Controlled Antenatal Thyroid Screening Study III: Effects of gestational thyroid status on adolescent brain morphology.

CONTEXT: Children born to mothers with gestational hypo- or hyperthyroidism may have increased risk of adverse neurodevelopmental outcomes. However, the effects of maternal thyroid status on offspring brain development are unclear. OBJECTIVE: To establish whether adolescent brain morphology is affected by suboptimal gestational thyroid function (SGTF). DESIGN AND SETTING: The Controlled Antenatal Thyroid Screening (CATS) study randomized mothers with SGTF to levothyroxine or no supplementation from ∼12 weeks' gestation. At age 9, children born to mothers who were over-treated with levothyroxine had a higher risk of conduct and hyperactivity traits. For the current CATS III study, children underwent neuroimaging studies, including T1-weighted structural magnetic resonance imaging (MRI). PARTICIPANTS: A total of 85 children aged 11-16 years had usable T1-weighted MRI data (exposed to untreated SGTF (n=21), normal GTF (n=24), or treated SGTF (optimally-treated (n=21), over-treated (n=20)). MAIN OUTCOME MEASURES: Primary outcome: to examine the association of SGTF and its treatment with global brain volumes. Secondary and exploratory outcomes: to investigate the association of maternal TSH and free T4 levels with global and subregional brain volumes. Results were adjusted for age, sex and pubertal scores. RESULTS: There were no significant differences in global brain volumetric measures between groups, including total gray matter volume (p=0.373). Weak positive correlations were found between maternal TSH, but not FT4, levels and several brain volumes, but these did not survive testing for multiple comparisons. CONCLUSIONS: We found no evidence that SGTF was associated with differences in adolescent brain morphology, and no impact of levothyroxine supplementation.

AvrSr27 is a zinc-bound effector with a modular structure important for immune recognition.

Effector proteins are central to the success of plant pathogens, while immunity in host plants is driven by receptor-mediated recognition of these effectors. Understanding the molecular details of effector-receptor interactions is key for the engineering of novel immune receptors. Here, we experimentally determined the crystal structure of the Puccinia graminis f. sp. tritici (Pgt) effector AvrSr27, which was not accurately predicted using AlphaFold2. We characterised the role of the conserved cysteine residues in AvrSr27 using in vitro biochemical assays and examined Sr27-mediated recognition using transient expression in Nicotiana spp. and wheat protoplasts. The AvrSr27 structure contains a novel ß-strand rich modular fold consisting of two structurally similar domains that bind to Zn2+ ions. The N-terminal domain of AvrSr27 is sufficient for interaction with Sr27 and triggering cell death. We identified two Pgt proteins structurally related to AvrSr27 but with low sequence identity that can also associate with Sr27, albeit more weakly. Though only the full-length proteins, trigger Sr27-dependent cell death in transient expression systems. Collectively, our findings have important implications for utilising protein prediction platforms for effector proteins, and those embarking on bespoke engineering of immunity receptors as solutions to plant disease.

A multi-tissue, splicing-based joint transcriptome-wide association study identifies susceptibility genes for breast cancer.

Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals of multiple excised introns in each gene across 11 tissues that are potentially relevant to breast cancer risk. We utilized summary statistics from a meta-analysis that combined genome-wide association study (GWAS) results of 424,650 women of European ancestry. Splicing-level prediction models were trained in GTEx (v.8) data. We identified 240 genes by the multi-tissue joint splicing-TWAS at the Bonferroni-corrected significance level; in the tissue-specific splicing-TWAS that combined TWAS signals of excised introns in genes in breast tissue only, we identified nine additional significant genes. Of these 249 genes, 88 genes in 62 loci have not been reported by previous TWASs, and 17 genes in seven loci are at least 1 Mb away from published GWAS index variants. By comparing the results of our splicing-TWASs with previous gene-expression-based TWASs that used the same summary statistics and expression prediction models trained in the same reference panel, we found that 110 genes in 70 loci that are identified only by the splicing-TWASs. Our results showed that for many genes, expression quantitative trait loci (eQTL) did not show a significant impact on breast cancer risk, whereas splicing quantitative trait loci (sQTL) showed a strong impact through intron excision events.

Tuning Excited State Character in Iridium(III) Photosensitizers and Its Influence on TTA-UC.

A series of mixed ligand, photoluminescent organometallic Ir(III) complexes have been synthesized to incorporate substituted 2-phenyl-1H-naphtho[2,3-d]imidazole cyclometalating ligands. The structures of three example complexes were categorically confirmed using X-ray crystallography each sharing very similar structural traits including evidence of interligand hydrogen bond contacts that account for the shielding effects observed in the 1H NMR spectra. The structural iterations of the cyclometalated ligand provide tuning of the principal electronic transitions that determine the visible absorption and emission properties of the complexes: emission can be tuned in the visible region between 550 and 610 nm and with triplet lifetimes up to 10 µs. The nature of the emitting state varies across the series of complexes, with different admixtures of ligand-centered and metal-to-ligand charge transfer triplet levels evident. Finally, the use of the complexes as photosensitizers in triplet-triplet annihilation energy upconversion (TTA-UC) was investigated in the solution state. The study showed that the complexes possessing the longest triplet lifetimes showed good viability as photosensitizers in TTA-UC. Therefore, the use of an electron-withdrawing group on the 2-phenyl-1H-naphtho[2,3-d]imidazole ligand framework can be used to rationally promote TTA-UC using this class of complex.

A de novo variant in PAK2 detected in an individual with Knobloch type 2 syndrome.

P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelic PAK2 variants cause Knobloch syndrome type 2 (KNO2)-a developmental disorder primarily characterized by ocular anomalies. Here, we identified a novel de novo heterozygous missense variant in PAK2, NM_002577.4:c.1273G>A, p.(D425N), by whole genome sequencing in an individual with features consistent with KNO2. Notable clinical phenotypes include global developmental delay, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, FTT, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging by in silico analysis. Previous clinical genetic testing did not report this variant due to unknown relevance of PAK2 variants at the time of testing, highlighting the importance of reanalysis. Our findings also substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical spectrum.

Population pharmacokinetics of imetelstat, a first-in-class oligonucleotide telomerase inhibitor.

Imetelstat is a novel, first-in-class, oligonucleotide telomerase inhibitor in development for the treatment of hematologic malignancies including lower-risk myelodysplastic syndromes and myelofibrosis. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetics of imetelstat and identify and quantify covariates that contribute to its pharmacokinetic variability. The model was developed using plasma concentrations from 7 clinical studies including 424 patients with solid tumors or hematologic malignancies who received single-agent imetelstat via intravenous infusion at various dose levels (0.4-11.7 mg/kg) and schedules (every week to every 4 weeks). Covariate analysis included factors related to demographics, disease, laboratory results, renal and hepatic function, and antidrug antibodies. Imetelstat was described by a two-compartment, nonlinear disposition model with saturable binding/distribution and dose- and time-dependent elimination from the central compartment. Theory-based allometric scaling for body weight was included in disposition parameters. The final covariates included sex, time, malignancy, and dose on clearance; malignancy and sex on volume of the central compartment; and malignancy and spleen volume on concentration of target. Clearance in females was modestly lower, resulting in nonclinically relevant increases in predicted exposure relative to males. No effects on imetelstat pharmacokinetics were identified for mild-to-moderate hepatic or renal impairment, age, race, and antidrug antibody status. All model parameters were estimated with adequate precision (relative standard error < 29%). Visual predictive checks confirmed the capacity of the model to describe the data. The analysis supports the imetelstat body-weight-based dosing approach and lack of need for dose individualizations for imetelstat-treated patients.

U.S. Preparedness and Response to Increasing Clade I Mpox Cases in the Democratic Republic of the Congo - United States, 2024.

Clade I monkeypox virus (MPXV), which can cause severe illness in more people than clade II MPXVs, is endemic in the Democratic Republic of the Congo (DRC), but the country has experienced an increase in suspected cases during 2023-2024. In light of the 2022 global outbreak of clade II mpox, the increase in suspected clade I cases in DRC raises concerns that the virus could spread to other countries and underscores the importance of coordinated, urgent global action to support DRC's efforts to contain the virus. To date, no cases of clade I mpox have been detected outside of countries in Central Africa where the virus is endemic. CDC and other partners are working to support DRC's response. In addition, CDC is enhancing U.S. preparedness by raising awareness, strengthening surveillance, expanding diagnostic testing capacity for clade I MPXV, ensuring appropriate specimen handling and waste management, emphasizing the importance of appropriate medical treatment, and communicating guidance on the recommended contact tracing, containment, behavior modification, and vaccination strategies.

Upper-limb neurovascular compression, pectoralis minor and quadrilateral space syndromes: A narrative review of current literature.

Pectoralis minor syndrome (PMS) and quadrilateral space syndrome (QSS) are uncommon neurovascular compression disorders affecting the upper extremity. PMS involves compression under the pectoralis minor muscle, and QSS results from compression in the quadrilateral space-both are classically observed in overhead-motion athletes. Diagnosing PMS and QSS may be challenging due to variable presentations and similarities with other, more common, upper-limb pathologies. Although there is no gold standard diagnostic, local analgesic muscle-block response in a patient with the appropriate clinical context is often all that is required for an accurate diagnosis after excluding more common etiologies. Treatment ranges from conservative physical therapy to decompressive surgery, which is reserved for refractory cases or severe, acute vascular presentations. Decompression generally yields favorable outcomes, with most patients experiencing significant relief and restored baseline function. In conclusion, PMS and QSS, although rare, can cause debilitating upper-extremity symptoms; accurate diagnosis and appropriate treatment offer excellent outcomes, alleviating pain and disability.

Calibration and validation of the HydroColor and Citclops smartphone applications for water quality monitoring.

Water quality monitoring, essential for safeguarding ecosystems and human health, has gained increasing significance as societies worldwide prioritize environmental awareness and sustainable practices. Therefore, this study evaluates the performance of two smartphone applications (APPs), HydroColor and Citclops (now EyeOnWater), in estimating water quality parameters such as turbidity, the concentration of suspended particulate matter ([SPM]), and colour. By comparing laboratory and hyperspectral sensors measurements with water quality parameters estimated from smartphone images, the study assessed the accuracy and efficiency of the transfer functions employed by these APPs. The study findings revealed varying degrees of accuracy, with HydroColor R2 values of 0.36 and 0.83 for turbidity and [SPM], respectively, while Citclops achieved an R2 value of 0.7 for colour estimation. The study identified limitations in both APPs, particularly in their applicability to different water systems. These insights underscore the importance of proper calibration and validation procedures for smartphone-based water quality monitoring APPs. Also, the findings underscore the growing significance of smartphone APPs in enabling accessible and real-time monitoring of water quality, highlighting their potential to revolutionize the democratization of environmental monitoring practices through citizen science. Ultimately, this research contributes to the advancement of smartphone-based monitoring initiatives to inform decision-making processes in environmental management, and enhancing our understanding of water quality dynamics in diverse environments.

Programmable synthesis of organic cages with reduced symmetry.

Integrating symmetry-reducing methods into self-assembly methodology is desirable to efficiently realise the full potential of molecular cages as hosts and catalysts. Although techniques have been explored for metal organic (coordination) cages, rational strategies to develop low symmetry organic cages remain limited. In this article, we describe rules to program the shape and symmetry of organic cage cavities by designing edge pieces that bias the orientation of the amide linkages. We apply the rules to synthesise cages with well-defined cavities, supported by evidence from crystallography, spectroscopy and modelling. Access to low-symmetry, self-assembled organic cages such as those presented, will widen the current bottleneck preventing study of organic enzyme mimics, and provide synthetic tools for novel functional material design.

Performance and Return to Play After Surgery for Thoracic Outlet Syndrome in Professional Baseball Players: A Matched Cohort Analysis.

BACKGROUND: Thoracic outlet syndrome (TOS) remains a rare diagnosis but is being recognized as a cause of upper extremity dysfunction in professional baseball players. PURPOSE/HYPOTHESIS: The purpose was to determine performance and return-to-play (RTP) outcomes in professional baseball players after surgical treatment of TOS. The hypothesis was that there would be a high RTP rate in professional baseball players after TOS surgery with no statistical differences in performance between pitchers who had TOS surgery and matched controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All professional baseball players who underwent surgical treatment of TOS between 2010 and 2017 were identified using the Major League Baseball Health and Injury Tracking System database. Demographic and performance data (before and after surgery) for each player were recorded. Performance variables were then compared between players who underwent TOS surgery and matched controls. The matching criteria were no history of previous surgeries on affected arm, age at time of surgery, throwing side, level of play (Major or Minor League Baseball), and years of experience playing professional baseball. RESULTS: Overall, 52 players underwent surgery for TOS, of whom 46 (88%) were pitchers. The type of TOS was neurogenic in 69% and venous in 29%. One player had arterial TOS. After TOS surgery, 79% of players returned to play at the same or higher level (RTSP) by 9.5 months and played ≥3 years after surgery. No differences were found in RTSP rate based on the type of TOS. No statistical difference was found in RTP rates between major and minor league players. Pitchers had a 76% RTSP, which was similar to the natural attrition for control pitchers (P = .874). After TOS surgery, pitchers saw a decline in several performance metrics, but these declines were not different from those of control pitchers, indicating that the decline in performance after TOS surgery was no faster than is seen in healthy professional pitchers as they age. CONCLUSION: The rate of RTSP after surgery for TOS in professional baseball players was 79%. There was no difference in RTP based on the type of TOS. Pitchers who underwent surgery for TOS had no significant differences in pitching performance metrics after surgery compared with matched controls.

High variability among surgeons in evaluation, treatment, and rehabilitation of medial ulnar collateral ligament injuries.

Hypothesis and/or Background: The incidence of elbow medial ulnar collateral ligament (MUCL) injuries has been increasing, leading to advances in surgical treatments. However, it is not clear that there is consensus among surgeons regarding diagnostic imaging, the indications for acute surgery and postoperative rehabilitation. The purpose of this study is evaluate surgeon variability in the presurgical, surgical, and postsurgical treatment of MUCL injuries regarding the imaging modalities used for diagnosis, indications for acute surgical treatment, and postoperative treatment recommendations for rehabilitation and return to play (RTP). Our hypothesis is that indications for acute surgical treatment will be highly variable based on MUCL tear patterns and that agreement on the time to RTP will be consistent for throwing athletes and inconsistent for nonthrowing athletes. Methods: A survey developed by 6 orthopedic surgeons with expertise in throwing athlete elbow injuries was distributed to 31 orthopedic surgeons who routinely treat MUCL injuries. The survey evaluated diagnostic and treatment topics related to MUCL injuries, and responses reaching 75% agreement were considered as high-level agreement. Results: Twenty-four surgeons responded to the survey, resulting in a 77% response rate. There is 75% or better agreement among surveyed surgeons regarding acute surgical treatment for distal full thickness tears, ulnar nerve transposition in symptomatic patients or with ulnar nerve subluxation, postoperative splinting for 1-2 weeks with initiation of rehabilitation within 2 weeks, the use of bracing after surgery and the initiation of a throwing program at 3 months after MUCL repair with internal brace by surgeons performing 20 or more MUCL surgeries per year. There were a considerable number of survey topics without high-level agreement, particularly regarding the indications for acute surgical treatment, the time to return to throwing and time RTP in both throwing and nonthrowing athletes. Discussion and/or Conclusion: The study reveals that there is agreement for the indication of acute surgical treatment of distal MUCL tears, duration of bracing after surgery, and the time to initiate physical therapy after surgery. There is not clear agreement on indications for surgical treatment for every MUCL tear pattern, RTP time for throwing, hitting and participation in nonthrowing sports.

Hydrogen Peroxide May Reduce the Risk for Revision Surgery and Infection in Primary Shoulder Arthroplasty: Two-year Follow-up From a Prospective, Blinded, Controlled Trial.

BACKGROUND: The purpose of this study was to determine whether the addition of hydrogen peroxide to the preoperative skin preparation for primary total shoulder arthroplasty is associated with a difference in patient-reported outcomes, risk for postoperative infection, and risk for revision surgery at a minimum of 2-year follow-up. METHODS: This was a prospective, blinded, and controlled trial, which included a consecutive series of patients undergoing primary shoulder arthroplasty. The control group underwent standard sterile skin preparation using ethyl alcohol and ChloraPrep applicators, and the peroxide group had the same preparation with the addition of hydrogen peroxide between the alcohol and ChloraPrep applications. We then compared patient-reported outcome scores (American Shoulder and Elbow Surgeons Shoulder Score [ASES], simple shoulder test [SST], visual analog scale [VAS]), infections, and revision surgeries between the two groups at 2-year follow-up. RESULTS: Of the 61 patients included in the original study, 52 of 58 (85%) living patients agreed to participate in this study. No preoperative differences were observed between groups. No difference was observed in ASES, SST, or VAS scores at 2 years. More revision surgeries were done in the control group (7 versus 2, P = 0.268) and Cutibacterium acnes infections (2 versus 0, P = 0.168). CONCLUSION: The addition of hydrogen peroxide to the preoperative skin preparation before primary shoulder arthroplasty is safe, and additional research is warranted to investigate whether it may decrease the risk for revision surgery and postoperative C acnes infection. LEVEL OF EVIDENCE: III.

Bioengineering methods for vascularizing organoids.

Organoids, self-organizing three-dimensional (3D) structures derived from stem cells, offer unique advantages for studying organ development, modeling diseases, and screening potential therapeutics. However, their translational potential and ability to mimic complex in vivo functions are often hindered by the lack of an integrated vascular network. To address this critical limitation, bioengineering strategies are rapidly advancing to enable efficient vascularization of organoids. These methods encompass co-culturing organoids with various vascular cell types, co-culturing lineage-specific organoids with vascular organoids, co-differentiating stem cells into organ-specific and vascular lineages, using organoid-on-a-chip technology to integrate perfusable vasculature within organoids, and using 3D bioprinting to also create perfusable organoids. This review explores the field of organoid vascularization, examining the biological principles that inform bioengineering approaches. Additionally, this review envisions how the converging disciplines of stem cell biology, biomaterials, and advanced fabrication technologies will propel the creation of increasingly sophisticated organoid models, ultimately accelerating biomedical discoveries and innovations.

Assessing readiness to use electronic health record data for outcome ascertainment in clinical trials - A case study.

BACKGROUND: Variable data quality poses a challenge to using electronic health record (EHR) data to ascertain acute clinical outcomes in multi-site clinical trials. Differing EHR platforms and data comprehensiveness across clinical trial sites, especially if patients received care outside of the clinical site's network, can also affect validity of results. Overcoming these challenges requires a structured approach. METHODS: We propose a framework and create a checklist to assess the readiness of clinical sites to contribute EHR data to a clinical trial for the purpose of outcome ascertainment, based on our experience with the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, which enrolled 5451 participants in 86 primary care practices across 10 healthcare systems (sites). RESULTS: The site readiness checklist includes assessment of the infrastructure (i.e., size and structure of the site's healthcare system or clinical network), data procurement (i.e., quality of the data), and cost of obtaining study data. The checklist emphasizes the importance of understanding how data are captured and integrated across a site's catchment area and having a protocol in place for data procurement to ensure consistent and uniform extraction across each site. CONCLUSIONS: We suggest rigorous, prospective vetting of the data quality and infrastructure of each clinical site before launching a multi-site trial dependent on EHR data. The proposed checklist serves as a guiding tool to help investigators ensure robust and unbiased data capture for their clinical trials. ORIGINAL TRIAL REGISTRATION NUMBER: NCT02475850.

The Effect of Lateralization and Distalization After Grammont-Style Reverse Total Shoulder Arthroplasty.

BACKGROUND: The purpose of this study is to evaluate the relationship between multiple radiographic measures of lateralization and distalization and clinical outcome scores after reverse total shoulder arthroplasty (RTSA). METHODS: We retrospectively evaluated all RTSAs performed by the senior author between January 1, 2007, and November 1, 2017. We then evaluated the visual analog scale for pain (VAS pain), Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) scores and complication and reoperation rates at a minimum of 2-year follow-up. We measured preoperative and postoperative (2-week) radiographs for the lateralization shoulder angle (LSA), the distalization shoulder angle (DSA), lateral humeral offset (LHO), and distance from glenoid to lateral aspect of the greater tuberosity (GLAGT). A multivariable analysis was performed evaluating the effect of the postoperative radiographic measurements on final patient reported outcomes (ASES scores, SST, VAS pain). RESULTS: The cohort included 216 shoulders from unique patients who had patient reported outcome scores available at a minimum of 2-year follow-up (average, 4.0±1.9 years) for a total follow-up rate of 70%. In the multivariable models, more lateralization (LSA) was associated with worse final ASES scores -0.52 (95% CI: -0.88 to -0.17; p=0.004), and more distalization (DSA) was associated with better final ASES scores 0.40 (95% CI: 0.11, 0.69; p=0.007). More lateralization (LSA) was associated with worse final SST scores -0.06 (95% CI: -0.11, -0.003; p=0.039). Finally, greater distalization (DSA) was associated with lower final VAS pain scores, Ratio = 0.98 (95% CI: 0.96, 1.00; p=0.021). CONCLUSION: Greater distalization and less lateralization are associated with better function and less pain after Grammont-style RTSA. If utilizing a Grammont-style implant, remaining consistent with Grammont's principles of implant placement will afford better final clinical outcomes.

Increased tolerance to commonly used antibiotics in a Pseudomonas aeruginosa ex vivo porcine keratitis model.

Introduction. Bacterial keratitis, particularly caused by Pseudomonas aeruginosa, is challenging to treat because of multi-drug tolerance, often associated with the formation of biofilms. Antibiotics in development are typically evaluated against planktonic bacteria in a culture medium, which may not accurately represent the complexity of infections in vivo.Hypothesis/Gap Statement. Developing a reliable, economic ex vivo keratitis model that replicates some complexity of tissue infections could facilitate a deeper understanding of antibiotic efficacy, thus aiding in the optimization of treatment strategies for bacterial keratitis.Methodology. Here we investigated the efficacy of three commonly used antibiotics (gentamicin, ciprofloxacin and meropenem) against Pseudomonas aeruginosa cytotoxic strain PA14 and invasive strain PA01 using an ex vivo porcine keratitis model.Results. Both strains of P. aeruginosa were susceptible to the MIC of the three tested antibiotics. However, significantly higher concentrations were necessary to inhibit bacterial growth in the minimum biofilm eradication concentration (MBEC) assay, with both strains tolerating concentrations greater than 512 mg l-1 of meropenem. When MIC and higher concentrations than MBEC (1024 mg l-1) of antibiotics were applied, ciprofloxacin exhibited the highest potency against both P. aeruginosa strains, followed by meropenem, while gentamicin showed the least potency. Despite this, none of the antibiotic concentrations used effectively cleared the infection, even after 18 h of continuous exposure.Conclusions. Further exploration of antibiotic concentrations and aligning dosing with clinical studies to validate the model is needed. Nonetheless, our ex vivo porcine keratitis model could be a valuable tool for assessing antibiotic efficacy.

Node-degree aware edge sampling mitigates inflated classification performance in biomedical random walk-based graph representation learning.

Motivation: Graph representation learning is a family of related approaches that learn low-dimensional vector representations of nodes and other graph elements called embeddings. Embeddings approximate characteristics of the graph and can be used for a variety of machine-learning tasks such as novel edge prediction. For many biomedical applications, partial knowledge exists about positive edges that represent relationships between pairs of entities, but little to no knowledge is available about negative edges that represent the explicit lack of a relationship between two nodes. For this reason, classification procedures are forced to assume that the vast majority of unlabeled edges are negative. Existing approaches to sampling negative edges for training and evaluating classifiers do so by uniformly sampling pairs of nodes. Results: We show here that this sampling strategy typically leads to sets of positive and negative examples with imbalanced node degree distributions. Using representative heterogeneous biomedical knowledge graph and random walk-based graph machine learning, we show that this strategy substantially impacts classification performance. If users of graph machine-learning models apply the models to prioritize examples that are drawn from approximately the same distribution as the positive examples are, then performance of models as estimated in the validation phase may be artificially inflated. We present a degree-aware node sampling approach that mitigates this effect and is simple to implement. Availability and implementation: Our code and data are publicly available at https://github.com/monarch-initiative/negativeExampleSelection.

Enhancing Value and Well-Being: The Basket of Motivators Framework for Aligning Neurology Clinical Practices With Performance Outcomes.

Purpose of Review: Physician burnout, which is prevalent in neurology, has accelerated in recent years. While multifactorial, a major contributing factor to burnout is a payment model that rewards volume over quality, leaving physicians overburdened and unfulfilled. The aim of this review was to investigate ways of reducing burnout while improving quality-based outcomes in a value-based health care model. Recent Findings: Burnout affects researchers, educators, clinicians, and administrators in all fields and tracks, but neurologists experience some of the worst burnout rates among specialties. Transitioning to a value-based health care model, which rewards quality and outcomes over volume, may contribute to reversing the burnout trend. However, this requires that physicians feel valued in the workplace in ways corresponding to their preferences. We propose to stratify neurologists using the "basket of motivators" framework, which operates multiple individual-based and team-based motivators including balance among work responsibilities, work-life balance, institutional pride, self-actualization at work, work environment, and finances. By tailoring individual-based and team-based financial and nonfinancial incentives, neurologists are empowered to work at the top of their license to provide high-impact clinical care while combating the most prominent causes of burnout. Summary: To address the neurologist burnout epidemic, a transition to value-based health care is needed that rewards quality-based performance outcomes through both individual-based and team-based approaches that apply financial and nonfinancial incentives. Understanding the underlying motivations behind neurologists' drives to work can inform tailored incentives that allow neurologists to provide value to their patients and feel valued by their organizations.

An open source knowledge graph ecosystem for the life sciences.

Translational research requires data at multiple scales of biological organization. Advancements in sequencing and multi-omics technologies have increased the availability of these data, but researchers face significant integration challenges. Knowledge graphs (KGs) are used to model complex phenomena, and methods exist to construct them automatically. However, tackling complex biomedical integration problems requires flexibility in the way knowledge is modeled. Moreover, existing KG construction methods provide robust tooling at the cost of fixed or limited choices among knowledge representation models. PheKnowLator (Phenotype Knowledge Translator) is a semantic ecosystem for automating the FAIR (Findable, Accessible, Interoperable, and Reusable) construction of ontologically grounded KGs with fully customizable knowledge representation. The ecosystem includes KG construction resources (e.g., data preparation APIs), analysis tools (e.g., SPARQL endpoint resources and abstraction algorithms), and benchmarks (e.g., prebuilt KGs). We evaluated the ecosystem by systematically comparing it to existing open-source KG construction methods and by analyzing its computational performance when used to construct 12 different large-scale KGs. With flexible knowledge representation, PheKnowLator enables fully customizable KGs without compromising performance or usability.