Telemedical support for prehospital emergency medical service in severe emergencies: an open-label randomised non-inferiority clinical trial.

BACKGROUND: A tele-emergency medical service with a remote emergency physician for severe prehospital emergencies may overcome the increasing number of emergency calls and shortage of emergency medical service providers. We analysed whether routine use of a tele-emergency medical service is non-inferior to a conventional physician-based one in the occurrence of intervention-related adverse events. METHODS: This open-label, randomised, controlled, parallel-group, non-inferiority trial included all routine severe emergency patients aged ≥ 18 years within the ground-based ambulance service of Aachen, Germany. Patients were randomised in a 1:1 allocation ratio to receive either tele-emergency medical service (n = 1764) or conventional physician-based emergency medical service (n = 1767). The primary outcome was the occurrence of intervention-related adverse events with suspected causality to the group assignment. The trial was registered with ClinicalTrials.gov (NCT02617875) on 30 November 2015 and is reported in accordance with the CONSORT statement for non-inferiority trials. RESULTS: Among 3531 randomised patients, 3220 were included in the primary analysis (mean age, 61.3 years; 53.8% female); 1676 were randomised to the conventional physician-based emergency medical service (control) group and 1544 to the tele-emergency medical service group. A physician was not deemed necessary in 108 of 1676 cases (6.4%) and 893 of 1544 cases (57.8%) in the control and tele-emergency medical service groups, respectively. The primary endpoint occurred only once in the tele-emergency medical service group. The Newcombe hybrid score method confirmed the non-inferiority of the tele-emergency medical service, as the non-inferiority margin of - 0.015 was not covered by the 97.5% confidence interval of - 0.0046 to 0.0025. CONCLUSIONS: Among severe emergency cases, tele-emergency medical service was non-inferior to conventional physician-based emergency medical service in terms of the occurrence of adverse events.

Intestinal permeability in patients with IgA nephropathy and other glomerular diseases: an observational study.

BACKGROUND: A dysregulated 'gut-kidney axis' may contribute to immunoglobulin A nephropathy (IgAN). We studied whether IgAN patients have disturbed intestinal permeability. METHODS: In a prospective, cross sectional, pilot study we assessed intestinal permeability in 35 IgAN patients, 18 patients with non-IgAN glomerulonephritides (GNs) and 19 healthy controls. After an overnight fast, trial participants ingested a multi-sugar solution and samples were obtained from 0 to 2, 2 to 5- and 5 to 24-h urine portions. Urinary sugar concentrations were quantified using isocratic ion-exchange high performance liquid chromatography. Indices of small intestinal permeability (0-2-h lactulose/L-rhamnose (L/R) ratio), distal small intestinal and proximal colonic permeability (2-5-h sucralose/erythritol (S/E) ratio) and colonic permeability (5-24-h sucralose/erythritol (S/E) ratio) were evaluated. Associations between groups and indices of intestinal permeability were investigated by a linear mixed model. RESULTS: Small intestinal permeability (0-2 h L/R-ratio) was significantly increased in patients with glomerular diseases versus healthy controls. More precisely, increased small intestinal permeability was exclusively noted in non-IgAN GN patients, whereas IgAN patients exhibited a trend towards elevated small intestinal permeability. In total, 54% of patients with IgAN and 67% of non-IgAN GN patients had increased small intestinal permeability. Neither distal small intestinal and proximal colonic permeability nor colonic gut permeability indices (i.e., 2-5 h and 5-24 h S/E ratios) were significantly different between controls and any of the GN patient groups. CONCLUSION: The present single center pilot study suggests that disturbed intestinal permeability is common in patients with glomerular diseases and is not specific for IgAN. TRIAL REGISTRATION NUMBER: German Clinical Trials Register DRKS00021533, Date: 24.04.2020.

Assessing prognosis in IgA nephropathy.

Assessing the prognosis is essential in chronic diseases, such as IgA nephropathy. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the "International IgAN Prediction Tool" (available at www.qxmd.com) for this. The key limitation was that the tool was only validated at the time of the kidney biopsy. An improved algorithm is now described, which allows assessing the prognosis at 1 or 2 years after biopsy. Herein, we review the strengths, limitations, and potential clinical usefulness of this new prediction tool.

Effects of empagliflozin on markers of calcium and phosphate homeostasis in patients with type 2 diabetes - Data from a randomized, placebo-controlled study.

BACKGROUND AND AIM: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucose-lowering drugs that increase urinary glucose excretion have been shown to reduce CV events in patients with type 2 diabetes (T2D). Furthermore, several studies have demonstrated that treatment with SGLT2 inhibitors affect calcium and phosphate homeostasis, but the effect of empagliflozin on these biomarkers is hitherto not investigated in detail. Therefore, this analysis of the EMPA hemodynamics study examined effects of empagliflozin on calcium and phosphate homeostasis. METHODS: In this placebo-controlled, randomized, double-blind study patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Biomarkers of calcium and phosphate homeostasis were assessed before, and after 3 days and 3 months of treatment. RESULTS: After 3 days of treatment empagliflozin significantly increased serum levels of phosphate (baseline: 1.10 ± 0.21 mmol/L; day 3: 1.25 ± 0.23 mmol/L; p = 0.036), parathyroid hormone (PTH) (baseline: 57.40 ± 30.49 pg/mL; day 3: 70.23 ± 39.25 pg/mL; p = 0.025), fibroblast growth factor 23 (FGF23) (baseline: 77.92 ± 24.31 pg/mL; day 3: 109.18 ± 58.20 pg/mL; p = 0.001) and decreased 1,25-dihydroxyvitamin D (baseline: 35.01 ± 14.01 ng/L; day 3: 22.09 ± 10.02 mg/L; p < 0.001), while no difference of these parameters was recorded after 3 months of treatment. Empagliflozin had no significant effects on serum calcium and markers of bone resorption (collagen type 1 ß-carboxy-telopeptide = ß-CTX) or formation (osteocalcin) after 3 days and 3 months of treatment. CONCLUSIONS: Empagliflozin treatment of patients with T2D transiently increases serum phosphate, PTH and FGF23, and decreases 1,25-dihydroxyvitamin D. This might reflect a temporal increase of sodium driven phosphate reabsorption in the proximal tubule of the kidney caused by increased sodium availability in response to SGLT2 inhibition.

Effect of different dental implant drilling template designs on heat generation during osteotomy - an in vitro study.

OBJECTIVES: This in vitro study examined the effect of different implant drilling template designs on heat generation during osteotomy and on cooling fluid distribution. MATERIAL AND METHODS: Five different template designs were investigated in a standardized setup against a control group and a negative control group: Occlusal-splint-design (OSD), OSD-covering, OSD-lateral opening, Bar design, and Orientation template. Pilot and one consecutive drill were run at 800 rpm with external irrigation and 2-kg load. Thermocouples recorded temperature changes at depths of 3, 6, and 9 mm in a bovine rib model. In the second experimental setup, the drill channel of one rib sample was perforated, and the irrigation volume passing through the drill channel was collected separately over time. RESULTS: Following mean temperature rises occurred [in °C]: control, 4.9; negative control, 12; OSD, 5.6; OSD-covering, 4.7; OSD-lateral opening, 3.8; Bar design, 5.1; and Orientation template, 4.9. The highest temperature increases were found at a drilling depth of 6 mm (p < .006). The 2.2-mm drill resulted in a significantly higher temperature rise than the 2.8-mm drill (p < .001). The mean volume (ml/min) of irrigation through the drill channel was Control group-flow, 28.5; OSD, 4.1; OSD-covering, 2; OSD-lateral opening; 5.8; bar design, 4; and Orientation template, 24.1. CONCLUSION: Within the limitations, it was shown that fully guided drilling templates reduce the amount of cooling liquid at the point of osteotomy. The template design had an influence on the effective volume of the cooling liquid. However, this did not seem to increase the intraosseous temperature significantly.

Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: the VitaVasK randomized controlled trial.

Background: Cardiovascular calcifications are prevented by matrix Gla protein (MGP), a vitamin K-dependent protein. Haemodialysis patients exhibit marked vitamin K deficiency. The randomized, prospective, open-label, multicentre VitaVasK trial analysed whether vitamin K1 supplementation reduces progression of coronary artery calcifications (CACs) and thoracic aortic calcifications (TACs). Methods: Patients with pre-existing CACs were randomized to continue on standard care or to additionally receive 5 mg of vitamin K1 orally thrice weekly. Hierarchically ordered primary endpoints were progression of TAC and CAC in computed tomography scans at 18 months. Linear mixed effects models with repeated measures at baseline and 12 and 18 months assessed treatment effects after adjusting for study site. Results: Of 60 randomized patients, 20 dropped out for reasons unrelated to vitamin K1, resulting in 23 control and 17 vitamin K1 patients. The trial was stopped early due to slow recruitment. At 18 months, the average TAC progression was 56% lower in the vitamin K1 compared with the control group (p = .039). CAC significantly progressed within the control group, but not within the vitamin K1 group. Average progression at 18 months was 68% lower in the vitamin K1 compared to the control group (P = .072). Vitamin K1 reduced plasma levels of pro-calcific uncarboxylated MGP by 69% at 18 months. No treatment-related adverse events were noted. Conclusion: Vitamin K1 intervention is a potent, safe and cost-effective approach to correct vitamin K deficiency and to potentially reduce cardiovascular calcification in this high-risk population.

Comparison of three full-mouth concepts for the non-surgical treatment of stage III and IV periodontitis: A randomized controlled trial.

AIM: To evaluate the clinical efficacy of full-mouth scaling (FMS), full-mouth disinfection (FMD), and FMD with adjuvant erythritol air-polishing (FMDAP) compared to quadrant-wise debridement (Q-SRP) in patients with periodontitis stage III/IV. METHODS: In this four-arm parallel, prospective, randomized, controlled multi-centre study, changes of pocket probing depths (PPDs), clinical attachment level (CAL), bleeding on probing (BOP), and proportion of closed pockets (PPD ≤4 mm without BOP) were evaluated at baseline and after 3 and 6 months. RESULTS: From 190 randomly participating patients, 172 were included in the final analysis. All groups showed significant (p < .05) improvements in all clinical parameters over 3 and 6 months. During the study period, FMDAP showed significantly higher reductions of mean PPD in teeth with moderate (PPD 4-6 mm) and deep (PPD > 6 mm) pockets and significantly increased proportions of pocket closure than Q-SRP. Patients treated with FMD had significantly greater PPD reduction in deep pockets and a higher percentage of pocket closure after 3 months but not after 6 months compared to Q-SRP. CAL and BOP changes did not significantly differ among all groups. Efficiency of treatment (time effort to gain one closed pocket) was significantly higher for FMDAP, FMD, and FMS compared to Q-SRP (6.3, 8.5, 9.5 vs. 17.8 min per closed pocket; p < .05). CONCLUSIONS: All treatment modalities were effective, without significant differences between full-mouth approaches. FMDAP showed improved clinical outcomes over Q-SRP for moderate and deep pockets after 6 months. Full-mouth protocols were more time-efficient than conventional Q-SRP. CLINICAL SIGNIFICANCE: The trial was registered in a clinical trial database (ClinicalTrials.gov: NCT03509233).

Effects of empagliflozin on lipoprotein subfractions in patients with type 2 diabetes: data from a randomized, placebo-controlled study.

BACKGROUND AND AIMS: Sodium-glucose cotransporter-2 inhibitors, glucose-lowering drugs that increase urinary glucose excretion, have been shown to reduce CV events in patients with type 2 diabetes (T2D), despite the fact that these agents increase blood levels of the proatherogenic low density lipoprotein cholesterol (LDL-C). It has been hypothesized that hemoconcentration due to osmotic diuresis, effects on calculated LDL particle size, or a modulation of lipoprotein subfractions may play a role in this context but to date the underlying mechanisms remain largely unexplored. Therefore, the present study examined effects of empagliflozin on LDL-C and lipoprotein subfractions including calculated LDL particle size and composition. METHODS: In this placebo-controlled, randomized, double blind study, patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Composition of lipoprotein subfractions was assessed before and after 3 months of treatment. Lipoproteins were separated using a combined ultracentrifugation-precipitation method (ß-quantification). RESULTS: Empagliflozin increased LDL-C after 3 months of treatment (from baseline: 103 ± 36 mg/dL to 112 ± 47 mg/dL; p < 0.001) while no difference was recorded after day 1 or day 3 of treatment. The increase of LDL-C was paralleled by an increase of total cholesterol (baseline: 169 ± 41 mg/dL, 3 months: 185 ± 48 mg/dL; p = 0.001). Analyses of lipoprotein subfractions revealed LDL phospholipids and LDL apolipoprotein B to be increased by empagliflozin after 3 months of treatment while calculated LDL particle size was not affected. In addition empagliflozin increased free fatty acid concentrations. CONCLUSIONS: Empagliflozin treatment of patients with T2D increased LDL-C and LDL apolipoprotein B levels but had no effect on calculated LDL particle size.

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy.

BACKGROUND: Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. METHODS: STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. RESULTS: Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. CONCLUSION: In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.