"This is real", "this is hard" and "I'm not making it up": Experience of diagnosis and living with non-epileptic attack disorder.

PURPOSE: To use a qualitative research approach to explore adults' experience of living with non-epileptic attack disorder. OBJECTIVE: The objective was to explore the experience of adults (18 years+) with a confirmed diagnosis of non-epileptic attack disorder (NEAD) across the trajectory of the disorder. The topics investigated included the onset of symptoms, the experience of non-epileptic attacks, the diagnostic process and living with NEAD. METHOD: Twelve people diagnosed with NEAD who attended a tertiary hospital neurology department took part in semi-structured interviews. The data generated were analysed using reflexive thematic analysis. RESULTS: Eleven women and one man with median age of 25 years took part. Three themes were developed: mind-body (dis)connect, a stigmatised diagnosis and a role for containment. Adults spoke about their experience of nonepileptic attacks, the diagnostic and management process and the impact of both nonepileptic attacks and the NEAD diagnosis on their lives. CONCLUSIONS: Adults' experience's within the healthcare system across the trajectory of NEAD influenced their own understanding and trust in their NEAD experience, how they shared this with others in their social and work lives and how they managed their NEAD symptoms on a daily basis. The research suggests the need for a consistent, timely implementation of a rule-in diagnostic approach and multi-disciplinary management of NEAD. It is recommended that lessons be taken from theoretical models including the common-sense model and a modified version of the reattribution model to support the de-stigmatisation of this diagnosis to inform psychoeducation and professionally facilitated peer-support groups.

Harnessing technology to improve sleep in frontline healthcare workers: A pilot study of electronic noise-masking earbuds on subjective and objective sleep measures.

Objective: This pilot study assessed the effects of electronic noise-masking earbuds on subjective sleep perception and objective sleep parameters among healthcare workers (HCWs) reporting sleep difficulties during the COVID-19 pandemic. Methods: Using a pre-post design, 77 HCWs underwent 3 nights of baseline assessment followed by a 7-night intervention period. Participants wore an at-home sleep monitoring headband to assess objective sleep measures and completed subjective self-report assessments. The difference in mean sleep measures from baseline to intervention was estimated in linear mixed models. Results: Compared to baseline assessments, HCWs reported significant improvements in sleep quality as measured by the Insomnia Severity Index (ISI) (Cohen's d = 1.74, p < 0.001) and a significant reduction in perceived sleep onset latency (SOL) during the intervention (M = 17.2 minutes, SD = 7.7) compared to baseline (M = 24.7 minutes, SD = 16.1), (Cohen's d = -0.42, p = 0.001). There were no significant changes in objective SOL (p = 0.703). However, there was a significant interaction between baseline objective SOL (<20 minutes vs >20 minutes) and condition (baseline vs intervention) (p = 0.002), such that individuals with objective SOL >20 minutes experienced a significant decrease in objective SOL during the intervention period compared to baseline (p = 0.015). Conclusions: HCWs experienced a significant improvement in perceived SOL and ISI scores after using the electronic noise-masking earbuds. Our data provide preliminary evidence for a nonpharmacological intervention to improve the sleep quality of HCWs which should be confirmed by future controlled studies.

Reduction of Environmental Pollutants and Travel Burden Through an Academic Medical Center-based Electronic Consultation Program.

Background: We evaluated the impact of electronic consultation (eConsult) in reducing the environmental pollutants associated with health care delivery. Methods: A retrospective analysis of the eConsult data between July 2018 and December 2022 was extracted from the electronic health record (Epic). Travel time and mileage from the patient home to the academic medical center (AMC) were calculated along with fuel expenditure and greenhouses gas savings. Projected savings through the end of the decade were forecast using a random walk model. Results: A total of 15,499 eConsults were submitted to AMC specialist providers from community primary care providers. Completed eConsults (n = 11,590) eliminated the need for a face-to-face visit with a specialist provider, eliminating mileage, fuel, time, and pollutants associated with face to face visits. In-state travel distance saved was 310,858 miles, travel time saved was 5,491 h, with an associated fuel reduction of 13,575 gallons and $56,893 savings. This reduced greenhouse gas emissions by 128 metric tons of carbon dioxide, 0.022 tons of nitrogen oxide, 0.005 tons of methane, and 0.001 tons of nitrous oxide. Out of state travel distance saved was 188,346 miles with 2,842 h reduced travel time, and associated fuel reduction of 8,225 gallons and of $34,118. Reduced greenhouse gas emissions were equivalent to 77 metric tons of carbon dioxide, 0.0132 tons of nitrogen oxide, 0.0033 tons of methane, and 0.0007 tons of nitrous oxide. Conclusion: This study indicates that medical care provided through telehealth modalities reduces the environmental impact of pollutants associated with face to face visits.

Communicating Patient Discharge Readiness: An Implementation Evaluation in an Inpatient Hospital Medicine Setting.

BACKGROUND: The progression of patients through a hospital from admission to discharge can be slowed by delays in patient discharge, increasing pressure on health care staff. We designed and piloted the Discharge Today tool, with the goal of improving the efficiency of patient discharge; however, adoption remained low. PURPOSE: To close this implementation gap, we deployed and evaluated a 4-part implementation strategy bundle. METHODS: We measured the success of implementation by evaluating validated implementation outcomes using both quantitative and qualitative methods, grounded in Normalization Process Theory. RESULTS: The implementation strategies used were effective for increasing use of the Discharge Today tool by hospital medicine physicians and advanced practice providers during both the active and passive implementation periods. CONCLUSIONS: While the implementation strategies used were effective, qualitative findings indicate that limitations in the functionality of the tool, alongside inconsistent use of the tool across clinical staff, continued to inhibit adoption.

Longitudinal mental health trends in cystic fibrosis.

BACKGROUND: Mental health screening in accordance with consensus guidelines became routine clinical practice in our cystic fibrosis (CF) Center in 2015. We hypothesized improvement in anxiety and depression symptoms over time and associations between elevated screening scores and disease severity. We aimed to observe the impact of the COVID-19 pandemic and modulator use on mental health symptoms. METHODS: Retrospective chart reviews were conducted for people 12 years and older with at least one Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9) screening for six years. Descriptive statistics were used to summarize demographic variables and logistic regression and linear mixed models were used to evaluate the relationship between screening scores and clinical variables. RESULTS: Analyses included 150 participants (ages 12-22 years). The percentage of minimal to no symptom scores increased over time for anxiety and depression. Increased mental health visits and CFRD were associated with higher PHQ-9 and GAD-7 scores. Higher FEV1pp was associated with lower GAD-7 and PHQ-9 scores. More effective modulator use was associated with lower PHQ-9 scores. Mean PHQ-9 and GAD-7 scores were not significantly different when comparing pre-pandemic and pandemic scores. CONCLUSION: Disruptions in screening during the pandemic were minimal and symptom scores remained stable. Individuals with higher mental health screening scores were more likely to have CFRD and utilization of mental health services. Consistent mental health monitoring and support is needed so individuals with CF can endure anticipated and unanticipated stressors including changes in physical health, healthcare, and societal stressors such as COVID-19 pandemic.

Development and Evaluation of an Enzyme-Linked Immunosorbent Assay Targeting Rabies-Specific IgM and IgG in Human Sera.

Immunity from rabies depends on rabies virus neutralizing antibodies (RVNA) induced after immunization; however, the influence of antibody isotype switching has not been extensively investigated. This has become particularly relevant with changes in World Health Organization (WHO) recommended rabies vaccine regimens that may influence RVNA isotype kinetics, potentially affecting the peak, and longevity, of RVNA immunoglobulin (IgG) levels. We developed rapid and reliable assays for quantifying the anti-rabies IgM/IgG class switch in human serum based on an indirect ELISA technique. The immune response was tracked in ten individuals naïve to the rabies vaccine by quantifying serum titers weekly, from day seven to day 42 post-immunization, using a serum neutralization assay and the ELISA IgM/IgG assays. The average RVNA IU/mL levels were at D0 ≤ 0.1, D7 0.24, D14 8.36, D21 12.84, D28 25.74 and D42 28.68. Levels of specific IgM antibodies to rabies glycoprotein (EU/mL) were higher, on average, at D7, 1.37, and from D14, 5.49, to D21, 6.59. In contrast, average IgG antibodies (EU/mL) predominated from D28, 10.03, to D42, 14.45. We conclude that levels of anti-rabies IgM/IgG at D28 characterize the isotype class switch. These assays, combined with serum neutralization assays, distinguished the RVNA levels in terms of the IgM/IgG responses and are expected to add to the diagnostic repertoire, provide additional information in establishing rabies vaccine regimens, both post- and pre-exposure prophylaxis, and contribute to research efforts.

Isolation and characterization of mammalian orthoreovirus from bats in the United States.

Mammalian orthoreovirus (MRV) infects many mammalian species including humans, bats, and domestic animals. To determine the prevalence of MRV in bats in the United States, we screened more than 900 bats of different species collected during 2015-2019 by a real-time reverse-transcription polymerase chain reaction assay; 4.4% bats tested MRV-positive and 13 MRVs were isolated. Sequence and phylogenetic analysis revealed that these isolates belonged to four different strains/genotypes of viruses in Serotypes 1 or 2, which contain genes similar to those of MRVs detected in humans, bats, bovine, and deer. Further characterization showed that these four MRV strains replicated efficiently on human, canine, monkey, ferret, and swine cell lines. The 40/Bat/USA/2018 strain belonging to the Serotype 1 demonstrated the ability to infect and transmit in pigs without prior adaptation. Taken together, this is evidence for different genotypes and serotypes of MRVs circulating in US bats, which can be a mixing vessel of MRVs that may spread to other species, including humans, resulting in cross-species infections.

Obesity in Adults: A 2022 Adapted Clinical Practice Guideline for Ireland.

BACKGROUND: This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. SUMMARY: It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. KEY MESSAGES: People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay.

The extent of violence inflicted on adolescent Aboriginal girls in the Northern Territory.

BACKGROUND: Australian Aboriginal and Torres Strait Islander women are at very high risk of violence but there is little evidence about the age at which their higher exposure to violence commences. The aim of this study was to investigate violence inflicted on Aboriginal girls during childhood and adolescence, relative to Aboriginal boys and non-Aboriginal girls. METHODS: This was a retrospective cohort study using de-identified administrative data for NT residents aged 0-17 years. This study used linked hospital and child protection data to investigate hospitalization for injury caused by assault and substantiated child maltreatment involving violence (physical and sexual abuse). RESULTS: The incidence of assault hospitalization and substantiated physical/sexual abuse was much higher for Aboriginal than non-Aboriginal adolescents but similar for girls and boys to about age ten, then increased much more for Aboriginal girls than boys. In the 14-17 age-group, assault hospitalization incidence was 125% higher for Aboriginal girls than boys but 56% lower for non-Aboriginal girls than boys. 4.6% of Aboriginal girls were hospitalized (30.9% more than once) for assault between twelfth and eighteenth birthdays, compared to 3.4% of Aboriginal boys and 0.3% of non-Aboriginal girls. The incidence of assault hospitalization during adolescence was over three times higher for Aboriginal children who had substantiated child maltreatment during childhood. CONCLUSION: The very high levels of violence suffered by Aboriginal women commence in the pre-teen years. Non-Aboriginal girls are 'protected' from the rising levels of violence that boys experience as they progress through adolescence, but Aboriginal girls are not afforded such protection.

Mother's Milk Messaging™: trial evaluation of app and texting for breastfeeding support.

BACKGROUND: New mothers experience BF challenges but have limited evidence-based technology-enabled support. OBJECTIVES: 1) Determine if using the Mother's Milk Messaging™ app improved aspects of breastfeeding and breastfeeding rates and 2) Describe engagement as well as themes from the qualitative feedback on the app. METHOD: Randomized Controlled Trial National sample of primiparous, singleton mothers recruited online and then randomized using stratification by language into three arms: 1) BF text messages plus app; 2) BF text messages, app and physician-moderated private Facebook (FB) group; 3) Attention control group who received injury prevention texts. Exclusive breastfeeding rates as primary outcome and knowledge/attitude, confidence, and social support as secondary outcomes. We determined engagement through analysis of app usage metrics. We conducted and content-coded interviews with participants to learn more about app usage and BF experience. Due to the nature of the intervention participants could not be blinded. RESULTS: There were a total of 346 participants in the trial, with 227 in the Intervention (n = 154 group 1 and n = 156 group 2) and 119 in the control group. Because of minimal Facebook activity, the two intervention groups 1 and 2 were combined. There were no differences in breastfeeding exclusivity and duration. (NS). Women in the intervention arm reported significantly higher confidence with breastfeeding and perceived social support to the control group (p < .05). Greater than 80% registered the app and those that engaged with the app had higher scores with time. Mothers appreciated receiving text messages and videos with reliable information. No harm was reported in this study. CONCLUSION: MMM increased confidence with breastfeeding and with gathering social supports. Exclusively BF was high in all participants. Mothers perceived it as useful and dependable especially the texting.

Correction: Briggs, D.J.; Moore, S.M. The Route of Administration of Rabies Vaccines: Comparing the Data. Viruses 2021, 13, 1252.

The authors wish to make the following corrections to this paper [...].

Robust humoral immune response against rabies virus in rabbits and guinea pigs immunized with plasmid DNA vectors encoding rabies virus glycoproteins - An approach to the production of polyclonal antibody reagents.

DNA-based immunization has been previously shown to be an efficient approach to induce robust immunity against infectious diseases in animals and humans. The advantages of DNA vaccines are simplicity of their construction and production, low cost, high stability, and ability to elicit a full spectrum of immune responses to target antigens. The goals of this study were (i) to assess the antibody immune response to rabies virus glycoproteins (rGPs) in rabbits and guinea pigs after intramuscular immunization with pTargeT and pVAC2-mcs mammalian expression vectors encoding either the wild-type (WT) or codon-optimized (cOPT) rGP genes; and (ii) to prepare in-house rabbit anti-rGP polyclonal antibody reagents suitable for in Single Radial Immunodiffusion (SRID) and Indirect Fluorescent Antibody (IFA) assays. The maximum antibody responses against rabies virus in rabbits and guinea pigs were observed after immunization series with 500 µg/dose of pVAC2-mcs vector encoding either the WT or cOPT rGP genes adjuvanted with Emulsigen-D. No significant difference in the anti-rabies virus neutralizing antibody titers was observed in rabbits immunized with the WT and cOPT rGPs. The in-house rabbit anti-rGP polyclonal antibody reagents reacted comparable to the current reference reagents in SRID and IFA assays. The results of the study demonstrated that the DNA immunization of animals with the WT or cOPT rGPs is a promising approach to either induction of high anti-rabies virus neutralizing antibody titers in vivo or for production of polyclonal antibody reagents against rabies.

A cocktail of human monoclonal antibodies broadly neutralizes North American rabies virus variants as a promising candidate for rabies post-exposure prophylaxis.

Human rabies remains a globally significant public health problem. Replacement of polyclonal anti-rabies immunoglobulin (RIG), a passive component of rabies post-exposure prophylaxis (PEP), with a monoclonal antibody (MAb), would eliminate the cost and availability constraints associated with RIG. Our team has developed and licensed a human monoclonal antibody RAB1 (Rabishield©), as the replacement for RIG where canine rabies is enzootic. However, for the highly diverse rabies viruses of North America, a cocktail containing two or more MAbs targeting different antigenic sites of the rabies glycoprotein should be included to ensure neutralization of all variants of the virus. In this study, two MAb cocktails, R172 (RAB1-RAB2) and R173 (RAB1-CR57), were identified and evaluated against a broad range of rabies variants from North America. R173 was found to be the most potent cocktail, as it neutralized all the tested North American RABV isolates and demonstrated broad coverage of isolates from both terrestrial and bat species. R173 could be a promising candidate as an alternative or replacement for RIG PEP in North America.

Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

Human rabies is an acute, progressive encephalomyelitis that is nearly always fatal once symptoms begin. Several measures have been implemented to prevent human rabies in the United States, including vaccination of targeted domesticated and wild animals, avoidance of behaviors that might precipitate an exposure (e.g., provoking high-risk animals), awareness of the types of animal contact that require postexposure prophylaxis (PEP), and use of proper personal protective equipment when handling animals or laboratory specimens. PEP is widely available in the United States and highly effective if administered after an exposure occurs. A small subset of persons has a higher level of risk for being exposed to rabies virus than does the general U.S. population; these persons are recommended to receive preexposure prophylaxis (PrEP), a series of human rabies vaccine doses administered before an exposure occurs, in addition to PEP after an exposure. PrEP does not eliminate the need for PEP; however, it does simplify the rabies PEP schedule (i.e., eliminates the need for rabies immunoglobulin and decreases the number of vaccine doses required for PEP). As rabies epidemiology has evolved and vaccine safety and efficacy have improved, Advisory Committee on Immunization Practices (ACIP) recommendations to prevent human rabies have changed. During September 2019-November 2021, the ACIP Rabies Work Group considered updates to the 2008 ACIP recommendations by evaluating newly published data, reviewing frequently asked questions, and identifying barriers to adherence to previous ACIP rabies vaccination recommendations. Topics were presented and discussed during six ACIP meetings. The following modifications to PrEP are summarized in this report: 1) redefined risk categories; 2) fewer vaccine doses in the primary vaccination schedule; 3) flexible options for ensuring long-term protection, or immunogenicity; 4) less frequent or no antibody titer checks for some risk groups; 5) a new minimum rabies antibody titer (0.5 international units [IUs]) per mL); and 6) clinical guidance, including for ensuring effective vaccination of certain special populations.

Sleep Disturbance and Quality of Life in Rheumatoid Arthritis: Prospective mHealth Study.

BACKGROUND: Sleep disturbances and poor health-related quality of life (HRQoL) are common in people with rheumatoid arthritis (RA). Sleep disturbances, such as less total sleep time, more waking periods after sleep onset, and higher levels of nonrestorative sleep, may be a driver of HRQoL. However, understanding whether these sleep disturbances reduce HRQoL has, to date, been challenging because of the need to collect complex time-varying data at high resolution. Such data collection is now made possible by the widespread availability and use of mobile health (mHealth) technologies. OBJECTIVE: This mHealth study aimed to test whether sleep disturbance (both absolute values and variability) causes poor HRQoL. METHODS: The quality of life, sleep, and RA study was a prospective mHealth study of adults with RA. Participants completed a baseline questionnaire, wore a triaxial accelerometer for 30 days to objectively assess sleep, and provided daily reports via a smartphone app that assessed sleep (Consensus Sleep Diary), pain, fatigue, mood, and other symptoms. Participants completed the World Health Organization Quality of Life-Brief (WHOQoL-BREF) questionnaire every 10 days. Multilevel modeling tested the relationship between sleep variables and the WHOQoL-BREF domains (physical, psychological, environmental, and social). RESULTS: Of the 268 recruited participants, 254 were included in the analysis. Across all WHOQoL-BREF domains, participants' scores were lower than the population average. Consensus Sleep Diary sleep parameters predicted the WHOQoL-BREF domain scores. For example, for each hour increase in the total time asleep physical domain scores increased by 1.11 points (ß=1.11, 95% CI 0.07-2.15) and social domain scores increased by 1.65 points. These associations were not explained by sociodemographic and lifestyle factors, disease activity, medication use, anxiety levels, sleep quality, or clinical sleep disorders. However, these changes were attenuated and no longer significant when pain, fatigue, and mood were included in the model. Increased variability in total time asleep was associated with poorer physical and psychological domain scores, independent of all covariates. There was no association between actigraphy-measured sleep and WHOQoL-BREF. CONCLUSIONS: Optimizing total sleep time, increasing sleep efficiency, decreasing sleep onset latency, and reducing variability in total sleep time could improve HRQoL in people with RA.

Assessment of a Mobile Health iPhone App for Semiautomated Self-management of Chronic Recurrent Medical Conditions Using an N-of-1 Trial Framework: Feasibility Pilot Study.

BACKGROUND: Management of chronic recurrent medical conditions (CRMCs), such as migraine headaches, chronic pain, and anxiety/depression, remains a major challenge for modern providers. Our team has developed an edge-based, semiautomated mobile health (mHealth) technology called iMTracker that employs the N-of-1 trial approach to allow self-management of CRMCs. OBJECTIVE: This study examines the patterns of adoption, identifies CRMCs that users selected for self-application, and explores barriers to use of the iMTracker app. METHODS: This is a feasibility pilot study with internet-based recruitment that ran from May 15, 2019, to December 23, 2020. We recruited 180 patients to pilot test the iMTracker app for user-selected CRMCs for a 3-month period. Patients were administered surveys before and after the study. RESULTS: We found reasonable usage rates: a total of 73/103 (70.9%) patients who were not lost to follow-up reported the full 3-month use of the app. Most users chose to use the iMTracker app to self-manage chronic pain (other than headaches; 80/212, 37.7%), followed by headaches in 36/212 (17.0%) and mental health (anxiety and depression) in 27/212 (12.8%). The recurrence rate of CRMCs was at least weekly in over 93% (169/180) of patients, with 36.1% (65/180) of CRMCs recurring multiple times in a day, 41.7% (75/180) daily, and 16.1% (29/180) weekly. We found that the main barriers to use were the design and technical function of the app, but that use of the app resulted in an improvement in confidence in the efficiency and safety/privacy of this approach. CONCLUSIONS: The iMTracker app provides a feasible platform for the N-of-1 trial approach to self-management of CRMCs, although internet-based recruitment provided limited follow-up, suggesting that in-person evaluation may be needed. The rate of CRMC recurrence was high enough to allow the N-of-1 trial assessment for most traits.

A One Medicine Mission for an Effective Rabies Therapy.

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast.

Commitment to cell division at the end of G1 phase, termed Start in the budding yeast Saccharomyces cerevisiae, is strongly influenced by nutrient availability. To identify new dominant activators of Start that might operate under different nutrient conditions, we screened a genome-wide ORF overexpression library for genes that bypass a Start arrest caused by absence of the G1 cyclin Cln3 and the transcriptional activator Bck2. We recovered a hypothetical gene YLR053c, renamed NRS1 for Nitrogen-Responsive Start regulator 1, which encodes a poorly characterized 108 amino acid microprotein. Endogenous Nrs1 was nuclear-localized, restricted to poor nitrogen conditions, induced upon TORC1 inhibition, and cell cycle-regulated with a peak at Start. NRS1 interacted genetically with SWI4 and SWI6, which encode subunits of the main G1/S transcription factor complex SBF. Correspondingly, Nrs1 physically interacted with Swi4 and Swi6 and was localized to G1/S promoter DNA. Nrs1 exhibited inherent transactivation activity, and fusion of Nrs1 to the SBF inhibitor Whi5 was sufficient to suppress other Start defects. Nrs1 appears to be a recently evolved microprotein that rewires the G1/S transcriptional machinery under poor nitrogen conditions.

Effect of Clinical Decision Support at Community Health Centers on the Risk of Cardiovascular Disease: A Cluster Randomized Clinical Trial.

Importance: Management of cardiovascular disease (CVD) risk in socioeconomically vulnerable patients is suboptimal; better risk factor control could improve CVD outcomes. Objective: To evaluate the impact of a clinical decision support system (CDSS) targeting CVD risk in community health centers (CHCs). Design, Setting, and Participants: This cluster randomized clinical trial included 70 CHC clinics randomized to an intervention group (42 clinics; 8 organizations) or a control group that received no intervention (28 clinics; 7 organizations) from September 20, 2018, to March 15, 2020. Randomization was by CHC organization accounting for organization size. Patients aged 40 to 75 years with (1) diabetes or atherosclerotic CVD and at least 1 uncontrolled major risk factor for CVD or (2) total reversible CVD risk of at least 10% were the population targeted by the CDSS intervention. Interventions: A point-of-care CDSS displaying real-time CVD risk factor control data and personalized, prioritized evidence-based care recommendations. Main Outcomes and Measures: One-year change in total CVD risk and reversible CVD risk (ie, the reduction in 10-year CVD risk that was considered achievable if 6 key risk factors reached evidence-based levels of control). Results: Among the 18 578 eligible patients (9490 [51.1%] women; mean [SD] age, 58.7 [8.8] years), patients seen in control clinics (n = 7419) had higher mean (SD) baseline CVD risk (16.6% [12.8%]) than patients seen in intervention clinics (n = 11 159) (15.6% [12.3%]; P < .001); baseline reversible CVD risk was similarly higher among patients seen in control clinics. The CDSS was used at 19.8% of 91 988 eligible intervention clinic encounters. No population-level reduction in CVD risk was seen in patients in control or intervention clinics; mean reversible risk improved significantly more among patients in control (-0.1% [95% CI, -0.3% to -0.02%]) than intervention clinics (0.4% [95% CI, 0.3% to 0.5%]; P < .001). However, when the CDSS was used, both risk measures decreased more among patients with high baseline risk in intervention than control clinics; notably, mean reversible risk decreased by an absolute 4.4% (95% CI, -5.2% to -3.7%) among patients in intervention clinics compared with 2.7% (95% CI, -3.4% to -1.9%) among patients in control clinics (P = .001). Conclusions and Relevance: The CDSS had low use rates and failed to improve CVD risk in the overall population but appeared to have a benefit on CVD risk when it was consistently used for patients with high baseline risk treated in CHCs. Despite some limitations, these results provide preliminary evidence that this technology has the potential to improve clinical care in socioeconomically vulnerable patients with high CVD risk. Trial Registration: ClinicalTrials.gov Identifier: NCT03001713.