Islet Harvest in Carbon Monoxide-Saturated Medium for Chronic Pancreatitis Patients Undergoing Islet Autotransplantation

Stresses encountered during human islet isolation lead to unavoidable beta-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, beta-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less beta-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

[Comment] Redefine statistical significance

The lack of reproducibility of scientific studies has caused growing concern over the credibility of claims of new discoveries based on “statistically significant” findings. There has been much progress toward documenting and addressing several causes of this lack of reproducibility (e.g., multiple testing, P-hacking, publication bias, and under-powered studies). However, we believe that a leading cause of non-reproducibility has not yet been adequately addressed: Statistical standards of evidence for claiming discoveries in many fields of science are simply too low. Associating “statistically significant” findings with P < 0.05 results in a high rate of false positives even in the absence of other experimental, procedural and reporting problems. For fields where the threshold for defining statistical significance is P<0.05, we propose a change to P<0.005. This simple step would immediately improve the reproducibility of scientific research in many fields. Results that would currently be called “significant” but do not meet the new threshold should instead be called “suggestive.” While statisticians have known the relative weakness of using P≈0.05 as a threshold for discovery and the proposal to lower it to 0.005 is not new (1, 2), a critical mass of researchers now endorse this change. We restrict our recommendation to claims of discovery of new effects. We do not address the appropriate threshold for confirmatory or contradictory replications of existing claims. We also do not advocate changes to discovery thresholds in fields that have already adopted more stringent standards (e.g., genomics and high-energy physics research; see Potential Objections below). We also restrict our recommendation to studies that conduct null hypothesis significance tests. We have diverse views about how best to improve reproducibility, and many of us believe that other ways of summarizing the data, such as Bayes factors or other posterior summaries based on clearly articulated model assumptions, are preferable to P-values. However, changing the P-value threshold is simple and might quickly achieve broad acceptance

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units

OBJECTIVE: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. METHODS: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. RESULTS: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. CONCLUSIONS: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation