Zfhx3-mediated genetic ablation of the SCN abolishes light entrainable circadian activity while sparing food anticipatory activity.

Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals

Slow implementation of mifepristone medical termination of pregnancy in Quebec, Canada: a qualitative investigation.

Objectives: Mifepristone for first-trimester medical termination of pregnancy (MTOP) became available in Quebec in 2018, one year after the rest of Canada. Using the theory of the Diffusion of Innovation (DOI) and the transtheoretical model of change (TTM), we investigated factors influencing the implementation of mifepristone MTOP in Quebec.Material and Methods: Semi-structured interviews were conducted with 37 Quebec physicians in early 2018. Deductive thematic analysis guided by the theory of DOI explored facilitators and barriers to physicians' adoption of mifepristone MTOP. We then classified participants into five stages of mifepristone adoption based on the TTM. Follow-up data collection one year later assessed further adoption.Results: At baseline, three physicians provided mifepristone MTOP (Maintenance) and two were about to start (Action). Thirteen physicians at Preparation and Advanced Contemplation stages intended to start while, within the Slow Contemplation, two intended to start and ten were unsure. Seven had no intention to provide mifepristone MTOP (Pre-Contemplation). Major reported barriers were: complexity of local health care organisations, medical policy restrictions, lack of support, and general uncertainty. One year later, ten physicians provided mifepristone MTOP (including three at baseline) and nine still intended to, while seventeen did not intend to start provision. Seven of sixteen participants (44%) who worked in TOP clinics at baseline were still not providing MTOP with mifepristone one year later.Conclusion: Despite ideological support, mifepristone MTOP uptake in Quebec is slow and laborious, mainly due to restrictive medical policies, vested interests in surgical provision and administrative inertia

A flexible Bayesian hierarchical model of preterm birth risk among US Hispanic subgroups in relation to maternal nativity and education

<p>Abstract</p> <p>Background</p> <p>Previous research has documented heterogeneity in the effects of maternal education on adverse birth outcomes by nativity and Hispanic subgroup in the United States. In this article, we considered the risk of preterm birth (PTB) using 9 years of vital statistics birth data from New York City. We employed finer categorizations of exposure than used previously and estimated the risk dose-response across the range of education by nativity and ethnicity.</p> <p>Methods</p> <p>Using Bayesian random effects logistic regression models with restricted quadratic spline terms for years of completed maternal education, we calculated and plotted the estimated posterior probabilities of PTB (gestational age < 37 weeks) for each year of education by ethnic and nativity subgroups adjusted for only maternal age, as well as with more extensive covariate adjustments. We then estimated the posterior risk difference between native and foreign born mothers by ethnicity over the continuous range of education exposures.</p> <p>Results</p> <p>The risk of PTB varied substantially by education, nativity and ethnicity. Native born groups showed higher absolute risk of PTB and declining risk associated with higher levels of education beyond about 10 years, as did foreign-born Puerto Ricans. For most other foreign born groups, however, risk of PTB was flatter across the education range. For Mexicans, Central Americans, Dominicans, South Americans and "Others", the protective effect of foreign birth diminished progressively across the educational range. Only for Puerto Ricans was there no nativity advantage for the foreign born, although small numbers of foreign born Cubans limited precision of estimates for that group.</p> <p>Conclusions</p> <p>Using flexible Bayesian regression models with random effects allowed us to estimate absolute risks without strong modeling assumptions. Risk comparisons for any sub-groups at any exposure level were simple to calculate. Shrinkage of posterior estimates through the use of random effects allowed for finer categorization of exposures without restricting joint effects to follow a fixed parametric scale. Although foreign born Hispanic women with the least education appeared to generally have low risk, this seems likely to be a marker for unmeasured environmental and behavioral factors, rather than a causally protective effect of low education itself.</p

General Destabilizing Effects of Eutrophication on Grassland Productivity at Multiple Spatial Scales

Eutrophication is a widespread environmental change that usually reduces the stabilizing effect of plant diversity on productivity in local communities. Whether this effect is scale dependent remains to be elucidated. Here, we determine the relationship between plant diversity and temporal stability of productivity for 243 plant communities from 42 grasslands across the globe and quantify the effect of chronic fertilization on these relationships. Unfertilized local communities with more plant species exhibit greater asynchronous dynamics among species in response to natural environmental fluctuations, resulting in greater local stability (alpha stability). Moreover, neighborhood communities that have greater spatial variation in plant species composition within sites (higher beta diversity) have greater spatial asynchrony of productivity among communities, resulting in greater stability at the larger scale (gamma stability). Importantly, fertilization consistently weakens the contribution of plant diversity to both of these stabilizing mechanisms, thus diminishing the positive effect of biodiversity on stability at differing spatial scales. Our findings suggest that preserving grassland functional stability requires conservation of plant diversity within and among ecological communities

A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders

CONTEXT: The childhood precursors of adult bipolar disorder (BP) are still a matter of controversy. OBJECTIVE: To report the lifetime prevalence and early clinical predictors of psychiatric disorders in offspring from families of probands with DSM-IV BP compared with offspring of control subjects. DESIGN: A longitudinal, prospective study of individuals at risk for BP and related disorders. We report initial (cross-sectional and retrospective) diagnostic and clinical characteristics following best-estimate procedures. SETTING: Assessment was performed at 4 university medical centers in the United States between June 1, 2006, and September 30, 2009. PARTICIPANTS: Offspring aged 12 to 21 years in families with a proband with BP (n = 141, designated as cases) and similarly aged offspring of control parents (n = 91). MAIN OUTCOME MEASURE: Lifetime DSM-IV diagnosis of a major affective disorder (BP type I; schizoaffective disorder, bipolar type; BP type II; or major depression). RESULTS: At a mean age of 17 years, cases showed a 23.4% lifetime prevalence of major affective disorders compared with 4.4% in controls (P = .002, adjusting for age, sex, ethnicity, and correlation between siblings). The prevalence of BP in cases was 8.5% vs 0% in controls (adjusted P = .007). No significant difference was seen in the prevalence of other affective, anxiety, disruptive behavior, or substance use disorders. Among case subjects manifesting major affective disorders (n = 33), there was an increased risk of anxiety and externalizing disorders compared with cases without mood disorder. In cases but not controls, a childhood diagnosis of an anxiety disorder (relative risk = 2.6; 95% CI, 1.1-6.3; P = .04) or an externalizing disorder (3.6; 1.4-9.0; P = .007) was predictive of later onset of major affective disorders. CONCLUSIONS: Childhood anxiety and externalizing diagnoses predict major affective illness in adolescent offspring in families with probands with BP

Real World Performance of the 21st Century Cures Act Population Level Application Programming Interface

OBJECTIVE: To evaluate the real-world performance in delivering patient data on populations, of the SMART/HL7 Bulk FHIR Access API, required in Electronic Health Records (EHRs) under the 21st Century Cures Act Rule. MATERIALS AND METHODS: We used an open-source Bulk FHIR Testing Suite at five healthcare sites from April to September 2023, including four hospitals using EHRs certified for interoperability, and one Health Information Exchange (HIE) using a custom, standards-compliant API build. We measured export speeds, data sizes, and completeness across six types of FHIR resources. RESULTS: Among the certified platforms, Oracle Cerner led in speed, managing 5-16 million resources at over 8,000 resources/min. Three Epic sites exported a FHIR data subset, achieving 1-12 million resources at 1,555-2,500 resources/min. Notably, the HIE's custom API outperformed, generating over 141 million resources at 12,000 resources/min. DISCUSSION: The HIE's custom API showcased superior performance, endorsing the effectiveness of SMART/HL7 Bulk FHIR in enabling large-scale data exchange while underlining the need for optimization in existing EHR platforms. Agility and scalability are essential for diverse health, research, and public health use cases. CONCLUSION: To fully realize the interoperability goals of the 21st Century Cures Act, addressing the performance limitations of Bulk FHIR API is critical. It would be beneficial to include performance metrics in both certification and reporting processes

Challenges in quantifying changes in the global water cycle

Human influences have likely already impacted the large-scale water cycle but natural variability and observational uncertainty are substantial. It is essential to maintain and improve observational capabilities to better characterize changes. Understanding observed changes to the global water cycle is key to predicting future climate changes and their impacts. While many datasets document crucial variables such as precipitation, ocean salinity, runoff, and humidity, most are uncertain for determining long-term changes. In situ networks provide long time-series over land but are sparse in many regions, particularly the tropics. Satellite and reanalysis datasets provide global coverage, but their long-term stability is lacking. However, comparisons of changes among related variables can give insights into the robustness of observed changes. For example, ocean salinity, interpreted with an understanding of ocean processes, can help cross-validate precipitation. Observational evidence for human influences on the water cycle is emerging, but uncertainties resulting from internal variability and observational errors are too large to determine whether the observed and simulated changes are consistent. Improvements to the in situ and satellite observing networks that monitor the changing water cycle are required, yet continued data coverage is threatened by funding reductions. Uncertainty both in the role of anthropogenic aerosols, and due to large climate variability presently limits confidence in attribution of observed changes

Perspectives Among Canadian Physicians on Factors Influencing Implementation of Mifepristone Medical Abortion: A National Qualitative Study.

PURPOSE: Access to family planning health services in Canada has been historically inadequate and inequitable. A potential solution appeared when Health Canada approved mifepristone, the gold standard for medical abortion, in July 2015. We sought to investigate the factors that influence successful initiation and ongoing provision of medical abortion services among Canadian health professionals and how these factors relate to abortion policies, systems, and service access throughout Canada. METHODS: We conducted 1-on-1 semistructured interviews with a national sample of abortion-providing and nonproviding physicians and health system stakeholders in Canadian health care settings. Our data collection, thematic analysis, and interpretation were guided by Diffusion of Innovation theory. RESULTS: We conducted interviews with 90 participants including rural practitioners and those with no previous abortion experience. In the course of our study, Health Canada removed mifepristone restrictions. Our results suggest that Health Canada's initial restrictions discouraged physicians from providing mifepristone and were inconsistent with provincial licensing standards, thereby limiting patient access. Once deregulated, remaining factors were primarily related to local and regional implementation processes. Participants held strong perceptions that mifepristone was the new standard of care for medical abortion in Canada and within the scope of primary care practice. CONCLUSION: Health Canada's removal of mifepristone restrictions facilitated the implementation of abortion care in the primary care setting. Our results are unique because Canada is the first country to facilitate provision of medical abortion in primary care via evidence-based deregulation of mifepristone

Advancing specificity in delirium: The delirium subtyping initiative

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning