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Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.
Get PDFBACKGROUND
Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies.
METHODS
We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses.
RESULTS
Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling.
CONCLUSIONS
TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted.
REGISTRATION
PROSPERO-ID: CRD42023451628
What is the agreement between principles and practice of antibiotic stewardship in the management of diabetic foot infection: an in-hospital quality control study.
Get PDFIntroduction: Standardization of diagnostic and treatment concepts in diabetes-related foot infection (DFI) is challenging. In 2019, specific recommendations regarding diagnostic principles and antibiotic therapy (ABT) for DFI, including the one for osteomyelitis (DFO), were introduced in our institution. In this study, we assessed the adherence to these in-house guidelines 2 years after their implementation. Methods: Adult patients with DFI with and without DFO who underwent surgical intervention between 2019 and 2021 were included. Patients' charts were retrospectively reviewed. Accordance to recommendations regarding biopsy sampling, labeling, requesting microbiological and histopathological examinations, and treatment duration were assessed. Results: A total of 80 patients with 117 hospital episodes and 163 surgical interventions were included; 84.6 % required an amputation. Patients with HbA1c levels of % more often required a revision during the same hospitalization than those with HbA1c levels of % (29.4 % vs. 12.1 %, respectively, ). Specimens were obtained in 71.8 % of operations and sent for histological examination in 63.2 %. The mean duration of ABT was 9 (interquartile range (IQR) 5-15) d in macroscopically surgically cured episodes and 40.5 (IQR 15-42) d in cases with resection margins in non-healthy bone ( ). Treatment duration results were similar when using histological results: 13 (IQR 8-42) d for healthy bone vs. 29 (IQR 13-42) d for resection margins consistent with osteomyelitis ( ). Conclusion: The adherence to recommendations in terms of biopsy sampling was good, moderate for histopathological analysis and poor for labeling the anatomic location. Adherence to recommendations for ABT duration was good, but further shortening of treatment duration for surgically cured cases is necessary
Obesity and overweight are associated with worse survival in early-onset colorectal cancer: Reply.
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Transiliac-Transsacral Screw Fixation is Superior to Lumbopelvic Stabilization in the Treatment of Minimally Displaced Sacral H-/U-Type Fragility Fractures.
No full textSTUDY DESIGN
Retrospective Cohort Study.
OBJECTIVES
To compare the outcomes and complications of transiliac-transsacral screw fixation (TIS) and lumbopelvic fixation (LPS), the 2 most common fixation methods for nondisplaced and minimally displaced H-/U- type sacral fragility fractures.
METHODS
Medical records of patients treated with TIS or LPS for nondisplaced and minimally displaced H-/U-type sacral fragility fractures at 2 level A trauma centers between 2012 and 2022 were analyzed. Postoperative low back pain and mobility levels were assessed as primary outcomes before discharge and at 6 weeks and 6 months postoperatively. Surgery time, blood loss, and surgical complication rates were assessed as secondary outcomes. Statistical analyses consisted of Fisher's exact tests for frequency distributions and Mann-Whitney-U tests and t-tests for group comparisons.
RESULTS
52 patients undergoing TIS (mean age: 78 ± 9 years) and 36 patients undergoing LPS (74 ± 10 years) with no discrepancy in demographic parameters were identified. There were no differences in low back pain levels between the 2 groups before surgery, before discharge, at 6 weeks postoperatively, and at 6 months postoperatively (P > 0.05). There were no differences in mobility levels before surgery, before discharge, at 6 weeks postoperatively, and at 6 months postoperatively (P > 0.05). Duration of surgery was shorter after TIS (36 ± 13 min) compared to LPS (113 ± 31 min) (P 0.05). Median length of stay was shorter after TIS (11 days) compared to LPS (14 days) (P < 0.05). Rates of reoperations directly related to the index surgery were lower after TIS (n = 2) compared to LPS (n = 10) (P < 0.01). Implant failures were observed only after LPS (n = 1).
CONCLUSION
Patients with nondisplaced and minimally displaced H-/U- type sacral fragility fractures may preferably be treated using TIS, as it is equivalent to LPS in terms of low back pain reduction and restoration of mobility, but allows for shorter operative time, less blood loss and lower reoperation rates. Prospective randomized studies should be conducted to substantiate our findings and develop distinct treatment recommendations
What do medical students think are characteristics of a good ultrasound tutor? A qualitative study.
Get PDFPURPOSE
This study was designed to elicit medical students' opinions on the characteristics of a good ultrasound tutor. The results should help educators to create an optimal teaching environment and inform tutor training.
MATERIALS AND METHODS
The qualitative study recruited 15 participants from a larger mixed-methods study of 64 medical students who underwent a basic course on abdominal ultrasound taught by faculty and near-peer tutors. During semi-structured interviews, they were asked which characteristics make a good ultrasound tutor. We used inductive thematic analysis to identify the most important categories.
RESULTS
Medical students identified teaching themes and subthemes relating to teaching skills (e.g., course structure, repetition, vocabulary, feedback, guidance of participants), tutors' attitudes (e.g., atmosphere creation, empathy) and knowledge as the crucial components of being a good ultrasound tutor.
CONCLUSIONS
While some of the themes that students identified are generic to medical education, others are specific to ultrasound teaching. Tutors can use our results to assess their own teaching. They should aim to address learning needs, optimise understanding, give adequate feedback, and create a non-threatening atmosphere with empathic interactions. Accounting for the ultrasound-specific setting they should possess the necessary knowledge, provide verbal guidance to their students, and distribute examination time wisely
Relapsing-Remitting Immunotherapy Responsive Small-Fiber Neuropathy: Longitudinal Tracking Through 10 Years Including Pregnancies.
Get PDFOBJECTIVES
To expand understanding of the pathogenesis, presentations, and treatment of initially idiopathic small fiber polyneuropathy (SFN).
METHODS
We longitudinally readministered validated metrics to track disease course and treatment responses in a previously healthy woman with acute, postinfectious, skin biopsy-confirmed, idiopathic SFN.
RESULTS
During 5 years, viral respiratory infections triggered 3 separated episodes of acute, disabling burning hand, foot, and face pain (erythromelalgia). The initial 2 resolved with high-dose prednisone, and the third responded to repeated immunoglobulin treatments. Pregnancy with miscarriage triggered a fourth exacerbation refractory to corticosteroids and cyclosporin. Immunoglobulins restored total remission for 2 months; then, 2 rituximab doses slightly improved later flaring. Subsequently, daratumumab initiated 100-day remission later maintained by belimumab, initiated to permit another pregnancy. Remission continued after gestational week 13 all-treatment withdrawal. A week 30 fifth flare responded to plasmapheresis, with healthy birth at week 40. At 11-week postpartum, as symptoms returned, restarting belimumab restored remission maintained during ≥19 months of breastfeeding.
DISCUSSION
This decade of tracking characterizes a relapsing-remitting course of SFN with initially separated monophasic episodes becoming more confluent, as with multiple sclerosis. This tempo and responsiveness to 5 immunotherapies suggest dysimmune causality. Validated metrics helped define the course and track treatment efficacy, particularly during pregnancy and breastfeeding.
CLASSIFICATION OF EVIDENCE
This is a single observational study without controls. This provides Class IV evidence
BDNF-TrkB signaling orchestrates the buildup process of local sleep.
Get PDFSleep debt accumulates during wakefulness, leading to increased slow wave activity (SWA) during sleep, an encephalographic marker for sleep need. The use-dependent demands of prior wakefulness increase sleep SWA locally. However, the circuitry and molecular identity of this "local sleep" remain unclear. Using pharmacology and optogenetic perturbations together with transcriptomics, we find that cortical brain-derived neurotrophic factor (BDNF) regulates SWA via the activation of tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We map BDNF/TrkB-induced sleep SWA to layer 5 (L5) pyramidal neurons of the cortex, independent of neuronal firing per se. Using mathematical modeling, we here propose a model of how BDNF's effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Proteomic analysis further reveals that TrkB activation enriches ubiquitin and proteasome subunits. Together, our study reveals that local SWA control is mediated by BDNF-TrkB-CREB signaling in L5 excitatory cortical neurons
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