Efficacy and Safety of Vasopressin and Terlipressin in Preterm Neonates:A Systematic Review

Introduction: The use of arginine vasopressin (AVP) and terlipressin to treat hypotension in preterm neonates is increasing. Our aim was to review the available evidence on the efficacy and safety of AVP and terlipressin for use in preterm neonates. Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar from inception to September 2021 were searched for studies of AVP and terlipressin in the treatment of hypotension of any cause in preterm neonates. Primary outcomes were improvement in end-organ perfusion and mortality. The risk of bias assessment and certainty of the evidence were performed using appropriate tools. Results: Fifteen studies describing the use of AVP (n = 12) or terlipressin (n = 3) among 148 preterm neonates were included. Certainly, the available evidence for the primary outcome of end-organ perfusion rated as very low. AVP or terlipressin were used to treat 144 and 4 neonates, respectively. Improvement in markers of end-organ perfusion was reported in 143 (99%) neonates treated with AVP and 3 (75%) treated with terlipressin. The mortality rate was 41% (n = 59) and 50% (n = 2) for neonates who received AVP and terlipressin, respectively. Hyponatremia was the most frequently reported adverse event (n = 37, 25%). Conclusion: AVP and terlipressin may improve measured blood pressure values and possibly end-organ perfusion among neonates with refractory hypotension. However, the efficacy–safety balance of these drugs should be assessed on an individual basis and as per the underlying cause. Studies on the optimal dosing, efficacy, and safety of AVP and terlipressin in preterm neonates with variable underlying conditions are critically needed

β-Catenin is a pH sensor with decreased stability at higher intracellular pH.

β-Catenin functions as an adherens junction protein for cell-cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein-protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R-β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Efficacy and safety of vasopressin and terlipressin in preterm neonates: a protocol for a systematic review

Background The use of vasoactive agents like arginine vasopressin (AVP) and terlipressin to treat hypotension or persistent pulmonary hypertension in critically ill preterm neonates is increasing. Therefore, a systematic review of the available data on dosing, efficacy and safety of AVP and terlipressin in this patient population appears beneficial.Methods We will conduct a systematic review of the available evidence on the use of AVP and terlipressin for the treatment of hypotension or persistent pulmonary hypertension in preterm neonates. We will search Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and Google Scholar from inception to March 2021. Two reviewers will independently screen titles and abstracts, review the full text of eligible studies, extract data, assess the risk of bias and judge the certainty of the evidence. Our primary outcome will be an (1) improvement of end-organ perfusion after initiation of AVP or terlipressin and (2) mortality prior to discharge. Our secondary outcomes will include (1) major neurosensory abnormality and (2) the occurrence of adverse events.Discussion The currently available evidence on the efficacy and safety of AVP and terlipressin in preterm neonates is limited. Yet, evidence on the pharmacology of these drugs and the pathophysiology of vasoplegic shock support the biological plausibility for their clinical effectiveness in this population. Therefore, we aim to address this gap concerning the use of vasopressin and terlipressin among critically ill preterm neonates.Trial registration This protocol has been submitted for registration to the international database of prospectively registered systematic reviews (PROSPERO, awaiting registration number)

β-Catenin is a pH sensor with decreased stability at higher intracellular pH.

β-Catenin functions as an adherens junction protein for cell-cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein-protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R-β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation

Alcohol abstinence stigma and alcohol use among HIV patients in Thai Nguyen, Vietnam.

BackgroundHazardous alcohol use is prevalent among people living with HIV (PWH), leading to sub-optimal HIV treatment outcomes. In Vietnam, alcohol use is highly normative making it socially challenging for PWH to reduce or abstain. We used mixed methods to develop a quantitative scale to assess alcohol abstinence stigma and examined the association between alcohol abstinence stigma with alcohol use among PWH in Vietnam.MethodsWe conducted qualitative interviews with 30 PWH with hazardous alcohol use from an antiretroviral therapy (ART) clinic in the Thai Nguyen to inform item development. Alcohol use was assessed using the Alcohol Use Disorders Identification Test. We tested items in a survey of 1,559 ART clinic patients to assess internal consistency and structural validity. We used log binomial modeling to estimate associations between any reported alcohol abstinence stigma and alcohol use.ResultsUsing the results from the qualitative interview data, we developed the alcohol abstinence stigma scale with seven final items with scores ranging from 0 (no stigma) to 28 (high stigma). The scale had good internal consistency (α = 0.75). Exploratory factor analysis suggested the presence of three factors: internalized, experienced, and anticipated stigma that explained 56.9% of the total variance. The mean score was 2.74, (SD = 4.28) and 46% reported any alcohol abstinence stigma. We observed a dose-response relationship between alcohol abstinence stigma and alcohol use. PWH who reported any alcohol abstinence stigma had greater hazardous alcohol use (aPR = 1.32, 95% CI: 1.12, 1.56), harmful alcohol use (aPR = 2.26, 95% CI: 1.37, 3.72), and dependence symptoms (aPR = 3.81, 95% CI: 2.19, 6.64).ConclusionAlcohol abstinence stigma is associated with increased alcohol levels of alcohol use among PWH in Vietnam, signaling challenges for alcohol reduction. Consideration of alcohol abstinence stigma will be essential for the design of effective alcohol reduction interventions and policy efforts to prevent adverse health consequences of alcohol use among PWH

Implementation of two alcohol reduction interventions among persons with hazardous alcohol use who are living with HIV in Thai Nguyen, Vietnam: a micro-costing analysis

Background Hazardous alcohol use is detrimental to persons with HIV (PWH), impacting medication adherence and liver function, yet globally resources to target alcohol use behavior in this population are limited. Few studies have identified the costs of integrating alcohol reduction interventions into HIV care. Objective To estimate the costs of implementing and delivering two evidence-based behavioral counseling interventions targeting hazardous alcohol use among persons with HIV and to estimate the costs of scale-up in ART clinics in Thai Nguyen, Vietnam. Methods We undertook a micro-costing approach to determine the costs of delivering two adapted evidence-based interventions to reduce alcohol use: an intensive combined cognitive behavioral therapy and motivational enhancement therapy-informed intervention (CoI) and an abbreviated brief alcohol intervention (BI). A total of 294 participants with hazardous alcohol use were identified through a brief screening tool and received the CoI (n = 147) and the BI (n = 147) over 3 months. We estimated costs using time and motion studies, budget analysis, staff interviews, and participant questionnaires. Data were collected from 2016 to 2018 in VND and converted to USD. Results The total cost of implementation and administration of the intervention to 147 participants receiving the CoI was $13,900 ($95 per participant) and to 147 participants receiving the BI was $5700 ($39 per participant). Implementation and startup costs including training accounted for 27% of costs for the CoI and 28% for the BI. Counselor costs accounted for a large proportion of both the CoI (41%) and the BI (30%). Conclusions Implementing and delivering alcohol reduction interventions to people with HIV in Vietnam with appropriate fidelity is costly. These costs may be reduced, particularly counselor labor costs, by using an evidence-based brief intervention format. Future research should explore the budgetary impact of brief and combined interventions to reduce hazardous alcohol use, particularly among vulnerable populations