Islet graft function by mixed meal tolerance testing is sustained over 4 years in young children undergoing total pancreatectomy with islet autotransplantation.

Children with intractable chronic pancreatitis may require total pancreatectomy with islet autotransplantation (TPIAT) for pain relief. The IAT reduces the severity of post- pancreatectomy diabetes. We analyzed 635 mixed meal tolerance tests (MMTT) in 134 children undergoing TPIAT to determine whether superior survival of islet grafts explains higher rates of insulin independence previously reported in young children (n = 52, age 3-11 years) versus adolescents (n = 82, age 12-18 years). For MMTT, children consumed Boost HP and we sampled C-peptide and glucose repeatedly over 2 h. The trajectory of outcomes before and after TPIAT was compared between children and adolescents using data from pre-TPIAT and 3, 6 months, 1, 2, 3, and 4 years post-TPIAT and mixed linear models with a random effect for child. Cox regression was used to analyze time outcomes (e.g., time to first off insulin). Islet mass transplanted, measured as islet equivalents (IEQ), was higher in adolescents (p = .003) but IEQ/kg was higher in young children (p < .001) because of their lower weight. AUC C-peptide in young children increased somewhat over 4 years, but was stable in adolescents (p = .0013). AUC glucose increased more in adolescents over time post-TPIAT (p = .0024). Islet function by AUC C-peptide:AUC glucose ratio was better preserved in young children (p < .001). Adolescents were less likely to wean off insulin (hazard ratio .44 [95% CI .28, .69]). These data support an advantage of young age in islet graft survival after TPIAT. The greater likelihood of insulin independence in young children may be driven by better islet survival after transplant.

Randomized controlled dose-escalation design to evaluate the safety of a novel pharmacological cardiopulmonary resuscitation strategy.

BACKGROUND/AIMS: The motivating randomized controlled phase I trial evaluates three sodium nitroprusside doses in a novel sodium nitroprusside-enhanced cardiopulmonary resuscitation strategy for improved end-organ perfusion relative to local standard of care. Sodium nitroprusside is a vasodilator with an established safety profile in other indications, whereas the local standard of care uses vasoconstrictors, typically epinephrine. The purpose of the proposed trial is to identify the highest safe dose of sodium nitroprusside in this new context as excessive doses may cause severe hypotension with compromised end-organ perfusion. METHODS: The proposed phase I trial design expands upon traditional dose-finding designs to include a randomized control arm, which is needed to assess safety through the relative increase in serum lactate on hospital admission. For guiding dose escalation, we propose and compare six Bayesian models which characterize expected serum lactate as a function of sodium nitroprusside dose and randomization group. Each model makes a different assumption about the expected change in serum lactate across control cohorts concurrently randomized with each dose. Model selection aims to minimize the expected number of times that a dose is incorrectly classified as safe or unsafe while sample size selection targets an expected number of incorrectly classified doses. Randomization is 1:1 for the initial cohort, and for subsequent cohorts is chosen to maximize the lower confidence bound. RESULTS: The spike-and-slab model minimizes the expected number of times that a dose is incorrectly classified as safe or unsafe under the most scenarios in the motivating three-dose trial, but all six models exhibit relatively similar performance. A 2:1 randomization ratio for the second and third cohorts maximizes the lower confidence bound when using the spike-and-slab model. With the optimal design, on average, 70 individuals will ensure 1 incorrectly classified dose in 6 opportunities. CONCLUSION: We recommend that the motivating trial use the spike-and-slab model with a 1:1 randomization ratio for the initial cohort and 2:1 randomization ratio for subsequent cohorts; however, the simpler fixed effects approaches performed similarly well.

Outpatient and inpatient anticoagulation therapy and the risk for hospital admission and death among COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. Limited data exist informing the relationship between anticoagulation therapy and risk for COVID-19 related hospitalization and mortality. METHODS: We evaluated all patients over the age of 18 diagnosed with COVID-19 in a prospective cohort study from March 4th to August 27th, 2020 among 12 hospitals and 60 clinics of M Health Fairview system (USA). We investigated the relationship between (1) 90-day anticoagulation therapy among outpatients before COVID-19 diagnosis and the risk for hospitalization and mortality and (2) Inpatient anticoagulation therapy and mortality risk. FINDINGS: Of 6195 patients, 598 were immediately hospitalized and 5597 were treated as outpatients. The overall case-fatality rate was 2•8% (n = 175 deaths). Among the patients who were hospitalized, the inpatient mortality was 13%. Among the 5597 COVID-19 patients initially treated as outpatients, 160 (2.9%) were on anticoagulation and 331 were eventually hospitalized (5.9%). In a multivariable analysis, outpatient anticoagulation use was associated with a 43% reduction in risk for hospital admission, HR (95% CI = 0.57, 0.38-0.86), p = 0.007, but was not associated with mortality, HR (95% CI=0.88, 0.50 - 1.52), p = 0.64. Inpatients who were not on anticoagulation (before or after hospitalization) had an increased risk for mortality, HR (95% CI = 2.26, 1.17-4.37), p = 0.015. INTERPRETATION: Outpatients with COVID-19 who were on outpatient anticoagulation at the time of diagnosis experienced a 43% reduced risk of hospitalization. Failure to initiate anticoagulation upon hospitalization or maintaining outpatient anticoagulation in hospitalized COVID-19 patients was associated with increased mortality risk. FUNDING: No funding was obtained for this study.