Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Laser interstitial thermal therapy of a single nodule in a complex epileptic network with multiple periventricular nodular heterotopias.

Surgical management of drug-resistant epilepsy (DRE) in patients with multiple periventricular nodular heterotopias (PVNHs) is challenging. Identifying the location of seizure onset within these complex epileptic networks is difficult, and open resection carries risks of injury to surrounding functional white matter tracts such as optic radiations (ORs). The authors demonstrate tractography-assisted laser ablation of a single nodule in a patient with DRE and multiple PVNHs. Following surgery, visual fields were intact, highlighting the benefits of OR tractographic reconstruction. At 12 months postoperatively, the patient remained seizure free, suggesting the potential efficacy of targeting a single heterotopia within complex networks in well-selected cases. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2417.

Rosettibacter primus gen. nov., sp. nov., and Rosettibacter firmus sp. nov., facultatively anaerobic moderately thermophilic bacteria of the class Ignavibacteria from hot springs of North Ossetia.

A novel facultatively anaerobic moderately thermophilic bacteria, strains 4137-MeT and 4148-MeT, were isolated from hot springs of Karmadon and Ursdon, respectively (North Ossetia, Russian Federation). Gram-negative, motile rods were present singly, in pairs, rosettes, and aggregates, or formed biofilms. Both strains grew optimally at 50-55 °C, pH 7.0 and did not require sodium chloride or yeast extract for growth. They were chemoorganoheterotrophs, growing on mono-, di- and polysaccharides (cellulose, starch, xylan, lichenan, galactan, xyloglucan, mannan, xanthan gum, guar gum) as well as proteinaceous substrates (gelatin, peptone, beef and yeast extract). Growth under anaerobic conditions was observed in presence and absence of external electron acceptors. Sulfur, thiosulfate, arsenate, Fe-citrate, and ferrihydrite were reduced with acetate, starch, or yeast extract as electron donors. The respiratory quinone was MK-7. Major cellular fatty acids of both strains were iso-C15:0, anteiso-C17:0, C15:0, iso-C16:0 and additionally iso-C17:0 for strain 4137-MeT. The size of the genome and genomic DNA G + C content of strain 4137-MeT were 3.24 Mb. and 29.9 %, respectively; for strain 4148-MeT - 3.33 Mb and 30.7 %. According to the 16S rRNA gene sequence and conserved protein sequences phylogenies, strains 4137-MeT and 4148-MeT represented a distinct lineage of the family Melioribacteraceae within the class Ignavibacteria. Based on phylogenetic analysis and phenotypic features, the novel isolates were assigned to a novel genus, for which the name Rosettibacter gen. nov. is proposed. Strain 4148-MeT represents its type species Rosettibacter primus sp. nov., while strain 4137-MeT represents a new species Rosettibacter firmus sp. nov.

Lipid droplet dynamics are essential for the development of the malaria parasite Plasmodium falciparum.

Lipid droplets (LDs) are organelles central to lipid and energy homeostasis across all eukaryotes. In the malaria-causing parasite Plasmodium falciparum the roles of LDs in lipid acquisition from its host cells and their metabolism are poorly understood, despite the high demand for lipids in parasite membrane synthesis. We systematically characterised LD size, composition and dynamics across the disease-causing blood infection. Applying split fluorescence emission analysis and 3D Focused Ion Beam-Scanning Electron Microscopy, we observed a decrease in LD size in late schizont stages. LD contraction likely signifies a switch from lipid accumulation to lipid utilisation in preparation for parasite egress from host red blood cells. We demonstrate connections between LDs and several parasite organelles, pointing to potential functional interactions. Chemical inhibition of triacylglyerol (TAG) synthesis or break-down revealed essential LD functions for schizogony and in counteracting lipid toxicity. The dynamics of lipid synthesis, storage and utilisation in P. falciparum LDs might provide a target for new anti-malarial intervention strategies.

AOC: Analysis of Orthologous Collections - an application for the characterization of natural selection in protein-coding sequences.

Motivation: Modern molecular sequence analysis increasingly relies on automated and robust software tools for interpretation, annotation, and biological insight. The Analysis of Orthologous Collections (AOC) application automates the identification of genomic sites and species/lineages influenced by natural selection in coding sequence analysis. AOC quantifies different types of selection: negative, diversifying or directional positive, or differential selection between groups of branches. We include all steps necessary to go from unaligned homologous sequences to complete results and interactive visualizations that are designed to aid in the useful interpretation and contextualization. Results: We are motivated by a desire to make evolutionary analyses as simple as possible, and to close the disparity in the literature between genes which draw a significant amount of interest and those that are largely overlooked and underexplored. We believe that such underappreciated and understudied genetic datasets can hold rich biological information and offer substantial insights into the diverse patterns and processes of evolution, especially if domain experts are able to perform the analyses themselves. Availability and implementation: A Snakemake [Mölder et al., 2021] application implementation is publicly available on GitHub at https://github.com/aglucaci/AnalysisOfOrthologousCollections and is accompanied by software documentation and a tutorial.

The Role of Family Support in Moderating Mental Health Outcomes for LGBTQ+ Youth in Primary Care.

Importance: Lesbian, gay, bisexual, transgender, queer, and/or questioning (LGBTQ+) youth face worse mental health outcomes than non-LGBTQ+ peers. Family support may mitigate this, but sparse evidence demonstrates this in clinical settings. Objectives: To compare depression and suicide risk between LGBTQ+ and non-LGBTQ+ youth in primary care settings and to investigate whether family support mitigates these negative mental health outcomes. Design, Setting, and Participants: This cross-sectional study uses data from well care visits completed by adolescents aged 13 to 19 years from February 2022 through May 2023, including the Patient Health Questionnaire-9 Modified for Teens (PHQ-9-M) and the Adolescent Health Questionnaire (AHQ; an electronic screener assessing identity, behaviors, and guardian support), at 32 urban or suburban care clinics in Pennsylvania and New Jersey. Exposures: The primary exposure was self-reported LGBTQ+ status. Family support moderators included parental discussion of adolescent strengths and listening to feelings. Race and ethnicity (determined via parent or guardian report at visit check-in), sex, payer, language, age, and geography were covariates. Main Outcomes and Measures: PHQ-9-M-derived mental health outcomes, including total score, recent suicidal ideation, and past suicide attempt. Results: The sample included 60 626 adolescents; among them, 9936 (16.4%) were LGBTQ+, 15 387 (25.5%) were Black, and 30 296 (50.0%) were assigned female sex at birth. LGBTQ+ youth, compared with non-LGBTQ+ youth, had significantly higher median (IQR) PHQ-9-M scores (5 [2-9] vs 1 [0-3]; P < .001) and prevalence of suicidal ideation (1568 [15.8%] vs 1723 [3.4%]; P < .001). Fewer LGBTQ+ youth endorsed parental support than non-LGBTQ+ youth (discussion of strengths, 8535 [85.9%] vs 47 003 [92.7%]; P < .001; and listening to feelings, 7930 [79.8%] vs 47 177 [93.1%]; P < .001). In linear regression adjusted for demographic characteristics and parental discussion of strengths, LGBTQ+ status was associated with a higher PHQ-9-M score (mean difference, 3.3 points; 95% CI, 3.2-3.3 points). In logistic regression, LGBTQ+ youth had increased adjusted odds of suicidal ideation (adjusted odds ratio, 4.3; 95% CI, 4.0-4.7) and prior suicide attempt (adjusted odds ratio, 4.4; 95% CI, 4.0-4.7). Parental support significantly moderated the association of LGBTQ+ status with PHQ-9-M score and suicidal ideation, with greater protection against these outcomes for LGBTQ+ vs non-LGBTQ+ youth. Conclusions and Relevance: Compared with non-LGBTQ+ youth, LGBTQ+ youth at primary care visits had more depressive symptoms and higher odds of suicidal ideation and prior suicide attempt. Youth-reported parental support was protective against these outcomes, suggesting potential benefits of family support-focused interventions to mitigate mental health inequities for LGBTQ+ youth.

Photofragmentation of corannulene (C20H10) and sumanene (C21H12) cations in the gas phase and their astrophysical implications.

Aromatic infrared bands (AIBs) dominate the mid-infrared spectra of many galactic and extragalactic sources. These AIBs are generally attributed to fluorescence emission from aromatic molecules. Unified efforts from experimentalists and theoreticians to assign these AIB features have recently received additional impetus with the launch of the James Webb Space Telescope (JWST) as the Mid-InfraRed Instrument (MIRI) delivers a mid-IR spectrum with greatly increased sensitivity and spectral resolution. PAHs in space can exist in either neutral or ionic form, absorb UV photons and undergo fragmentation, becoming a rich source of small hydrocarbons. This top-down mechanism of larger PAHs fragmenting into smaller species is of utmost importance in photo-dissociation regions (PDR) in space. In this work, we experimentally and theoretically investigate the photo-fragmentation pathways of two astronomically significant PAH cations - corannulene (C20H10) and sumanene (C21H12), which are structural motifs of fullerene C60, to understand their sequential fragmentation pathways. The photo-fragmentation experiments exhibit channels that are significantly different from planar PAHs. The breakdown of the carbon skeleton is found to follow different pathways for C20H10 and C21H12 because of the number and positioning of pentagon rings, yet the most abundant low mass cations produced by these two species are found to be similar. The low mass cations showcased in this work could be of interest due to their possible astronomical detections. For completeness, the qualitative photofragmentation behaviour of dicationic corannulene and sumanene has also been investigated, but the potential energy surface of these dications is beyond the scope of this paper.

CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.

Unravelling the complexity of ventilator-associated pneumonia: a systematic methodological literature review of diagnostic criteria and definitions used in clinical research.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a prevalent and grave hospital-acquired infection that affects mechanically ventilated patients. Diverse diagnostic criteria can significantly affect VAP research by complicating the identification and management of the condition, which may also impact clinical management. OBJECTIVES: We conducted this review to assess the diagnostic criteria and the definitions of the term "ventilator-associated" used in randomised controlled trials (RCTs) of VAP management. SEARCH METHODS: Based on the protocol (PROSPERO 2019 CRD42019147411), we conducted a systematic search on MEDLINE/PubMed and Cochrane CENTRAL for RCTs, published or registered between 2010 and 2024. SELECTION CRITERIA: We included completed and ongoing RCTs that assessed pharmacological or non-pharmacological interventions in adults with VAP. DATA COLLECTION AND SYNTHESIS: Data were collected using a tested extraction sheet, as endorsed by the Cochrane Collaboration. After cross-checking, data were summarised in a narrative and tabular form. RESULTS: In total, 7,173 records were identified through the literature search. Following the exclusion of records that did not meet the eligibility criteria, 119 studies were included. Diagnostic criteria were provided in 51.2% of studies, and the term "ventilator-associated" was defined in 52.1% of studies. The most frequently included diagnostic criteria were pulmonary infiltrates (96.7%), fever (86.9%), hypothermia (49.1%), sputum (70.5%), and hypoxia (32.8%). The different criteria were used in 38 combinations across studies. The term "ventilator-associated" was defined in nine different ways. CONCLUSIONS: When provided, diagnostic criteria and definitions of VAP in RCTs display notable variability. Continuous efforts to harmonise VAP diagnostic criteria in future clinical trials are crucial to improve quality of care, enable accurate epidemiological assessments, and guide effective antimicrobial stewardship.

Polymer-Assisted Polymorph Transition in Melt-Processed Molecular Semiconductor Crystals.

A previously unreported polymorph of 5,11-bis(triisopropylsilylethynyl)anthradithiophene (TIPS ADT), Form II, crystallizes from melt-processed TIPS ADT films blended with 16 ± 1 wt % medium density polyethylene (PE). TIPS ADT/PE blends that initially are crystallized from the melt produce twisted TIPS ADT crystals of a metastable polymorph (Form IV, space group P1̅) with a brickwork packing motif distinct from the slipstack packing by solution-processed TIPS ADT crystals (Form I, space group P21/c) at room temperature. When these films were cooled to room temperature and subsequently annealed at 100 °C, near a PE melting temperature of 110 °C, Form II crystals nucleated and grew while consuming Form IV. The growth rate and orientations of Form II crystals were predetermined by the twisting pitch and growth direction of the original banded spherulites in the melt-processed films of the blends. Notably, the Form IV → II transition was not observed during thermal annealing of neat TIPS ADT films without PE. The presence of the mobile PE phase during thermal annealing of TIPS ADT/PE blend films increases the diffusion rate of TIPS ADT molecules, and the rate of nucleation of Form II. Form IV crystals are more conductive but less emissive compared to Form II crystals.

Spinal Cord Stimulator Inequities Within the US Military Health System.

OBJECTIVES: Although studies have described inequities in spinal cord stimulation (SCS) receipt, there is a lack of information to inform system-level changes to support health care equity. This study evaluated whether Black patients exhaust more treatment options than do White patients, before receiving SCS. MATERIALS AND METHODS: This retrospective cohort study included claims data of Black and non-Latinx White patients who were active-duty service members or military retirees who received a persistent spinal pain syndrome (PSPS) diagnosis associated with back surgery within the US Military Health System, January 2017 to January 2020 (N = 8753). A generalized linear model examined predictors of SCS receipt within two years of diagnosis, including the interaction between race and number of pain-treatment types received. RESULTS: In the generalized linear model, Black patients (10.3% [8.7%, 12.0%]) were less likely to receive SCS than were White patients (13.6% [12.7%, 14.6%]) The interaction term was significant; White patients who received zero to three different types of treatments were more likely to receive SCS than were Black patients who received zero to three treatments, whereas Black and White patients who received >three treatments had similar likelihoods of receiving a SCS. CONCLUSIONS: In a health care system with intended universal access, White patients diagnosed with PSPS tried fewer treatment types before receiving SCS, whereas the number of treatment types tried was not significantly related to SCS receipt in Black patients. Overall, Black patients received SCS less often than did White patients. Findings indicate the need for structured referral pathways, provider evaluation on equity metrics, and top-down support.

Mechanisms for dysregulation of excitatory-inhibitory balance underlying allodynia in dorsal horn neural subcircuits.

Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common type of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord. In this work, we analyze biophysically-motivated subcircuit structures that represent common motifs in neural circuits in layers I-II of the dorsal horn. These circuits are hypothesized to be part of the neural pathways that mediate two different types of allodynia: static and dynamic. We use neural firing rate models to describe the activity of populations of excitatory and inhibitory interneurons within each subcircuit. By accounting for experimentally-observed responses under healthy conditions, we specify model parameters defining populations of subcircuits that yield typical behavior under normal conditions. Then, we implement a sensitivity analysis approach to identify the mechanisms most likely to cause allodynia-producing dysregulation of the subcircuit's E-I signaling. We find that disruption of E-I balance generally occurs either due to downregulation of inhibitory signaling so that excitatory neurons are "released" from inhibitory control, or due to upregulation of excitatory neuron responses so that excitatory neurons "escape" their inhibitory control. Which of these mechanisms is most likely to occur, the subcircuit components involved in the mechanism, and the proportion of subcircuits exhibiting the mechanism can vary depending on the subcircuit structure. These results suggest specific hypotheses about diverse mechanisms that may be most likely responsible for allodynia, thus offering predictions for the high interindividual variability observed in allodynia and identifying targets for further experimental studies on the underlying mechanisms of this chronic pain condition.

Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system.

Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition of nearly any gene target. Yet, achieving efficacious drug delivery throughout deep brain structures of the CNS remains a considerable hurdle. We herein describe a lipid-siRNA conjugate that, following delivery into the cerebrospinal fluid (CSF), is transported effectively through perivascular spaces, enabling broad dispersion within CSF compartments and through the CNS parenchyma. We provide a detailed examination of the temporal kinetics of gene silencing, highlighting potent knockdown for up to five months from a single injection without detectable toxicity. Single-cell RNA sequencing further demonstrates gene silencing activity across diverse cell populations in the parenchyma and at brain borders, which may provide new avenues for neurological disease-modifying therapies.

A late-Ediacaran crown-group sponge animal.

Sponges are the most basal metazoan phylum1 and may have played important roles in modulating the redox architecture of Neoproterozoic oceans2. Although molecular clocks predict that sponges diverged in the Neoproterozoic era3,4, their fossils have not been unequivocally demonstrated before the Cambrian period5-8, possibly because Precambrian sponges were aspiculate and non-biomineralized9. Here we describe a late-Ediacaran fossil, Helicolocellus cantori gen. et sp. nov., from the Dengying Formation (around 551-539 million years ago) of South China. This fossil is reconstructed as a large, stemmed benthic organism with a goblet-shaped body more than 0.4 m in height, with a body wall consisting of at least three orders of nested grids defined by quadrate fields, resembling a Cantor dust fractal pattern. The resulting lattice is interpreted as an organic skeleton comprising orthogonally arranged cruciform elements, architecturally similar to some hexactinellid sponges, although the latter are built with biomineralized spicules. A Bayesian phylogenetic analysis resolves H. cantori as a crown-group sponge related to the Hexactinellida. H. cantori confirms that sponges diverged and existed in the Precambrian as non-biomineralizing animals with an organic skeleton. Considering that siliceous biomineralization may have evolved independently among sponge classes10-13, we question the validity of biomineralized spicules as a necessary criterion for the identification of Precambrian sponge fossils.

α-Latrotoxin Tetramers Spontaneously Form Two-Dimensional Crystals in Solution and Coordinated Multi-Pore Assemblies in Biological Membranes.

α-Latrotoxin (α-LTX) was found to form two-dimensional (2D) monolayer arrays in solution at relatively low concentrations (0.1 mg/mL), with the toxin tetramer constituting a unit cell. The crystals were imaged using cryogenic electron microscopy (cryoEM), and image analysis yielded a ~12 Å projection map. At this resolution, no major conformational changes between the crystalline and solution states of α-LTX tetramers were observed. Electrophysiological studies showed that, under the conditions of crystallization, α-LTX simultaneously formed multiple channels in biological membranes that displayed coordinated gating. Two types of channels with conductance levels of 120 and 208 pS were identified. Furthermore, we observed two distinct tetramer conformations of tetramers both when observed as monodisperse single particles and within the 2D crystals, with pore diameters of 11 and 13.5 Å, suggestive of a flickering pore in the middle of the tetramer, which may correspond to the two states of toxin channels with different conductance levels. We discuss the structural changes that occur in α-LTX tetramers in solution and propose a mechanism of α-LTX insertion into the membrane. The propensity of α-LTX tetramers to form 2D crystals may explain many features of α-LTX toxicology and suggest that other pore-forming toxins may also form arrays of channels to exert maximal toxic effect.

Accelerating Innovation in Primary Care to Support Adolescent Health Discussions.

BACKGROUND AND OBJECTIVES: Adolescent strengths and risks are not routinely captured in systematized and actionable ways in pediatric primary care. To address this problem, we developed a comprehensive adolescent health questionnaire (AHQ) integrated within the electronic health record and evaluated the AHQ's impact on collection of information on prioritized health-related domains. METHODS: We developed and pilot tested the AHQ. We then scaled and assessed the AHQ's impact on data collection. AHQ development used innovation methods and measured feasibility and acceptability outcomes. Scaling and postscaling outcomes included Reach, Effectiveness, Adoption, Implementation, Maintenance and Sustainability measures: Reach (total questionnaires completed), Effectiveness (capture of key information across health domains pre- vs post-AHQ scaling), Adoption (proportion of practices that adopted the AHQ), Implementation (proportion of eligible adolescents who completed the AHQ), and Maintenance (monthly completion rates). RESULTS: AHQ development led to a tool that was feasible and acceptable for use. During scaling (October 2020-December 2021), 22 147 questionnaires were completed by 20 749 unique adolescents aged 13 to 21 years at their preventive visit. Comparing pre- versus post-AHQ scaling data, use of the AHQ increased collection of information across domains, especially for strengths, gun safety, substance use, sexual activity, sexual orientation, and gender identity, from ranges of 0%-25% to 92%-95%. All 31 practices adopted the AHQ with completion at 88.7% of visits (n = 24 968). Two years postscaling, completion rates were >91% per month. CONCLUSIONS: We successfully developed, scaled, and maintained an AHQ in a widely-used electronic health record system, a model for improving adolescent care and foundation for developing future interventions.

Better Guidelines and Policies: AAP's Partnership for Policy Implementation.

OBJECTIVES: In 2005, the American Academy of Pediatrics founded the Partnership for Policy Implementation (PPI). The PPI has collaborated with authors to improve the quality of clinical guidelines, technical reports, and policies that standardize care delivery, improve care quality and patient outcomes, and reduce variation and costs. METHODS: In this article, we describe how the PPI trained informaticians apply a variety of tools and techniques to these guidance documents, eliminating ambiguity in clinical recommendations and allowing guideline recommendations to be implemented by practicing clinicians and electronic health record (EHR) developers more easily. RESULTS: Since its inception, the PPI has participated in the development of 45 published and 27 in-progress clinical practice guidelines, policy statements, technical and clinical reports, and other projects endorsed by the American Academy of Pediatrics. The partnership has trained informaticians to apply a variety of tools and techniques to eliminate ambiguity or lack of decidability and can be implemented by practicing clinicians and EHR developers. CONCLUSIONS: With the increasing use of EHRs in pediatrics, the need for medical societies to improve the clarity, decidability, and actionability of their guidelines has become more important than ever.

Heart Rate Variability Applications in Strength and Conditioning: A Narrative Review.

Heart rate variability (HRV) is defined as the fluctuation of time intervals between adjacent heartbeats and is commonly used as a surrogate measure of autonomic function. HRV has become an increasingly measured variable by wearable technology for use in fitness and sport applications. However, with its increased use, a gap has arisen between the research and the application of this technology in strength and conditioning. The goal of this narrative literature review is to discuss current evidence and propose preliminary guidelines regarding the application of HRV in strength and conditioning. A literature review was conducted searching for HRV and strength and conditioning, aiming to focus on studies with time-domain measurements. Studies suggest that HRV is a helpful metric to assess training status, adaptability, and recovery after a training program. Although reduced HRV may be a sign of overreaching and/or overtraining syndrome, it may not be a sensitive marker in aerobic-trained athletes and therefore has different utilities for different athletic populations. There is likely utility to HRV-guided programming compared to predefined programming in several types of training. Evidence-based preliminary guidelines for the application of HRV in strength and conditioning are discussed. This is an evolving area of research, and more data are needed to evaluate the best practices for applying HRV in strength and conditioning.

Association between switching to integrase strand transfer inhibitors and incident diabetes in people with HIV: a longitudinal cohort study.

OBJECTIVE: Integrase strand transfer inhibitors (INSTI) are associated with weight gain in people with HIV (PWH), but their impact on diabetes is unclear. We evaluated the association between switching from nonnucleoside reverse-transcriptase inhibitors (NNRTI) or protease inhibitors (PI) to INSTI and incident diabetes. DESIGN: Longitudinal cohort study. METHODS: We included PWH aged ≥18 years from the Johns Hopkins HIV Clinical Cohort (2007-2023) without history of diabetes who had used NNRTI or PI for ≥180 days. We followed participants up to 10 years from HIV primary care visits where they switched to INSTI or continued NNRTI or PI. We estimated the hazard of incident diabetes associated with switching to INSTI using weighted Cox regression with robust variance estimator. RESULTS: We included 2,075 PWH who attended 22,116 visits where they continued NNRTI or PI and 631 visits where they switched to INSTI. Switching to INSTI was associated with a weighted hazard ratio (wHR) of 1.11 (95% confidence interval [CI], 0.77-1.59) for incident diabetes. The association if no weight gain occurred during the first two years was not qualitatively different (wHR 1.22; 95% CI, 0.82-1.80). In a posthoc analysis, switching to INSTI conferred a significant wHR of 1.79 (95% CI, 1.13-2.84) for diabetes within the first two years but not after. CONCLUSIONS: Switching from NNRTI or PI to INSTI did not significantly increase overall diabetes incidence in PWH, although there may be elevated risk in the first two years. These findings can inform considerations when switching to INSTI-based regimens.

Suppression of Disorder in Benzamide and Thiobenzamide Crystals by Fluorine Substitution.

Disorder is a common feature of molecular crystals that complicates determination of structures and can potentially affect electric and mechanical properties. Suppression of disorder is observed in otherwise severely disordered benzamide and thiobenzamide crystals by substituting hydrogen with fluorine in the ortho-position of the phenyl ring. Fluorine occupancies of 20-30% are sufficient to suppress disorder without changing the packing motif. Crystal structure prediction calculations reveal a much denser lattice energy landscape for benzamide compared to 2-fluorobenzamide, suggesting that fluorine substitution makes disorder less likely.