Ulcus cruris venosum: Was bringt die frühzeitige endovenöse Ablation bei venösen Ulzerationen?

<b>Importance:</b> One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux. <b>Objective:</b> To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration. <b>Design, Setting, and Participants:</b> Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months’ duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019. <b>Interventions:</b> Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team. <b>Main Outcomes and Measures:</b> The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness. <b>Results:</b> The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57–1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480–0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12–1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8% likely at a threshold of £35 000 ($45 995) per quality-adjusted life year. <b>Conclusions and Relevance:</b> Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence. <b>Trial Registration:</b> ClinicalTrials.gov identifier: ISRCTN02335796.

Dulaglutide exerts beneficial anti atherosclerotic effects in ApoE knockout mice with diabetes: the earlier, the better

There has been no report about the mechanism for anti-atherosclerotic effects of dulaglutide (Dula) and/or about the difference of its effectiveness between in an early and a late phase of diabetes. To address such questions, streptozotocin (STZ) was intraperitoneally injected to ApoE knockout mice at 8 weeks of age. Either Dula or vehicle was administered to STZ-induced diabetic ApoE knockout mice from 10 to 18 weeks of age as an early intervention group and from 18 to 26 weeks as a late intervention group. Next, non-diabetic ApoE knockout mice without STZ injection were subcutaneously injected with either Dula or vehicle. In an early intervention group, atherosclerotic lesion in aortic arch and Mac-2 and CD68-positive areas in aortic root were significantly smaller in Dula group. In abdominal aorta, expression levels of some villain factors were lower in Dula group. In a late intervention group, there were no immunohistological differences in aortic root and expression levels of various factors between two groups. Furthermore, even in non-diabetic ApoE knockout mice, expression levels of inflammatory and macrophage markers were reduced by treatment with Dula. Taken together, Dula exerts more beneficial anti-atherosclerotic effects in an early phase of diabetes rather than in a late phase.

Butyrate induced Tregs are capable of migration from the GALT to the pancreas to restore immunological tolerance during type-1 diabetes

Type-1 diabetes (T1D) is an autoimmune disease caused by progressive loss of insulin-producing beta cells in the pancreas. Butyrate is a commensal microbial-derived metabolite, implicated in intestinal homeostasis and immune regulation. Here, we investigated the mechanism of diabetes remission in non-obese diabetic (NOD) mice following butyrate administration. Sodium butyrate (150 mM) was administered to female NOD mice in drinking water after the onset of hyperglycemia (15–25 weeks age) and at 4 weeks of age (early-intervention group). Butyrate administration reduced the progression of hyperglycemia in diabetic mice and delayed onset of diabetes in the early-intervention group with a reduction in insulitis. Butyrate administration increased regulatory T cells (Tregs) in the colon, mesenteric lymph nodes, Peyer’s patches, and its protective effects diminished upon depletion of Tregs. Further, an increase in α4β7, CCR9, and GPR15 expressing Tregs in the pancreatic lymph nodes (PLN) and pancreas in butyrate-treated mice suggested migration of gut-primed Tregs towards the pancreas. Finally, the adoptive transfer experiments demonstrated that induced Tregs from gut-associated lymphoid tissue can migrate towards the pancreas and PLN and delay the onset of diabetes. Our results thus suggest that early administration of butyrate can restore immunological tolerance during T1D via induction of Tregs with migratory capabilities.

Post-cholecystectomy bile duct injuries: when to repair?

Background: Post cholecystectomy bile duct injury (BDI) though rarely happens; it has its own impact on postoperative outcomes. There is controversy on the optimal time for repair of such injuries. The aim of this study was to analyze the different time modalities used for repair of these injuries and its outcomes.Methods: This was a prospective randomized study conducted at General Surgery Department, Sohag university hospital, from August 2013 to March 2017. It included forty patients diagnosed to have BDI after cholecystectomy divided into 3 groups according to the time of intervention; early, intermediate, and late. We compared them regarding the pre-operative, operative variables and analyzed the post-operative outcomes among groups with one year follow-up after repair. Results: Bile leakage was the main presenting symptom in 100% of patients of early intervention group while there was combination of jaundice (71.43%) and bile leakage (28.57%) in the other two groups, 28.57% of patients of intermediate intervention required ICU admission. In the early intervention group there were tendency towards less severe injuries requiring simpler maneuvers for repair with primary repairs or end to end anastomoses while in late intervention group there were tendency towards more severe injuries requiring more complex maneuvers for reconstruction. In the post-operative course there was a tendency for intermediate intervention group to have higher incidence of complications in the early and late post-operative course (57%, p=0.007). Add to this the intermediate intervention group had the longest hospital stay (p=0.008) and was plagued by mortality rate of 21% (p=0.049).Conclusions: Late repair is superior to other time modalities of intervention in post-cholecystectomy BDI in terms of postoperative outcomes.

Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial

ObjectiveMeasurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes.SettingTwo tertiary referral centres in New Zealand.ParticipantsWomen <14 weeks’ gestation and HbA1c ≥5.9%–6.4% (41–46 mmol/mol) measured at booking, without pre-existing diabetes.InterventionsRandomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks’ gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy.Outcome measuresRecruitment rate, adherence to protocol and validation of potential primary outcomes.ResultsRecruitment rates were lower than expected, especially in Māori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement.ConclusionsFor a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs.Trial registration numberACTRN12615000904572; Pre-results.

Impact of Simulation Training on Time to Initiation of Cardiopulmonary Resuscitation for First-Year Pediatrics Residents

Background Pediatrics residents have few opportunities to perform cardiopulmonary resuscitation (CPR). Enhancing the quality of CPR is a key factor to improving outcomes for cardiopulmonary arrest in children and requires effective training strategies. Objective To evaluate the effectiveness of a simulation-based intervention to reduce first-year pediatrics residents' time for 3 critical actions in CPR: (1) call for help, (2) initiate bag-mask ventilation, and (3) initiate chest compressions. Methods A prospective study involving 31 first-year pediatrics residents at a children's hospital assigned to an early or late (control) intervention group. Residents underwent baseline assessment followed by repeat evaluations at 3 and 6 months. Time to critical actions was scored by video review. A 90-minute educational intervention focused on skill practice was conducted following baseline evaluation for the early-intervention group and following 3-month evaluation for the late-intervention group. Primary outcome was change in time to initiating the 3 critical actions. Change in time was analyzed by comparison of Kaplan-Meier curves, using the log-rank test. A 10% sample was timed by a second rater. Agreement was assessed using intraclass correlation (ICC). Results There was a statistically significant reduction in time for all 3 critical actions between baseline and 3-month evaluation in the early intervention group; this was not observed in the late (control) group. Rater agreement was excellent (ICC ≥ 0.99). Conclusions A simulation-based educational intervention significantly reduced time to initiation of CPR for first-year pediatrics residents. Simulation training facilitated acquisition of critical CPR skills that have the potential to impact patient outcome.

Erythroid Response to Epoetin alfa (EPO) 120,000 Units (U) Every Three Weeks (Q3W) Initiated Early or at a Standard Threshold in Chemotherapy-Induced Anemia (CIA).

In the setting of CIA, EPO is effective in maintaining hemoglobin (Hb) levels above the threshold at which packed red blood cell (PRBC) transfusions would be required (usually 8–10 g/dL). This is the first study to evaluate whether Hb levels could be adequately maintained with Q3W EPO initiation treatment. This 16-week open-label randomized study enrolled patients with non-myeloid malignancy, baseline Hb ≥11.0 and ≤12.0 g/dL, and chemotherapy planned for ≥9 weeks. Patients were randomized (1:1) to receive EPO 120,000 U subcutaneously Q3W immediately (early intervention group) or when Hb fell to &lt;11.0 g/dL (standard intervention group). If, at any dosing visit after the 1st EPO dose, Hb decreased to &lt;10.0 g/dL, patients were switched to EPO 40,000 U weekly (QW). Dose was withheld for Hb &gt;13.0 g/dL at any dosing visit; dose was reduced for Hb &gt;12.0 g/dL or Hb increase &gt;1.5 g/dL in a 3-week period (current labeling recommends Hb not to exceed 12 g/dL). Results for the protocol-specified primary efficacy endpoint of Percent Values in Range (PVR; the proportion of weekly Hb levels that were ≥11.0 and ≤13.0 g/dL) were reported previously1. The current abstract presents observed case hematologic profiles for the two interventions. Hb data following a switch to 40,000 U QW were censored. A total of 136 patients were randomized (68 per group). Demographics were similar; mean baseline Hb was 11.47 g/dL in the early intervention group and 11.48 g/dL in the standard intervention group. With the exception of Week 2, when the mean Hb level decreased slightly to 11.35 g/dL, weekly mean Hb levels in the early intervention group remained above the baseline mean and increased gradually through Week 16/end of study (FIGURE). In the standard intervention group (which includes 17 patients who never experienced Hb &lt;11.0 g/dL and never received EPO therapy), mean Hb levels remained below baseline until Week 7. From Week 7 forward, mean Hb levels in the standard intervention group remained at or above the baseline mean and increased gradually through Week 16/end of study. Mean Hb change from baseline to Week 16 was 0.77 g/dL in the early intervention group and 0.59 g/dL in the standard intervention group. On-study PRBC transfusion rates were 13% in the early intervention group and 7% in the standard intervention group. EPO was well tolerated: 6 patients in each group experienced a clinically relevant thrombotic vascular event, and 2 deaths were reported in each group. Early intervention (initiation at Hb ≥11.0 and ≤12.0 g/dL) with EPO 120,000 U Q3W resulted in early gains in mean Hb level relative to standard intervention (initiation at Hb &lt;11.0 g/dL). As increasing numbers of standard intervention patients dropped below 11 g/dL and were started on EPO therapy, mean Hb level recovered and then increased over baseline. Both groups achieved modest increases in mean Hb level over the course of the study period. Initiation treatment with EPO 120,000 U Q3W is effective in maintaining Hb concentrations at a level above that necessitating PRBC transfusions in CIA. 1ASCO 2007 Annual Meeting, Abstract 19564. Mean Hemoglobin Over Time by Study Week and Treatment Group - Observed Case (OC) Approach Modified Intent to Treatment Population - Randamized patients Mean Hemoglobin Over Time by Study Week and Treatment Group - Observed Case (OC) Approach Modified Intent to Treatment Population - Randamized patients