Epidemiological characteristics of patients with Hutchinson-Gilford progeria syndrome and progeroid laminopathies in China.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to investigate the epidemiological and genotypic characteristics of patients with HGPS/PL in China. METHODS: Using a cross-sectional study design, general characteristics and genotypic data of 46 patients with HGPS/PL from 17 provinces in China were analyzed. RESULTS: Among the 46 patients with HGPS/PL, 20 patients are HGPS, and the rest are PL; the identified total prevalence of HGPS/PL is 1/23 million. Among 42 patients with gene reports, 3 carried compound heterozygous mutations in the ZMPSTE24 while the other 39 carried LMNA mutations. Among PL, LMNA c.1579 C > T homozygous mutation was the most common. The onset of classic genotype HGPS is skin sclerosis in the first month after birth. The primary clinical manifestations of PL patients include skin abnormalities, growth retardation, and joint stiffness. The median age of onset for PL was 12 (6,12) months. CONCLUSIONS: In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL were located in LMNA, and the rest in ZMPSTE24. Most patients of HGPS/PL have skin abnormalities as the earliest manifestation. Compared to PL, the classic genotype HGPS starts earlier. IMPACT STATEMENT: Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. To date, there is a paucity of epidemiological data related to HGPS/PL in China. This study first examined the genotypic, phenotypic, and prevalence characteristics of 40-50% of the cases of HGPS/PL in mainland China through a collaborative international registry effort. In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL are located in LMNA. LMNA c.1579 C > T homozygous mutations are the most common form of gene mutations among the Chinese PL population.

Safety Responsiveness and Psychological Distress Among Health Care Workers During COVID-19 (2020-2022) in the Pacific Northwest.

Objectives. The COVID-19 pandemic imposed unprecedented safety challenges on health care facilities. This study examined whether health care workers who deemed a better safety response to the pandemic by their units or employers experienced lower psychological distress. Methods. Patient care workers at a health care system in the Pacific Northwest were surveyed every 6 to 8 months from May 2020 to May 2022 (n = 3468). Psychological distress was measured with the Well-being Index (range: -2 to 7 points). Safety response was scored on the basis of participants' ratings (on a 1-5 scale) of equipment sufficiency and responsiveness to safety concerns by their health care system and unit. Results. Adjusted multilevel regressions showed an inverse association between safety responsiveness and psychological distress at the individual level (b = -0.54; 95% confidence interval [CI] = -0.67, -0.41) and the unit level (b = -0.73; 95% CI = -1.46, -0.01). The cross-level interaction was also statistically significant (b = -0.46; 95% CI = -0.87, -0.05). Conclusions. Health care workers who deemed a better response to safety challenges reported lower psychological distress. This study highlights the need for continued efforts to ensure adequate safety resources. (Am J Public Health. 2024;114(S2):S204-S212. https://doi.org/10.2105/AJPH.2024.307582).

Can supervisor support improve daily employee well-being? Evidence of supervisor training effectiveness in a study of veteran employee emotions.

Workplace supportive supervisor interventions offer an effective, though underutilized mechanism to bolster employee well-being, which may have important benefits particularly for understudied groups such as military veterans in the civilian workforce. The present study employed a two-wave daily diary study to test the effectiveness of a supportive supervisor training on positive and negative emotions of veteran employees. Daily diaries are instrumental to understanding well-being, in that they accurately capture emotions as they are experienced without retrospective biases that reflect more global emotional assessments. Each wave (baseline and 6 months later) comprised emotion reports over 32-day periods. Thirty-five organizations were randomized into intervention and control groups; 144 veterans (91% men) participated in the daily diaries at baseline. The training significantly improved well-being facets including improvements in unactivated positive (i.e., calm) emotions at follow-up. Two significant moderation effects were also revealed for PTSD screening. For veteran employees with positive PTSD screens, the intervention functioned to reduce negative emotions. For those employees with negative PTSD screens, the intervention enhanced positive emotions. Our work highlights the benefit of workplace supervisor support to positive and negative employee mood.

Military sexual trauma among women Veterans: The buffering effect of coworker support.

Prior research has demonstrated the impact of military sexual trauma (MST) on health and well-being. However, little empirical work has been published identifying protective factors for women who have experienced MST. We examined the impact of two different forms of MST, harassment-only and assault MST, on PTSD symptoms and social functional impairment in a sample of women Veterans employed in the civilian workforce. The effects of MST were examined at three different times over a period of 9 months. We found that MST that included both harassment and assault was associated with significantly higher levels of PTSD symptoms and social functional impairment across three different time points among women Veterans employed in civilian jobs. Further, the pattern of results suggested that coworker support can buffer against these negative outcomes experienced by women who reported assault MST. Overall, findings suggest that coworker support is one critical resource for women Veterans who experienced assault MST.

A Framework for Protecting and Promoting Employee Mental Health through Supervisor Supportive Behaviors.

The attention to workplace mental health is timely given extreme levels of burnout, anxiety, depression and trauma experienced by workers due to serious extraorganizational stressors - the COVID-19 pandemic, threats to climate change, and extreme social and political unrest. Workplace-based risk factors, such as high stress and low support, are contributing factors to poor mental health and suicidality (Choi, 2018; Milner et al., 2013, 2018), just as low levels of social connectedness and belonging are established risk factors for poor mental health (Joiner et al., 2009), suggesting that social support at work (e.g., from supervisors) may be a key approach to protecting and promoting employee mental health. Social connections provide numerous benefits for health outcomes and are as, or more, important to mortality as other well-known health behaviors such as smoking and alcohol consumption (Holt-Lundstad et al., 2015), and can serve as a resource or buffer against the deleterious effects of stress or strain on psychological health (Cohen & Wills, 1985). This manuscript provides an evidence-based framework for understanding how supervisor supportive behaviors can serve to protect employees against psychosocial workplace risk factors and promote social connection and belongingness protective factors related to employee mental health. We identify six theoretically-based Mental Health Supportive Supervisor Behaviors (MHSSB; i.e., emotional support, practical support, role modeling, reducing stigma, warning sign recognition, warning sign response) that can be enacted and used by supervisors and managers to protect and promote the mental health of employees. A brief overview of mental health, mental disorders, and workplace mental health is provided. This is followed by the theoretical grounding and introduction of MHSSB. Suggestions for future research and practice follow, all with the focus of developing a better understanding of the role of supervisors in protecting and promoting employee mental health in the workplace.

Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior.

Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like Receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small molecule NPYLR7 agonists that suppress host-seeking and blood feeding when fed to mosquitoes at high micromolar doses. Using structure activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified 3 compounds that suppressed blood feeding from a live host when fed to mosquitoes at a 1 µM dose, a 100-fold improvement over the original reference compound. Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito/human host interactions that lead to pathogen transmission.

Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior.

BACKGROUND: Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses. METHODS: Using structure-activity relationship analysis and structure-guided design we synthesized 128 compounds with similarity to known NPYLR7 agonists. RESULTS: Although in vitro potency (EC50) was not strictly predictive of in vivo effect, we identified three compounds that reduced blood-feeding from a live host when fed to mosquitoes at a dose of 1 µM-a 100-fold improvement over the original reference compound. CONCLUSIONS: Exogenous activation of NPYLR7 represents an innovative vector control strategy to block mosquito biting behavior and prevent mosquito-human host interactions that lead to pathogen transmission.

Student challenges during third-year perioperative clerkships through the lens of faculty and residents: A qualitative study.

PURPOSE: Studies of medical students suggest they often find the transition from the pre-clinical curriculum to clinical rotations particularly challenging during perioperative clerkships. Educators could add a new perspective into students' clerkship experiences and potential interventions to improve them. The purpose of this study was to examine the educator perspective on students' experiences in perioperative clerkships. The findings could inform potential curricular interventions to facilitate student transition from a didactic environment into perioperative clerkships. METHODS: Semi-structured qualitative interviews were conducted with 16 faculty and residents in the departments of anaesthesia, obstetrics and gynaecology (OBGYN), and general surgery across multiple clinical teaching sites at one institution. Interview questions explored their perceptions of the challenges students face during their transition into perioperative clerkships and probed thoughts on curriculum interventions they believed would be the most beneficial. Interviews were recorded, transcribed and analysed thematically. FINDINGS: Three themes were identified. Faculty and residents perceive that student experiences on perioperative clerkships are shaped by (1) students' ability to adapt to the specialty and operating room norms on these clerkships, (2) students' understanding of how they can meaningfully contribute to the clinical team, and (3) dedicated teaching time constraints. Interventions were suggested to address educator expectations and student gaps, such as implementing a pre-clerkship orientation across anaesthesia, general surgery and OBGYN. CONCLUSIONS: To facilitate the medical student transition to perioperative clerkships, interventions should aid students in adapting to clerkship norms for these specialties and clarifying their role and expectations within the care team.

The Work-life Check-ins randomized controlled trial: A leader-based adaptive, semi-structured burnout intervention in primary care clinics.

BACKGROUND: Burnout in primary care undermines worker well-being and patient care. Many factors contribute to burnout, including high workloads, emotional stress, and unsupportive supervisors. Formative evidence suggests that burnout might be reduced if clinic leaders hold quarterly and brief (∼30 min) one-on-one check-ins with team members to acknowledge and address work-life stressors (e.g., schedules, workflow breakdowns, time off requests). This paper describes the intervention protocol for a randomized controlled trial (RCT) designed to evaluate the effectiveness and process of the check-ins in reducing burnout among primary care professionals. METHODS: Two-arm RCT conducted at 12 primary care clinics of a healthcare system in the Pacific Northwest. Six clinics received an adaptive design, semi-structured intervention, including predefined training modules with evidence-based tactics to reduce burnout through the check-ins, followed by clinic-specific feedback sessions prior to offering and conducting quarterly leader-employee check-ins. Six clinics were randomized as waitlist controls. Burnout was measured using the Maslach Burnout Inventory (MBI) at baseline and at the 12-month follow-up. Secondary outcomes include organizational constraints, psychological safety, and supervisor support. Multilevel modeling and qualitative methods were applied to evaluate the effects and process of the intervention. CONCLUSION: By focusing on modifiable work-life factors such as stressors and supervisor support, the check-ins intervention aims to reduce burnout rates among primary care professionals. Findings from this trial will shed light on the conditions upon which check-ins might reduce burnout. Results will also inform policies and interventions aimed at improving mental health and well-being in primary care settings. CLINICALTRIALS: gov: ID NCT05436548.

Acceptability and Feasibility of a Smartphone-Based Real-Time Assessment of Suicide Among Black Men: Mixed Methods Pilot Study.

BACKGROUND: Suicide rates in the United States have increased recently among Black men. To address this public health crisis, smartphone-based ecological momentary assessment (EMA) platforms are a promising way to collect dynamic, real-time data that can help improve suicide prevention efforts. Despite the promise of this methodology, little is known about its suitability in detecting experiences related to suicidal thoughts and behavior (STB) among Black men. OBJECTIVE: This study aims to clarify the acceptability and feasibility of using smartphone-based EMA through a pilot study that assesses the user experience among Black men. METHODS: We recruited Black men aged 18 years and older using the MyChart patient portal messaging (the patient-facing side of the Epic electronic medical record system) or outpatient provider referrals. Eligible participants self-identified as Black men with a previous history of STB and ownership of an Android or iOS smartphone. Eligible participants completed a 7-day smartphone-based EMA study. They received a prompt 4 times per day to complete a brief survey detailing their STB, as well as proximal risk factors, such as depression, social isolation, and feeling like a burden to others. At the conclusion of each day, participants also received a daily diary survey detailing their sleep quality and their daily experiences of everyday discrimination. Participants completed a semistructured exit interview of 60-90 minutes at the study's conclusion. RESULTS: In total, 10 participants completed 166 EMA surveys and 39 daily diary entries. A total of 4 of the 10 participants completed 75% (21/28) or more of the EMA surveys, while 9 (90%) out of 10 completed 25% (7/28) or more. The average completion rate of all surveys was 58% (20.3/35), with a minimum of 17% (6/35) and maximum of 100% (35/35). A total of 4 (40%) out of 10 participants completed daily diary entries for the full pilot study. No safety-related incidents were reported. On average, participants took 2.08 minutes to complete EMA prompts and 2.72 minutes for daily diary surveys. Our qualitative results generally affirm the acceptability and feasibility of the study procedures, but the participants noted difficulties with the technology and the redundancy of the survey questions. Emerging themes also addressed issues such as reduced EMA survey compliance and diminished mood related to deficit-framed questions related to suicide. CONCLUSIONS: Findings from this study will be used to clarify the suitability of EMA for Black men. Overall, our EMA pilot study demonstrated mixed feasibility and acceptability when delivered through smartphone-based apps to Black men. Specific recommendations are provided for managing safety within these study designs and for refinements in future intervention and implementation science research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/31241.

Intervention for critical aortic stenosis in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending average untreated lifespan of 14.5 years by 4.3 years (30%). With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS has the potential for immediate improvement in healthspan and lifespan. However, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. An international group of experts in HGPS, pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to identify strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases that typify HGPS clinical pathology. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. These breakthrough interventions for treating critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have high impact on treatment success.

Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

Plastic, It's What's for Dinner: A Preliminary Comparison of Ingested Particles in Bottlenose Dolphins and Their Prey.

Microplastic ingestion was reported for common bottlenose dolphins (Tursiops truncatus) inhabiting Sarasota Bay, FL, USA, a community that also has prevalent exposure to plasticizers (i.e., phthalates) at concentrations higher than human reference populations. Exposure sources are currently unknown, but plastic-contaminated prey could be a vector. To explore the potential for trophic exposure, prey fish muscle and gastrointestinal tract (GIT) tissues and contents were screened for suspected microplastics, and particle properties (e.g., color, shape, surface texture) were compared with those observed in gastric samples from free-ranging dolphins. Twenty-nine fish across four species (hardhead catfish, Ariopsis felis; pigfish, Orthopristis chrysoptera; pinfish, Lagodon rhomboides; and Gulf toadfish, Opsanus beta) were collected from Sarasota Bay during September 2022. Overall, 97% of fish (n = 28) had suspected microplastics, and GIT abundance was higher than muscle. Fish and dolphin samples contained fibers and films; however, foams were common in dolphin samples and not observed in fish. Suspected tire wear particles (TWPs) were not in dolphin samples, but 23.1% and 32.0% of fish muscle and GIT samples, respectively, contained at least one suspected TWP. While some similarities in particles were shared between dolphins and fish, small sample sizes and incongruent findings for foams and TWPs suggest further investigation is warranted to understand trophic transfer potential.

Infecciones respiratorias agudas (IRA) en la infancia

La enfermedad humana resultante de la infección por Streptococcus pneumoniae siempre ha estado asociada a un significativo grado de morbi - mortalidad como así tambien a problemas económicos. Aunque los mayores esfuerzos se dirigen al desarrollo de vacunas conjugadas polisacárido- proteínas, la naturaleza inmunogenica de las proteínas neumocóccicas, hacen que estas tambien sean blancos para nuevas estrategias de vacuna. Aunque ciertas proteínas neumocóccicas son capaces de inducir inmunidad protectora en ratones, la PspA es la unica que puede inducir anticuerpos que protegen a los ratones contra un inóculo al menos 100 veces mayor que la dosis letal 50 por ciento (DL50). La PspA aumenta la virulencia del neumococo y es capaz de inducir protección inmunológica contra la sepsis neumocóccica y la portación nasofaríngea. Aunque PspA es serológicamente variable presenta suficiente reacción cruzada como para que la inmunización con una única PspA induzca protección contra diversas cepas de Streptococcus pneumoniae. El diseño de una vacuna neumocóccica debe tener en consideración la extrema variabilidad del neumococo. Debido a la natural protección cruzada de PspA, se puede anticipar que la elección apropiada de una mezcla de diferentes PspAs o fragmentos de PspA (en posible combinación con otras proteínas del neumococo) puede ser capaz de inducir una amplia protección contra esta enfermedad