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Transgenerational adaptation to hypoxia
Full text linkEpigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased P0 longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs. Here, we find tha
ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism
No full textFatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism
Trainee perspectives on diversity, equity, and inclusion: A group concept mapping study
No full textGrowing work highlights the importance of diversity, equity, and inclusion (DEI) initiatives in graduate medical education. Few studies have employed participatory research approaches to solicit trainee perspectives related to DEI. Our goal was to utilize group concept mapping (GCM), a mixed-methods participatory research approach, to describe resident perspectives on DEI within a large pediatric residency program. To organize and represent their perspectives on DEI, trainees completed brainstorming, sorting/rating, and interpretation activities in accordance with GCM methodology. Activities occurred via two synchronous discussion sessions (brainstorming and interpretation) and an electronic survey (sorting/rating). Items from the brainstorming session were sorted (i.e. grouped into categories by similarity) and rated (i.e. ranked on perceived importance and likelihood to change) by participants individually. Multidimensional scaling and hierarchical clustering were used to generate point maps, cluster maps, and go-zone illustrations for use in the interpretation session. We present data regarding participant characteristics and engagement, results from GCM activities, and action steps from this process. There were a total of 127 trainees in the residency program in 2021-2022. Participation varied across activities (brainstorming session: 21 participants; sorting/rating: 48 participants; interpretation session: 20 participants). A total of 64 unique items were generated from brainstorming. Five clusters emerged: 1) city factors, 2) institutional factors, 3) program representation, 4) program components, 5) non-DEI program perks. Program representation and program components clusters were rated as the most important and the most likely to be changed. Participants identified several action steps during the interpretation session which were shared with institutional leadership to direct programmatic reform. We demonstrate the utility of GCM, a structured and scalable participatory research method, to characterize trainee perceptions of DEI in graduate medical education
Comparison of clinical features and outcomes of Chinese patients with Takotsubo syndrome and acute myocardial infarction- Results from the first Chinese Takotsubo syndrome registry
No full textBACKGROUND: Takotsubo syndrome (TTS) differs significantly from acute myocardial infarction (AMI) in clinical features and pathological mechanisms, but evidence in Asian populations remains limited. The aim of this study is to compare clinical features and outcomes between patients with TTS and AMI in the first Chinese registry of TTS (ChiTTS Registry, ChiCTR1900026725).
METHODS: In this multicenter 6-year retrospective cohort study (February 2016-June 2022), a total of 116 consecutive TTS patients diagnosed according to the international Takotsubo diagnostic criteria and 232 age- and sex-matched AMI patients (1:2 ratio) meeting the 2023 European Society of Cardiology guidelines criteria were enrolled from 10 tertiary medical centers across China. Clinical characteristics, in-hospital outcomes, and major adverse cardiovascular and cerebrovascular events (MACCEs) were compared between groups using Student\u27s
RESULTS: The median follow-up time was 1.23 [interquartile range (IQR), 0.33-2.63] years in ChiTTS Registry patients and 2.35 (IQR, 1.68-3.68) years in AMI patients. In contrast to AMI patients, TTS patients presented with more clinical manifestations associated with acute heart failure. TTS patients developed approximately twice as many in-hospital complications as AMI patients (42.2%
CONCLUSIONS: In comparison to AMI patients, Chinese TTS patients developed more in-hospital complications and had a worse short-term prognosis. The cardiovascular issues in TTS patients underscore the need for effective treatment and personalized strategies to enhance outcomes and mitigate risks
Disparities in electronic health record patient portal activation and use among people with hematological malignancies
No full textApoE-calypse tau: ApoE-tau synergy in Alzheimer\u27s disease
No full textAlzheimer\u27s disease (AD), the most common cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) in senile plaques and abnormally hyperphosphorylated tau proteins in neurofibrillary tangles. While much of the research has focused on Aβ, tau-mediated neurodegeneration is more closely associated with synaptic loss and cognitive decline in AD, emphasizing the need for a deeper understanding of tau pathology. In this context, the interaction between tau and APOE, particularly the main genetic risk factor for AD APOE ε4, remains underexplored. APOE encodes apolipoprotein E (apoE), a protein important in lipid metabolism. In addition to promoting Aβ deposition, emerging evidence suggests that APOE ε4 exacerbates tau-mediated neurodegeneration and tau-related pathology. This review consolidates current knowledge on the interplay between apoE and tau, highlighting its potential as a key factor in disease progression. Targeting the apoE-tau axis may offer promising therapeutic strategies to address the molecular mechanisms driving AD and primary tauopathies
Functions of communication during emergency care of children with medical complexity: Caregiver perspectives
No full textOBJECTIVE: We investigated communication experiences of caregivers of children with medical complexity (CMC) during emergency care.
METHODS: Fifteen caregivers of CMC participated in semi-structured interviews regarding communication while seeking care for their child in the emergency department (ED). Thematic analysis was applied using a previously established functional communication model as an a priori framework.
RESULTS: Each of the previously established 8 core functions of communication were identified in this population. Building relationships manifested as clinicians soliciting caregiver input and responding to the needs of the caregiver. Exchanging information included clearly explaining next steps to caregivers. Responding to emotions acknowledged the inherent distress of seeking emergency care. Providing validation included recognizing caregivers as the expert of their own child. Enabling self-management manifested as identifying caregiver needs and directing toward resources. Making decisions manifested as involving caregivers in the decision-making process and recognizing caregiver decision fatigue. Managing uncertainty involved developing plans with caregivers. Supporting hope was the least commonly described function and manifested as emphasizing positive aspects of a child\u27s condition. Many caregivers described negative communication experiences in which their concerns and insights were unheard or invalidated.
CONCLUSION: Caregivers of CMC described communication experiences and goals that align with 8 communication functions that were identified in other serious childhood illnesses with unique operationalizations.
PRACTICE IMPLICATIONS: This communication framework can support ED clinicians in better understanding the communication needs of caregivers of CMC during emergency care
Telemedicine preexposure prophylaxis prescribing from a large online US company
No full textIMPORTANCE: HIV preexposure prophylaxis (PrEP) is highly effective in HIV prevention; telemedicine is a promising avenue for delivering PrEP care.
OBJECTIVE: To explore telemedicine delivery of PrEP care (telePrEP) by the largest telePrEP company in the US.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective, single-arm cohort study used health record data of patients receiving telePrEP from MISTR LLC, a for-profit telehealth company, from November 27, 2018, to March 5, 2025. Patient characteristics and AIDSVu data were assessed to determine levels of PrEP use nationally. Retention in care was assessed for persons initiating PrEP in 2020, 2021, and 2022. Data were analyzed from March 5 to May 29, 2025.
EXPOSURE: Use of telePrEP.
MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients receiving telePrEP among all patients receiving PrEP in the US. Persons were classified as PrEP users if they received at least 1 day of prescribed PrEP in a calendar year.
RESULTS: From 2018 through 2025, 162 422 unique patients received telePrEP prescriptions from the telehealth company. Patients were predominantly young (mean [SD] age, 33.3 [10.3] years) and male (156 255 of 162 417 [96%]). Of 162 406 patients with data available, 19 610 (12%) were African American or Black, 12 075 (7%) were Asian, 39 744 (25%) were Hispanic or Latino, 82 222 (51%) were White, and 8755 (5%) were of other race or ethnicity. Most had not previously used PrEP (57 597 of 74 860 [77%]), and more than one-third (58 761 of 162 403 [36%]) were uninsured. Most users (131 875 [81%]) opted for home laboratory specimen collection as part of their care. TelePrEP use increased substantially from 6443 patients in 2020 to 110 068 in 2024. TelePrEP as a proportion of all national PrEP use was 2% in 2020, 9% in 2022, and 19% in 2024. Retention in care was similar for cohorts starting in 2020, 2021, and 2022; 67% (16 716 of 24 976) to 73% (4571 of 6287) were retained in the calendar year after initiation, 42% (8408 of 19 916) to 43% (2732 of 6287) in the second year, and 32% (2043 of 6287) to 33% (6546 of 19 916) in the third year. Annual care reinitiation ranged from 2% to 5%.
CONCLUSIONS AND RELEVANCE: This cohort study found that nearly 1 in 5 PrEP users in the US received their PrEP prescriptions from a single national telemedicine company in 2024. Most were new to PrEP and more than one-third were uninsured. TelePrEP provision benefits from facilitating policies such as Affordable Care Act coverage and the 340B Drug Pricing Program. The rapid growth and overall magnitude of telePrEP provision suggests that it is a critical part of HIV prevention infrastructure in the US that merits continued regulatory support
PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating
No full textInwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials in both excitable and non-excitable cells and is regulated through various ligands, including specific membrane lipids. Phosphatidyl-4,5-bisphosphate (PIP2) is required for activity of all Kir channels, binding to the cytoplasmic domain in a compact conformation tightly tethered to the transmembrane domain. Most Kir2 channel structures determined in complex with PIP2 molecules are nevertheless in a closed state, requiring additional conformational changes for channel opening. We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the channel. In the presence of bound PIP2, the cytoplasmic domain performs clockwise twisting motions, with a pivot residing near the C-linker in each subunit. These motions are reduced when PIP2 is removed, leading to narrowing of the critical gate at the M2 helix bundle crossing (HBC), but expansion at the region G-loop, as well as reduced overall fourfold symmetry, in turn coupled to cessation of ion permeation
Methylation-based signature to distinguish indolent and aggressive prostate cancer
No full textProstate cancer management faces significant challenges in distinguishing indolent from aggressive disease, particularly since most patients are intermediate-risk and therefore hinders the ability to recommend standardized treatment recommendations. Moreover, current prognostic tools including Gleason scoring and tumor staging demonstrate limited accuracy for predicting disease progression and tumor recurrence. DNA methylation serves as a stable epigenetic modification that directly regulates gene expression, making it an ideal biomarker for cancer prognosis. Therefore, this study leveraged whole-genome enzymatic methylation sequencing on 120 patients to develop a novel prognostic signature for aggressive prostate cancer progression. We analyzed 20,849 differentially methylated regions (DMRs) and employed multiple machine learning approaches to identify optimal biomarkers. This revealed a 14-region DNA methylation signature that can serve as independent prognostic prediction factors outperforming traditional clinical indices. Further, when combined into a risk score it achieved a clinically meaningful odds ratio. This methylation-based approach provides actionable information for treatment decisions and surveillance strategies, representing a significant advancement toward precision medicine in prostate cancer management through biologically informed risk stratification