation, will Barundi refugees gain control of their lives, and Tanzania's long-standing goal of the liberation of African peoples be realized.</p

Refugees and underdevelopment in Africa

Using an empirical study of the Barundi refugee settlements of Ulyankulu, Mishamo, and particularly Katumba in Western Tanzania, this study argues that the causes and consequences of the African refugee problem must be examined outside the normative humanitarian framework. It postulates that the refugee problem can be understood only in the historical context of the integration of African communities into the capitalist system and their resultant underdevelopment. Furthermore, that the neo-colonial state, its class character, and ethnic divisions, aggravated by economic crisis, fosters a climate of repression - prompting forced migration. The unequal relationship between western capital and Tanzania is exemplified in the microcosm of the refugee phenomenon, where international/ regional policy, legislation, security considerations, and aid not only demobilize a potential political force, but usurp the authority of the national and local state. Donor/state/refugee relationships are further discussed in the context of the settlements. The schemes, located in remote areas and with tight restrictions on mobility, while providing a humanitarian solution, act as mechanisms for the control of the Barundi refugees. Utilization of their labour is intentionally part of Tanzania's development strategy. Settlement and integration are discussed in relation to the contribution of Barundi people to the development of commodity production in Tanzania both historically and with regard to their current potential. While dismissing the notion of an undifferentiated mass of refugees, this study reveals how donor activities and the objective material conditions of the rural areas contribute to commodity production and mercantilist activities with increasing inequalities. It concludes that large groups of refugees in rural areas will inevitably heighten local tensions, and that only through greater x political liberalization' - removal of restrictions on mobility and political representation, will Barundi refugees gain control of their lives, and Tanzania's long-standing goal of the liberation of African peoples be realized.</p

Ex-combatants as social activists: war, peace and ideology in Burundi

Post-print (lokagerð höfundar)In both academic literature and policy discourse, ex-combatants are at times depicted as a threat to peace rather than agents of positive change. However, many of my ex-combatant interlocutors in Burundi were working actively on conflict resolution and peace-building projects. In addition, their experience and knowledge of combat was frequently stated as a deterrent for going back to such a situation. Though it may seem contradictory, the reasons my informants gave for having joined the war sounded remarkably similar to motivations for social activism. They usually expressed it as a desire to contribute to a better, more just, community. I argue that ideology played an important part in motivation to join armed groups during the war and carries over in participation in social activism today. These decisions need not be seen as polar opposites, but rather as similar motivations towards contributing to positive change taken in different circumstances.The research received grants from the Icelandic Research Fund [grant number 152143-053]; the Nordic Africa Institute and Icelandic International Development Agency.Peer reviewe

Securitization of HIV/AIDS in context: gendered vulnerability in Burundi

In this article, it is argued that concerns about the impact of HIV/AIDS on national and international security do not adequately address the ways in which people, particularly women, are made vulnerable to HIV/AIDS in conflicts. In fact, policies inspired by the security framing of HIV/AIDS can engender new vulnerabilities in post-conflict contexts. The article analyses the ways in which gender relations create vulnerabilities for various groups when such relations are put under pressure during periods of conflict. Drawing on research conducted in Burundi, the article argues that postulated links between security and HIV/AIDS fail to take into account the vulnerability structures that exist in societies, the ways in which these are instrumentalized during conflict and in post-conflict contexts, and how they are also maintained and changed as a result of people's experiences during conflict