51628 research outputs found
Sort by
Morbidity and mortality after anaesthesia in early life
No full textBackground: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. Results: Infants (n=5609) born at mean (standard deviation [SD]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04–1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15–1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7–3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64–7.71) and mortality (RR=19.80; 95% CI, 5.87–66.7). Conclusions: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants. Clinical trial registration: NCT02350348.</p
The implementation of national dementia plans
No full textIn a theory-driven, qualitative, multiple-case study, we examined the implementation of national dementia plans (NDPs) in Denmark, Germany, and Italy to determine how stakeholders involved in implementing the NDPs evaluate contextual factors in light of the World Health Organ-ization’s seven action areas of dementia-focused policy. To analyse the NDPs, we used a driver diagram of large-scale change and conducted both document analysis and semi-structured inter-views, after which we performed three-way open coding to analyse the methods. The results show that the implementation of NDPs has increased awareness of dementia in all three countries by positioning the disease as a national public health concern. The study also reveals that resources, the use of change theory, and the monitoring of implementation and fragmentation are crucial factors to consider for countries when implementing NDPs. Although stakeholders find the NDPs use-ful, many challenges remain for their successful implementation due to the highly limited means for implementation and evaluation. Moreover, present NDPs all lack a communication plan that encompasses all layers of society to address ways of achieving change. Patients with dementia, and their informal caregivers, should be included more in the design, implementation, and evaluation of NDPs in order to improve their usefulness and effectiveness.</p
Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children
No full textBackground and Objective: Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Methods: Critically ill children (aged 0–18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%). Results: Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1–16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m2, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. Conclusions: The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. Clinical Trial Registration: POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).</p
Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency
No full textImportance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. Design, Setting, and Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Main Outcomes and Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P =.56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P =.13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2to -2.2 × 10-2; P <.001), high cerebrospinal fluid NfL (b = -9.2 × 10-5SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4to -5.6 × 10-5; P <.001), and high CSF t-tau (-7.2 × 10-4SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3to -9.5 × 10-5; P =.03). Conclusions and Relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. Trial Registration: ClinicalTrials.gov Identifier: NCT02149160.</p
The global climate of land politics
No full textLand is a key input in economic production and production-waste sink. This links land to the causes of and responses to climate change. The dominant climate action ideas are based on the concept of ‘land tenure security’ which, in a global context marked by land-based inequities, means ratifying what already exists. This reinforces undemocratic social structures and institutions that themselves contribute to climate change. A restructuring of global land politics is called for, without which any analyses of and responses to climate change are at best superficial, and at worst, flawed and self-defeating. What is needed is to acknowledge the pervasive land-based social inequities in the world, and to end such inequities by pursuing a redistribution of a range of access to a range of land and resources in ways that categorically benefit the working people.</p
Friendship stability in adolescence is associated with ventral striatum responses to vicarious rewards
Get PDFAn important task for adolescents is to form and maintain friendships. In this three-wave biannual study, we used a longitudinal neuroscience perspective to examine the dynamics of friendship stability. Relative to childhood and adulthood, adolescence is marked by elevated ventral striatum activity when gaining self-serving rewards. Using a sample of participants between the ages of eight and twenty-eight, we tested age-related changes in ventral striatum response to gaining for stable (n = 48) versus unstable best friends (n = 75) (and self). In participants with stable friendships, we observed a quadratic developmental trajectory of ventral striatum responses to winning versus losing rewards for friends, whereas participants with unstable best friends showed no age-related changes. Ventral striatum activity in response to winning versus losing for friends further varied with friendship closeness for participants with unstable friendships. We suggest that these findings may reflect changing social motivations related to formation and maintenance of friendships across adolescence
Preferences for e-Mental Health Interventions in Germany
Get PDF_Objectives:_ Recent evidence suggests that e-mental health interventions can be effective at improving mental health but that there is still a notable hesitation among patients to use them. Previous research has revealed that they are perceived by patients as being less helpful than face-to-face psychotherapy. The reasons for this unfavorable perception are, however, not yet well understood. The aim of our study was to address this question by eliciting preferences for individual components of e-mental health interventions in a discrete choice experiment.
_Methods:_ Using a stepwise qualitative approach, we developed the following 5 attributes of eMHIs: introductory training,human contact, peer support, proven effectiveness, content delivery, and price. Additionally, we asked questions about re-spondents’ demographics, attitudes, and previous experience of traditional psychotherapy, as well as their distress level.
_Results:_ A total of 1984 respondents completed the survey. Using mixed logit models, we found that personal contact with a psychotherapist in blended care, proven effectiveness, and low price were highly valued by participants. Participants were indifferent toward the mode of content delivery but showed a slight preference for introductory training via phone, as well as for peer support via online forum alongside coach-led group meetings on site.
_Discussion:_ Our results suggest a clear preference for blended care that includes face-to-face contact with a psychotherapist. This preference remained stable irrespective of sociodemographics, previous experience of psychotherapy, distress level, and the 2 context scenarios used in our discrete choice experiment. Further investigations looking at the potential benefits and risks of blended care are needed
Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report
Get PDFBackground: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. Methods: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. Results: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. Conclusion: As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. Further long-term follow-up is suggested in order to delineate the full clinical spectrum associated with IBDD
Prototype multi-biomarker test for point-of-care leprosy diagnostics
Get PDFTo end the decade-long, obstinately stagnant number of new leprosy cases, there is an urgent need for field-applicable diagnostic tools that detect infection with Mycobacterium leprae, leprosy's etiologic agent. Since immunity against M. leprae is characterized by humoral and cellular markers, we developed a lateral flow test measuring multiple host proteins based on six previously identified biomarkers for various leprosy phenotypes. This multi-biomarker test (MBT) demonstrated feasibility of quantitative detection of six host serum proteins simultaneously, jointly allowing discrimination of patients with multibacillary and paucibacillary leprosy from control individuals in high and low leprosy endemic areas. Pilot testing of fingerstick blood showed similar MBT performance in point-of-care (POC) settings as observed for plasma and serum. Thus, this newly developed prototype MBT measures six biomarkers covering immunity against M. leprae across the leprosy spectrum. The MBT thereby provides the basis for immunodiagnostic POC tests for leprosy with potential for other (infectious) diseases as well.Diagnostic Technique in Health Technology; Applied Microbiology; Biotechnolog
Red-shifted click beetle luciferase mutant expands the multicolor bioluminescent palette for deep tissue imaging
Get PDFFor in vivo multicolor bioluminescence applications, red and near-infrared signals are desirable over shorter wavelength signals because they are not as susceptible to light attenuation by blood and tissue. Herein, we describe the development of a new click beetle luciferase mutant, CBG2, with a red-shifted color emission. When paired with NH2-NpLH2 luciferin, CBG2 (λ = 660 nm) and CBR2 (λ = 730 nm) luciferases can be used for simultaneous dual-color bioluminescence imaging in deep tissue. Using a spectral unmixing algorithm tool it is possible to distinguish each spectral contribution. Ultimately, this enzyme pair can expand the near-infrared bioluminescent toolbox to enable rapid visualization of multiple biological processes in deep tissue using a single substrate.Optical Imaging; Biological Services; Biophysic