Glucose-Lowering Medications and Post-Dementia Survival in Patients with Diabetes and Dementia

Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients.

Primary systemic therapy for patients with brain metastases from lung cancer ineligible for targeted agents

Purpose The purpose of this study was to evaluate overall survival after systemic therapy, largely chemotherapy, in patients with small cell or non-small cell lung cancer and brain metastases. After completion of systemic therapy, some patients received planned brain irradiation, while others were followed. Methods Retrospective cohort study. Results Thirty-eight patients were included (28 small cell, 20 followed with imaging). Six of these 20 patients (30%) received delayed radiotherapy during follow-up. Planned radiotherapy (n = 18, intention-to-treat) was associated with longer survival from diagnosis of brain metastases, median 10.8 versus 6.1 months, p = 0.025. Delayed radiotherapy still resulted in numerically better survival than no radiotherapy at all (median 8.8 versus 5.3 months, not significant). If calculated from the start of delayed radiotherapy, median survival was only 2.7 months. In a multivariable analysis, both Karnofsky performance status ≥ 70 (p = 0.03) and planned radiotherapy (p = 0.05) were associated with better survival. Conclusion In patients ineligible for targeted agents, planned radiotherapy in a modern treatment setting was associated with longer survival compared to no radiotherapy. Timing and type of radiotherapy in such patients should be evaluated in prospective trials to identify patients who might not need planned radiotherapy.

Empiric “Three-in-One” Bismuth Quadruple Therapy for Second-Line Helicobacter pylori Eradication: An Intervention Study in Southern Italy

The eradication of Helicobacter pylori (H. pylori) may be difficult due to antibiotic resistance. Indeed, after one failure, a second-line therapy is needed and a bismuth containing quadruple therapy (BQT) with a three-in-one capsule formulation is becoming very popular. Therefore, we aimed to evaluate effectiveness and safety of BQT as a second-line therapy. We recruited consecutive patients with one therapy failure. For ten days patients received the three-in-one BQT Pylera® therapy, in combination with a proton-pump inhibitor (PPI), decided at the choice of the investigator, at full dose bid. The eradication rate was calculated by intention-to-treat (ITT) and per-protocol (PP)analyses and 95% confidence intervals (CI) were calculated. Seventy-three patients were recruited, 41 females and 32 males (mean age 53.0±13.1 years). Fifty-five patients failed triple therapy with amoxicillin and clarithromycin and the remaining 18 received sequential therapy. Seventy-two patients consumed at least 90% of the capsules, while only one did not complete the therapy due to adverse events (nausea and diarrhea). By ITT analysis, BQT was successful in 62 subjects (eradication rate 84.9%, 95%CI 76.7–93.1%). By PP analysis, the eradication rate was 86.1% (95%CI 78.1–94.1%).Adverse events were observed in 14 subjects (20.5%).In conclusion, our report confirmed that BQT is effective as an empiric second-line regimen.

Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial

Aim Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. Methods After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. Results Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, −0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. Conclusions These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy. Trial Registration: ClinicalTrials.gov (NCT03716505).

Final results of the Choroid Plexus Tumor study CPT-SIOP-2000

Introduction Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. Methods CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. Results For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. Conclusions Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation.

Identification of causal effects in case-control studies

Background Case-control designs are an important yet commonly misunderstood tool in the epidemiologist’s arsenal for causal inference. We reconsider classical concepts, assumptions and principles and explore when the results of case-control studies can be endowed a causal interpretation. Results We establish how, and under which conditions, various causal estimands relating to intention-to-treat or per-protocol effects can be identified based on the data that are collected under popular sampling schemes (case-base, survivor, and risk-set sampling, with or without matching). We present a concise summary of our identification results that link the estimands to the (distribution of the) available data and articulate under which conditions these links hold. Conclusion The modern epidemiologist’s arsenal for causal inference is well-suited to make transparent for case-control designs what assumptions are necessary or sufficient to endow the respective study results with a causal interpretation and, in turn, help resolve or prevent misunderstanding. Our approach may inform future research on different estimands, other variations of the case-control design or settings with additional complexities.

The Diabetes Transition of Hospital Care (DiaTOHC) Pilot Study: A Randomized Controlled Trial of an Intervention Designed to Reduce Readmission Risk of Adults with Diabetes

Hospital readmission within 30 days of discharge (30-day readmission) is a high-priority quality measure and cost target. The purpose of this study was to explore the feasibility and efficacy of the Diabetes Transition of Hospital Care (DiaTOHC) Program on readmission risk in high-risk adults with diabetes. This was a non-blinded pilot randomized controlled trial (RCT) that compared usual care (UC) to DiaTOHC at a safety-net hospital. The primary outcome was all-cause 30-day readmission. Between 10/16/2017 and 05/30/2019, 115 patients were randomized. In the intention-to-treat (ITT) population, 14 (31.1%) of 45 DiaTOHC subjects and 15 (32.6%) of 46 UC subjects had a 30-day readmission (p=0.88) while 35.6% DiaTOHC and 39.1% UC subjects had a 30-day readmission or ED visit (p=0.72). The Intervention:UC cost ratio was 0.33 (0.13-0.79)95%CI (p<0.01). Among the 69 subjects with baseline HbA1c >7.0% (53 mmol/mol), 30-day readmission rates were 23.5% (DiaTOHC) and 31.4% (UC, p=0.46) and composite 30-day readmission or ED visit rates were 26.5% (DiaTOHC) and 40.0% (UC, p=0.23). In this subgroup, the Intervention:UC cost ratio was 0.21 (0.08-0.58)95%CI (p=0.002). The DiaTOHC Program is feasible and may decrease combined 30-day readmission/ED visit risk as well as healthcare costs among patients with higher HbA1c levels.

Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial

Background: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, supplemental strategies to mitigate the spread and severity of COVID-19 are urgently needed. Emerging evidence suggests susceptibility to infections, including respiratory tract infections, may be reduced by probiotic interventions. Therefore, probiotics may be a low-risk, widely implementable modality to mitigate risk of COVID-19 disease, particularly in areas with low vaccine availability and/or uptake. Methods: We conducted a randomized, double-blind, placebo-controlled trial across the United States testing the probiotic Lactobacillus rhamnosus GG (LGG) as post-COVID-19-exposure prophylaxis. We enrolled individuals > 1 year of age with a household contact with a recent (≤ 7 days) diagnosis of COVID-19. Participants were randomized to receive daily LGG or placebo for 28 days. Stool was collected to evaluate the microbiome. The primary outcome was development of symptoms of illness compatible with COVID-19 within 28 days. Findings: We enrolled 182 COVID-19-exposed participants. Intention-to-treat analysis showed that participants randomized to LGG were less likely to develop symptoms versus those randomized to placebo (26.4% vs. 42.9%, p=0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank p=0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis was not significantly different between LGG (8.8%) and placebo (15.4%) (p=0.17). LGG was well-tolerated with no increased side effects versus placebo. Interpretation: These findings suggest that LGG probiotic may protect against the development of COVID-19 infection and symptoms when used as post-exposure prophylaxis within 7 days after exposure. Funding: This work was supported by a grant from the Duke Microbiome Center to A.D.S. and P.E.W. and private philanthropic donations to A.D.S. DSM/iHealth donated the LGG and placebo for the trial but had no role in its design, conduct, analysis, or writing. Trial registration: NCT04399252

Quality initiative to improve emergency department sepsis bundle compliance through utilisation of an electronic health record tool

IntroductionSepsis is a common cause of emergency department (ED) presentation and hospital admission, accounting for a disproportionate number of deaths each year relative to its incidence. Sepsis outcomes have improved with increased recognition and treatment standards promoted by the Surviving Sepsis Campaign. Due to delay in recognition and other barriers, sepsis bundle compliance remains low nationally. We hypothesised that a targeted education intervention regarding use of an electronic health record (EHR) tool for identification and management of sepsis would lead to increased EHR tool utilisation and increased sepsis bundle compliance.MethodsWe created a multidisciplinary quality improvement team to provide training and feedback on EHR tool utilisation within our ED. A prospective evaluation of the rate of EHR tool utilisation was monitored from June through December 2020. Simultaneously, we conducted two retrospective cohort studies comparing overall sepsis bundle compliance for patients when EHR tool was used versus not used. The first cohort was all patients with intention-to-treat for any sepsis severity. The second cohort of patients included adult patients with time of recognition of sepsis in the ED admitted with a diagnosis of severe sepsis or septic shock.ResultsEHR tool utilisation increased from 23.3% baseline prior to intervention to 87.2% during the study. In the intention-to-treat cohort, there was a statistically significant difference in compliance between EHR tool utilisation versus no utilisation in overall bundle compliance (p<0.001) and for several individual components: initial lactate (p=0.009), repeat lactate (p=0.001), timely antibiotics (p=0.031), blood cultures before antibiotics (p=0.001), initial fluid bolus (p<0.001) and fluid reassessment (p<0.001). In the severe sepsis and septic shock cohort, EHR tool use increased from 71.2% pre-intervention to 85.0% post-intervention (p=0.008).ConclusionWith training, feedback and EHR optimisation, an EHR tool can be successfully integrated into current workflows and appears to increase sepsis bundle compliance.

Spin in the neurosurgical trauma literature: prevalence and associated factors – a systematic review protocol

IntroductionSpin is defined as an inaccurate interpretation of results, intentionally or not, leading to equivocal conclusions and misdirecting readers to look at the data in an overly optimistic way. Previous studies have shown a high prevalence of spin in scientific papers and this systematic review aims to investigate the nature and prevalence of spin in the neurosurgical trauma literature. Any associated factors will be identified to guide future research practice recommendations.Methods and analysisThe Preferred Reporting Item for Systematic Reviews and Meta-Analyses recommendations will be followed. Randomised clinical trials (RCTs) that enrolled only patients with traumatic brain injury and investigated any type of intervention (surgical or non-surgical) will be eligible for inclusion. The MEDLINE/PubMed database will be searched for articles in English published in 15 top-ranked journals. Spin will be defined as (1) a focus on statistically significant results not based on the primary outcome; (2) interpreting statistically non-significant results for a superiority analysis of the primary outcome; (3) claiming or emphasising the beneficial effect of the treatment despite statistically non-significant results; (4) conclusion focused in the per-protocol or as-treated analysis instead of the intention-to-treat results; (5) incorrect statistical analysis; (6) republication of a significant secondary analysis without proper acknowledgement of the primary outcome analysis result. Traditional descriptive statistics will be used to present RCT characteristics. Standardised differences between the groups with or without spin will be calculated. The variables with a standardised difference equal or above 0.2 and 0.5 will be considered weakly and strongly associated with spin, respectively.Ethics and disseminationThis study will not involve primary data collection and patients will not be involved.Trial registration number10.17605/OSF.IO/H3FGY.