Comparative efficacy of two primary care interventions to assist withdrawal from long term benzodiazepine use: A protocol for a clustered, randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Although benzodiazepines are effective, long-term use is not recommended because of potential adverse effects; the risks of tolerance and dependence; and an increased risk of hip fractures, motor vehicle accidents, and memory impairment. The estimated prevalence of long-term benzodiazepine use in the general population is about 2,2 to 2,6%, is higher in women and increases steadily with age. Interventions performed by General Practitioners may help patients to discontinue long-term benzodiazepine use. We have designed a trial to evaluate the effectiveness and safety of two brief general practitioner-provided interventions, based on gradual dose reduction, and will compare the effectiveness of these interventions with that of routine clinical practice.</p> <p>Methods/Design</p> <p>In a three-arm cluster randomized controlled trial, general practitioners will be randomly allocated to: a) a group in which the first patient visit will feature a structured interview, followed by visits every 2-3 weeks to the end of dose reduction; b) a group in which the first patient visit will feature a structured interview plus delivery of written instructions to self-reduce benzodiazepine dose, or c) routine care. Using a computerized pharmaceutical prescription database, 495 patients, aged 18-80 years, taking benzodiazepine for at least 6 months, will be recruited in primary care health districts of three regions of Spain (the Balearic Islands, Catalonia, and Valencia). The primary outcome will be benzodiazepine use at 12 months. The secondary outcomes will include measurements of anxiety and depression symptoms, benzodiazepine dependence, quality of sleep, and alcohol consumption.</p> <p>Discussion</p> <p>Although some interventions have been shown to be effective in reducing benzodiazepine consumption by long-term users, the clinical relevance of such interventions is limited by their complexity. This randomized trial will compare the effectiveness and safety of two complex stepped care interventions with that of routine care in a study with sufficient statistical power to detect clinically relevant differences.</p> <p>Trial Registration</p> <p>Current Controlled Trials: <a href="http://www.controlled-trials.com/ISRCTN13024375">ISRCTN13024375</a></p

Very low frequency Syndromes

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCThe aim of this chapter is to summarize updated knowledge about the clinical characteristics, etiology, genetic and molecular aspects, as well as mechanisms involved in syndromes having very low frequency, in order to promote their better recognition. During the last five years, a total of 30 syndromes have been published in this chapter of the Boletín del ECEMC. This issue includes the following selected syndromes: Crouzon, Pfeiffer, Apert, Saethre-Chotzen, Carpenter and Muenke. All share craniosynostosis as the main clinical feature but also present with other birth defects, the most important being limb malformations, specially syndactyly and polydactyly. Over 100 syndromes with craniosynostosis have been described, usually involving multiple sutures, and several of them are associated with limb malformations. The clinical overlapping between those syndromes makes difficult to perform a neonatal diagnosis, based on their clinical findings. However, molecular genetic testing, specifically of the FRGR1-3 and TWIST1 genes, could help to establish the diagnosis of some of them. Early diagnosis is important for establishing the most suitable treatment for each patient, as well as to offer an accurate genetic counselling and the possibility of preimplantational and/or prenatal diagnosis.N

A flagship for Austral temperate forest conservation: an action plan for Darwin's frogs brings key stakeholders together

Darwin’s frogs Rhinoderma darwinii and Rhinoderma rufum are the only known species of amphibians in which males brood their offspring in their vocal sacs. We propose these frogs as flagship species for the conservation of the Austral temperate forests of Chile and Argentina. This recommendation forms part of the vision of the Binational Conservation Strategy for Darwin’s Frogs, which was launched in 2018. The strategy is a conservation initiative led by the IUCN SSC Amphibian Specialist Group, which in 2017 convened 30 governmental, non-profit and private organizations from Chile, Argentina and elsewhere. Darwin’s frogs are iconic examples of the global amphibian conservation crisis: R. rufum is categorized as Critically Endangered (Possibly Extinct) on the IUCN Red List, and R. darwinii as Endangered. Here we articulate the conservation planning process that led to the development of the conservation strategy for these species and present its main findings and recommendations. Using an evidence-based approach, the Binational Conservation Strategy for Darwin’s Frogs contains a comprehensive status review of Rhinoderma spp., including critical threat analyses, and proposes 39 prioritized conservation actions. Its goal is that by 2028, key information gaps on Rhinoderma spp. will be filled, the main threats to these species will be reduced, and financial, legal and societal support will have been achieved. The strategy is a multi-disciplinary, transnational endeavour aimed at ensuring the long-term viability of these unique frogs and their particular habitat

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

Forouzanfar MH, Afshin A, Alexander LT, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. LANCET. 2016;388(10053):1659-1724.Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Copyright (C) The Author(s). Published by Elsevier Ltd

Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B

Cerebral Oximetry Monitoring in Extremely Preterm Infants

Background: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. Methods: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, &lt;28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. Results: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. Conclusions: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.)