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Designer receptors exclusively activated by designer drugs (DREADDs) are established tools for modulating neuronal activity. Calcium-mobilizing DREADD hM3Dq has been widely used to enhance neuronal activity. hM3Dq activates the Gq protein signaling cascade and mimics the action of native Gq protein-coupled receptors such as muscarinic m1 and m3 receptors leading to calcium release from intracellular storages. Depolarization evoked by increased intracellular calcium levels is an important factor for neuronal maturation. Here, we used repetitive activation of biolistically overexpressed hM3Dq to increase the activity of individual neurons differentiating in organotypic slice cultures of rat visual cortex. HM3Dq was activated by 3 μM clozapine-N-oxide (CNO) dissolved in H 2 O. Transfectants expressing hM3Dq mock-stimulated with H 2 O served as batch-internal controls. Pyramidal cells and multipolar interneurons were analyzed after treatment from DIV 5–10, DIV 10–20, and DIV 15–20 to investigate if Gq signaling is involved in dendritic maturation. Results show that hM3Dq activation accelerated the maturation of apical dendrites of L2/3 pyramidal cells in the early, but no longer in the later time windows. In contrast, dendritic dimensions of L5/6 pyramidal cells and interneurons were not altered at DIV 10. These findings suggest a growth-promoting role of activated Gq signaling selectively for early postnatal L2/3 pyramidal cells. Unexpectedly, hM3Dq activation from DIV 10–20 reduced the dendritic complexity of L5/6 pyramidal cells and multipolar interneurons. Together, results suggest a role of Gq signaling for neuronal differentiation and support evidence that it may also limit dendritic growth.

Severe autoimmune-mediated neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and paranodopathies, often remain refractory to established immunotherapies. 1–3 Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promising therapeutic potential in autoimmune conditions through substantial and sustained B-cell depletion. 4,5 Here, we report treatment of two patients with severe, treatment-refractory autoimmune neuropathies using autologous anti-CD19 CAR T cells ( appendix pp 2–3). In March, 2023, the patient first presented to our university hospital with rapid progression to symmetric tetraplegia despite extensive immunotherapy (intravenous immunoglobulin, corticosteroids, plasmapheresis, cyclophosphamide, rituximab, obinutuzumab, and bortezomib; appendix pp 4–6). JM declares stock ownership from Amgen, Bayer, and Sanofi; travel grants from Alnylam, Biogen Idec, Novartis, Teva, Eisai, Neuraxpharm, Bristol Myers Squibb, and Kyverna; consulting fees from Novartis and Alnylam; and research funding from Klaus Tschira Foundation, Ruhr-University Bochum (FoRUM program), Deutsche Multiple Sklerose Gesellschaft, Hertie Foundation, Novartis, and Kyverna, not related to this work.

Screening, brief intervention and referral to treatment (SBIRT) is a programme to reduce alcohol consumption for drinkers with high alcohol consumption levels. Only 2.9% of patients in primary health care (PHC) are screened for their alcohol use in Germany, despite high levels of alcohol consumption and attributable harm. We developed an open-access simulation model to estimate the impact of higher SBIRT delivery rates in German PHC settings on population-level alcohol consumption. A hypothetical population of drinkers and non-drinkers was simulated by sex, age, and educational status for the year 2009 based on survey and sales data. Risky drinking persons receiving BI or RT were sampled from this population based on screening coverage and other parameters. Running the simulation model for a ten-year period, drinking levels and heavy episodic drinking (HED) status were changed based on effect sizes from meta-analyses. In the baseline scenario of 2.9% screening coverage, 2.4% of the adult German population received a subsequent intervention between 2009 and 2018. If every second PHC patient would have been screened for alcohol use, 21% of adult residents in Germany would have received BI or RT by the end of the ten-year simulation period. In this scenario, population-level alcohol consumption would be 11% lower than it was in 2018, without any impact on HED prevalence. Screening coverage rates below 10% were not found to have a measurable effect on drinking levels. Large-scale implementation of SBIRT in PHC settings can yield substantial reductions of alcohol consumption in Germany. As high screening coverage rates may only be achievable in the long run, other effective alcohol policies are required to achieve short-term reduction of alcohol use and attributable harm in Germany. There is large potential to apply this open-access simulation model to other settings and for other alcohol interventions.

PurposeWe aimed to test the effects of providing municipal support and training to primary health care providers compared to both training alone and to care as usual on the proportion of adult patients having their alcohol consumption measured.MethodsWe undertook a quasi-experimental study reporting on a 5-month implementation period in 58 primary health care centres from municipal areas within Bogotá (Colombia), Mexico City (Mexico), and Lima (Peru). Within the municipal areas, units were randomized to four arms: (1) care as usual (control); (2) training alone; (3) training and municipal support, designed specifically for the study, using a less intensive clinical and training package; and (4) training and municipal support, designed specifically for the study, using a more intense clinical and training package. The primary outcome was the cumulative proportion of consulting adult patients out of the population registered within the centre whose alcohol consumption was measured (coverage).ResultsThe combination of municipal support and training did not result in higher coverage than training alone (incidence rate ratio (IRR) = 1.0, 95% CI = 0.6 to 0.8). Training alone resulted in higher coverage than no training (IRR = 9.8, 95% CI = 4.1 to 24.7). Coverage did not differ by intensity of the clinical and training package (coefficient = 0.8, 95% CI 0.4 to 1.5).ConclusionsTraining of providers is key to increasing coverage of alcohol measurement amongst primary health care patients. Although municipal support provided no added value, it is too early to conclude this finding, since full implementation was shortened due to COVID-19 restrictions.Trial RegistrationClinical Trials.gov ID: NCT03524599; Registered 15 May 2018; https://clinicaltrials.gov/ct2/show/NCT03524599

Implementation of evidence-based care for heavy drinking and depression remains low in global health systems. We tested the impact of providing community support, training, and clinical packages of varied intensity on depression screening and management for heavy drinking patients in Latin American primary healthcare. Quasi-experimental study involving 58 primary healthcare units in Colombia, Mexico and Peru randomized to receive: (1) usual care (control); (2) training using a brief clinical package; (3) community support plus training using a brief clinical package; (4) community support plus training using a standard clinical package. Outcomes were proportion of: (1) heavy drinking patients screened for depression; (2) screen-positive patients receiving appropriate support; (3) all consulting patients screened for depression, irrespective of drinking status. 550/615 identified heavy drinkers were screened for depression (89.4%). 147/230 patients screening positive for depression received appropriate support (64%). Amongst identified heavy drinkers, adjusting for country, sex, age and provider profession, provision of community support and training had no impact on depression activity rates. Intensity of clinical package also did not affect delivery rates, with comparable performance for brief and standard versions. However, amongst all consulting patients, training providers resulted in significantly higher rates of alcohol measurement and in turn higher depression screening rates; 2.7 times higher compared to those not trained. Training using a brief clinical package increased depression screening rates in Latin American primary healthcare. It is not possible to determine the effectiveness of community support on depression activity rates due to the impact of COVID-19.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Heavy drinking is a cause of considerable disability, morbidity and mortality.2 Heavy drinking is a causal factor for some communicable diseases (including TB and HIV/AIDS), for many non-communicable diseases (NCDs, including cancers, cardiovascular diseases and gastrointestinal diseases) and for many mental and behavioural disorders, including depression, dementias and suicide.3 4 In PHC settings, two-fifths of people with heavy drinking have depression, with risks of incident depression higher for heavier as opposed to lighter drinkers.5 In addition to its role in the aetiology of depression, heavy drinking is associated with worsening the depression course, including suicide risk, impaired social functioning and impaired healthcare utilisation.6 Heavy drinking is also a major contributor to global health inequalities, with alcohol-related harm aggravated by lower socioeconomic status7 and extending beyond the individual drinker to families, communities, health systems and the wider economy. Tackling the multiple individual and societal level harms caused by heavy drinking is essential for achieving global targets of reducing deaths from NCDs by 25% between 2010 and 2025,8 more so as risk of exposure to harmful use of alcohol increases with increasing socioeconomic status.9 In line with tackling harm due to lower socioeconomic status, United Nations Sustainable Development Goals include Target 3.5, to strengthen the prevention and treatment of harmful use of alcohol, with two proposed indicators: coverage of treatment interventions (pharmacological, psychosocial and rehabilitation and aftercare services) for harmful use of alcohol; and per capita alcohol consumption.10 11 Countries in Latin America have the highest alcohol-attributable disease burden after Eastern Europe and sub-Saharan Africa, with particularly high risks in alcohol-attributable traffic injury including violence.12 The burden of alcohol-attributable diseases in Latin America lead to marked economic costs, with numerous calls to implement effective and cost-effective policies.13 A robust and extensive body of literature demonstrates the range of evidence-based strategies that can be implemented to reduce heavy drinking in healthcare settings.14 Questionnaire-based measurement and brief advice programmes delivered in PHC are effective15 and cost-effective16 17 in reducing heavy drinking. In addition to brief advice, treatment for heavy drinking includes cognitive behavioural therapy and pharmacotherapy, both of which are found to be effective in reducing heavy drinking.18 Were the proportion of eligible patients receiving advice and treatment for heavy drinking to increase to 30% of eligible patients, the prevalence of harmful use of alcohol could decrease by between 10% and 15% across OECD (Organisation for Economic Co-operation) and member countries.19 However, to date, measurement and brief advice and treatment programmes have failed to achieve widespread take-up.19 Two systematic reviews20 21 and two multicountry studies22–24 have demonstrated that the proportion of PHC patients whose alcohol consumption is measured, and of heavy drinking patients given advice can be increased by providing training and support to PHC providers, although from very low baseline levels, and with effects not generally sustained over the longer term. [...]while there has been some previous research in countries of Latin America,25–30 most implementation work to date has been undertaken in high-income countries. Similar conclusions were reached by the European Optimising Delivery of Healthcare Interventions (ODHIN) study42 and the US-based Substance Abuse and Mental Health Services Administration Screening, Brief Intervention and Referral to Treatment initiative.43–45 The second barrier is that standard cut-off points for the frequently used alcohol measurement instrument, Alcohol Use Disorders Identification Test, 3-item consumption version (AUDIT-C)46 (commonly a score of five for both men and women, or five for men and four for women) to trigger advice are too low,47 being equivalent to an average daily alcohol consumption of about 20 g of alcohol (around two standard drinks) or less.48 Practitioners may well find it problematic to give advice at such levels, which would also have huge time implications, with one in three or four patients being eligible for advice in many countries, under this criterion.24 49 We have argued to adopt similar models to blood pressure, where cut-off points for managing raised blood pressure are often determined by levels of blood pressure at which treatment has shown to be effective.50 51 Similarly, cut-off points for brief advice could be the baseline levels of alcohol consumption found in the randomised controlled trials that have investigated the effectiveness of PHC-delivered brief advice.

Implementation of evidence-based care for heavy drinking and depression remains low in global health systems. We tested the impact of providing community support, training, and clinical packages of varied intensity on depression screening and management for heavy drinking patients in Latin American primary healthcare. Quasi-experimental study involving 58 primary healthcare units in Colombia, Mexico and Peru randomized to receive: (1) usual care (control); (2) training using a brief clinical package; (3) community support plus training using a brief clinical package; (4) community support plus training using a standard clinical package. Outcomes were proportion of: (1) heavy drinking patients screened for depression; (2) screen-positive patients receiving appropriate support; (3) all consulting patients screened for depression, irrespective of drinking status. 550/615 identified heavy drinkers were screened for depression (89.4%). 147/230 patients screening positive for depression received appropriate support (64%). Amongst identified heavy drinkers, adjusting for country, sex, age and provider profession, provision of community support and training had no impact on depression activity rates. Intensity of clinical package also did not affect delivery rates, with comparable performance for brief and standard versions. However, amongst all consulting patients, training providers resulted in significantly higher rates of alcohol measurement and in turn higher depression screening rates; 2.7 times higher compared to those not trained. Training using a brief clinical package increased depression screening rates in Latin American primary healthcare. It is not possible to determine the effectiveness of community support on depression activity rates due to the impact of COVID-19.

During the COVID-19 pandemic, an increase of heavy alcohol use has been reported in several high-income countries. We examined changes in alcohol use during the pandemic among primary health care (PHC) patients in two middle income countries, Colombia and Mexico. Data were collected during routine consultations in 34 PHC centres as part of a large-scale implementation study. Providers measured patients' alcohol consumption with the three item 'Alcohol Use Disorders Identification Test' (AUDIT-C). Generalized linear mixed models were performed to examine changes in two dependent variables over time (pre-pandemic and during pandemic): 1) the AUDIT-C score and 2) the proportion of heavy drinking patients (8+ on AUDIT-C). Over a period of more than 600 days, data from N = 17 273 patients were collected. During the pandemic, the number of patients with their alcohol consumption measured decreased in Colombia and Mexico. Each month into the pandemic was associated with a 1.5% and 1.9% reduction in the mean AUDIT-C score in Colombia and Mexico, respectively. The proportion of heavy drinking patients declined during the pandemic in Colombia (pre-pandemic: 5.4%, 95% confidence interval (CI) = 4.8% to 6.0%; during the pandemic: 0.8%, 95% CI = 0.6% to 1.1%) but did not change in Mexico. Average consumption levels declined and the prevalence of heavy drinking patterns did not increase. In addition to reduced opportunities for social drinking during the pandemic, changes in the population seeking PHC and restrictions in alcohol availability and affordability are likely drivers for lower levels of alcohol use by patients in this study.

BackgroundScreening, brief intervention and referral to treatment (SBIRT) is a programme to reduce alcohol consumption for drinkers with high alcohol consumption levels. Only 2.9% of patients in primary health care (PHC) are screened for their alcohol use in Germany, despite high levels of alcohol consumption and attributable harm. We developed an open-access simulation model to estimate the impact of higher SBIRT delivery rates in German PHC settings on population-level alcohol consumption.Methods and findingsA hypothetical population of drinkers and non-drinkers was simulated by sex, age, and educational status for the year 2009 based on survey and sales data. Risky drinking persons receiving BI or RT were sampled from this population based on screening coverage and other parameters. Running the simulation model for a ten-year period, drinking levels and heavy episodic drinking (HED) status were changed based on effect sizes from meta-analyses. In the baseline scenario of 2.9% screening coverage, 2.4% of the adult German population received a subsequent intervention between 2009 and 2018. If every second PHC patient would have been screened for alcohol use, 21% of adult residents in Germany would have received BI or RT by the end of the ten-year simulation period. In this scenario, population-level alcohol consumption would be 11% lower than it was in 2018, without any impact on HED prevalence. Screening coverage rates below 10% were not found to have a measurable effect on drinking levels.ConclusionsLarge-scale implementation of SBIRT in PHC settings can yield substantial reductions of alcohol consumption in Germany. As high screening coverage rates may only be achievable in the long run, other effective alcohol policies are required to achieve short-term reduction of alcohol use and attributable harm in Germany. There is large potential to apply this open-access simulation model to other settings and for other alcohol interventions.