Toxicity of rare earth elements (REEs) to marine organisms: Using species sensitivity distributions to establish water quality guidelines for protecting marine life.

A lack of chronic rare earth element (REE) toxicity data for marine organisms has impeded the establishment of numerical REE water quality benchmarks (e.g., guidelines) to protect marine life and assess ecological risk. This study determined the chronic no (significant) effect concentrations (N(S)ECs) and median-effect concentrations (EC50s) of eight key REEs (yttrium (Y), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), gadolinium (Gd), dysprosium (Dy) and lutetium (Lu)) for 30 coastal marine organisms (encompassing 22 phyla and five trophic levels from temperate and tropical habitats). Organisms with calcifying life stages were most vulnerable to REEs, which competitively inhibit calcium uptake. The most sensitive organism was a sea urchin, with N(S)ECs ranging from 0.64 µg/L for Y to 1.9 µg/L for La and Pr, and EC50s ranging from 4.3 µg/L for Y to 14.4 µg/L for Pr. Conversely, the least sensitive organism was a cyanobacterium, with N(S)ECs ranging from 21 µg/L for Y to 73 µg/L for Pr, and EC50s ranging from 153 µg/L for Y to 535 µg/L for La. Median sensitivity varied 215-fold across all organisms. The two-fold difference in median toxicity (µmol/L EC50) among REEs (Y∼Gd > Lu∼Nd∼Dy∼Ce > La∼Pr) was attributed to offset differences in binding affinity (log K) to cell surface receptors and the percentage of free metal ion (REE3+) in the test waters. The toxicity (EC50) of the remaining REEs (samarium, europium, terbium, holmium, thulium and ytterbium) was predicted using a combination of physicochemical data and measured EC50s for the eight tested REEs, with good agreement between predicted and measured EC50s for selected organisms. Numerical REE water quality guidelines to protect marine life were established using species sensitivity distributions (e.g., for 95 % species protection, values ranged from 1.1 µg/L for Y to 3.0 µg/L for La, Pr or Lu).

Disposition and Follow-up for Low-Risk Febrile Infants: A Secondary Analysis of a Multicenter Study.

OBJECTIVE: American Academy of Pediatrics guidelines recommend that febrile infants at low risk for invasive bacterial infection be discharged from the emergency department (ED) if primary care provider (PCP) follow-up occurs within 24 hours. We aimed to (1) assess the association between having electronic health record (EHR) documentation of a PCP and ED disposition and (2) describe documentation of potential barriers to discharge and plans for post-discharge follow-up in low-risk febrile infants. METHODS: We conducted a secondary analysis of a multicenter, cross-sectional study of low-risk febrile infants. Descriptive statistics characterized ED disposition on the basis of the day of the visit, EHR documentation of PCP, scheduled or recommended PCP follow-up, and barriers to discharge. RESULTS: Most infants (3565/4042, 90.5%) had EHR documentation of a PCP. Compared with discharged infants, a similar proportion of hospitalized infants had EHR documentation of PCP (90.3% vs 91.2%, P = .47). Few infants (1.5%) had barriers to discharge documented. Of the 3360 infants (83.1%) discharged from the ED, 1544 (46.0%) had documentation of scheduled or recommended 24-hour PCP follow-up. Discharged infants with weekday visits were more likely than those with weekend visits to have documentation of scheduled or recommended 24-hour follow-up (50.0% vs 35.5%, P < .001). CONCLUSIONS: Most infants had a documented PCP, yet fewer than half had documentation of a scheduled or recommended 24-hour follow-up. A dedicated focus on determining post-ED care plans that are safe and patient-centered may improve the quality of care for this population.

Correlation Among Neighborhood-level Measures of the Tobacco Retail Environment.

INTRODUCTION: Tobacco retailer density and distance to tobacco retailers are understood to influence tobacco-related behaviors; however, there is no general agreement on how to best characterize or measure the tobacco retail environment (TRE). In this data-driven analysis, we examine similarities among neighborhood-level measures of the TRE and assess how geographic resolution of the neighborhood units may affect them. METHODS: We used locations of likely tobacco retailers in the United States (US) to calculate multiple retailer count, density, and distance measures. Measures were calculated at the Census block group, tract, and county (including county equivalents) levels of geographic aggregation. Spearman's correlation was used to evaluate similarity among the TRE measures. RESULTS: At the block group and tract level, correlation among all TRE measures ranged from slightly negative (ρ = -0.03) to nearly perfect (ρ = 0.99). At both levels of aggregation, distance-based TRE measures were highly correlated (ρ > 0.76). At the block group level, simple count of retailers was highly correlated with the density measures (ρ > 0.83), and at the tract level, simple count was moderately to highly correlated with the density measures (ρ > 0.5). Findings were generally similar at the county level; a notable deviation was that retailers per person was negatively correlated with all other TRE measures (range from ρ = -0.08 to ρ = -0.32). CONCLUSIONS: Some common measures were not correlated, suggesting they capture different aspects of the TRE; similarity among the various measures also varied by level of geographic aggregation. IMPLICATIONS: Because the tobacco retail environment shapes people's tobacco-related behaviors, using appropriate measures to characterize it at a neighborhood-level is paramount. Our work highlights both the similarities and differences among a set of common measures, thereby suggesting the measures may be capturing different aspects of the overall retail environment. Our findings regarding geographic level of aggregation underscore the importance of neighborhood definition in any tobacco retail environment analysis.

An assessment of compositional methods for the analysis of DNA methylation-based deconvolution estimates.

DNA methylation (DNAm)-based deconvolution estimates contain relative data, forming a composition, that standard methods (testing directly on cell proportions) are ill-suited to handle. In this study we examined the performance of an alternative method, analysis of compositions of microbiomes (ANCOM), for the analysis of DNAm-based deconvolution estimates. We performed two different simulation studies comparing ANCOM to a standard approach (two sample t-test performed directly on cell proportions) and analyzed a real-world data from the Women's Health Initiative to evaluate the applicability of ANCOM to DNAm-based deconvolution estimates. Our findings indicate that ANCOM can effectively account for the compositional nature of DNAm-based deconvolution estimates. ANCOM adequately controls the false discovery rate while maintaining statistical power comparable to that of standard methods.

DNA methylation (DNAm)-based deconvolution provides highly accurate estimates of the proportion of each cell type in a mixed-cell type biological sample (e.g., whole-blood). These estimates can be used for examining the association between cell type proportions and biological or clinical end points; for example, comparing the estimated neutrophil proportion in whole blood between smokers and non-smokers. Cell proportion data has unique features which present challenges for traditional and widely used statistical methods. In response to this issue, our work presents two simulation studies and a real-world analysis that benchmark the performance of current standard statistical methods against an alternative method called analysis composition of microbes (ANCOM), which was originally developed for the analysis of microbiome data. In our real-world analysis we used DNAm data collected from Women's Health Initiative Long Life Study I and compared the results of each method against a gold-standard that is typically not available for these analyses. In each of our simulation studies, ANCOM was able to detect true differences in cell proportions between the groups being compared but had a much lower rate of false discovery compared with the standard statistical methods. Our real-world analysis demonstrated similar findings. Overall, our study highlights the potential of ANCOM as a powerful and robust method for analyzing DNAm-derived deconvolution estimates when the interest is comparisons of cell type proportions and biological or clinical end points. ANCOM's ability to minimize false discovery while maintaining robust statistical power positions it as a valuable addition to the epigenomic analysis toolkit.

Effect of Silyl Ether Bulk on Excited-State Intramolecular Proton Transfer-Based Sensing of Extant Hydrogen Fluoride for G-Series Nerve Agent Detection.

Luminescence-based sensing provides a method for the rapid detection of nerve agents. Previous approaches have generally focused on sensing materials containing a nucleophilic group that can react with the electrophilic phosphorus atom found in nerve agents. Herein we report an alternative approach for the detection of phosphonofluoridate-based G-series nerve agents that utilizes the fact they contain hydrogen fluoride. We have developed silylated sensing materials based on an excited-state intramolecular proton transfer (ESIPT) reporter compound, 2-[benzo[d]thiazol-2-yl]phenol. Thin films of differently silylated 2-[benzo[d]thiazol-2-yl]phenol were found to react with the hydrogen fluoride found in di-iso-propyl fluorophosphate (DFP), a simulant of sarin (G-series nerve agent), and turn on the ESIPT emission of the reporter compound. The use of the ESIPT emission reduced the impact of background fluorescence and improved the sensitivity of the detection. The effectiveness of the approach was dependent on the stability of the silyl protecting group used, with the least sterically hindered (trimethylsilyl) found to be too unstable to the ambient environment while the most sterically hindered, e.g., tri-iso-propylsilyl and tert-butyldiphenylsilyl were found to be insufficiently reactive to be useful in a real detection scenario. The sensing material composed of the tert-butyl dimethylsilyl protected 2-[benzo[d]thiazol-2-yl]phenol was found to have the best balance between stability under ambient conditions, and reactivity and selectivity to hydrogen fluoride. In a 3 s exposure, it could detect hydrogen fluoride down to a concentration of around 23 ppm in DFP with 99% purity.

The Impact of Double Pelvic Osteotomy on Dorsolateral Subluxation in 24 Dogs.

OBJECTIVE: The aim of this study was to determine the effect of double pelvic osteotomy (DPO) on dorsolateral subluxation (DLS) of the femoral head in a weight-bearing position. STUDY DESIGN: Retrospective observational study with treatment effect analysis. Twenty-four client-owned dogs that underwent DPO due to hip dysplasia. METHODS: Computed tomography (CT) studies were performed on 24 dogs that underwent a DPO between 2015 and 2021. The patients were positioned with the femora in a weight-bearing position. The DLS score was measured pre-DPO, immediately post-DPO, and at follow-up to determine if DPO resulted in an increase in the DLS score. RESULTS: A total of 21 dogs underwent single-stage bilateral DPO and 3 dogs underwent unilateral DPO resulting in 45 hip joints available for analysis. Follow-up CT was available for 29 of these at a median of 51 days (range: 35-482 days). The mean DLS score was 36.1% ± 14.6 preoperatively, 71.4% ± 12.5 post-DPO, and 70.0% ± 15.3 at follow-up. The increase between the pre- and postoperative measurement was significant (p < 0.001). CONCLUSION: DPO results in reduced subluxation of the femoral head in a weight-bearing position. CLINICAL SIGNIFICANCE: The in vivo results suggest that DPO will result in reduced femoral subluxation during weight-bearing.

Exploring modes of microbial interactions with implications for methane cycling.

Methanotrophs are the sole biological sink of methane. Volatile organic compounds (VOCs) produced by heterotrophic bacteria have been demonstrated to be a potential modulating factor of methane consumption. Here, we identify and disentangle the impact of the volatolome of heterotrophic bacteria on the methanotroph activity and proteome, using Methylomonas as model organism. Our study unambiguously shows how methanotrophy can be influenced by other organisms without direct physical contact. This influence is mediated by VOCs (e.g. dimethyl-polysulphides) or/and CO2 emitted during respiration, which can inhibit growth and methane uptake of the methanotroph, while other VOCs had a stimulating effect on methanotroph activity. Depending on whether the methanotroph was exposed to the volatolome of the heterotroph or to CO2, proteomics revealed differential protein expression patterns with the soluble methane monooxygenase being the most affected enzyme. The interaction between methanotrophs and heterotrophs can have strong positive or negative effects on methane consumption, depending on the species interacting with the methanotroph. We identified potential VOCs involved in the inhibition while positive effects may be triggered by CO2 released by heterotrophic respiration. Our experimental proof of methanotroph-heterotroph interactions clearly calls for detailed research into strategies on how to mitigate methane emissions.

Training approaches for the dissemination of clinical guidelines for NSSI: a quasi-experimental trial.

BACKGROUND: Non-suicidal self-injury (NSSI) is of high clinical relevance due to its high prevalence and negative long-term implications. In 2016, the German consensus-based clinical guidelines for diagnostic, assessment and treatment of NSSI in childhood and adolescence were published. However, research indicates that clinical guidelines are often poorly implemented in clinical practice. One crucial part of this process is the training of healthcare professionals to transfer knowledge and capacities to bring guideline recommendations into clinical practice. METHODS: The effect of three different dissemination strategies (printed educational material, e-learning, and blended-learning) on the NSSI guidelines´ recommendations was examined among 671 physicians and psychotherapists via an online-survey. The quasi-experimental study included three measurement points (before the training, after the training, 3-month follow-up) and mixed effects models were used to test for changes in knowledge, competences and attitudes toward NSSI and treatment. Moreover, the transfer of gained competences to practical work and user satisfaction were reviewed. RESULTS: With all three training formats, the intended changes of the outcome variables could be observed. Hereby, the printed educational material condition showed the lowest improvement in the scores for the 'negative attitudes toward NSSI and those who self-injure'. The training effect remained stable throughout the follow-up measurement. The highest application rate of acquired intervention techniques in clinical practice was reported for the blended-learning condition. For all three training strategies, user satisfaction was high and evaluation of training quality was positive, with printed educational material receiving the lowest and blended-learning the highest evaluations. CONCLUSIONS: In summary, all three training formats were perceived to be of high quality and seem to be suited to cover the needs of a heterogeneous group of physicians and psychotherapists. The choice of training method could be driven by considering which training goals are desired to be achieved and by the benefit-cost ratio allowing for tailored training approaches.

Achieving Equitable Cardiovascular Care for All: ACC Board of Trustees Health Equity Task Force Action Plan.

Advancements in cardiovascular (CV) disease management are notable, yet health inequities prevail, associated with increased morbidity and mortality noted among non-Hispanic African Americans in the United States. The 2002 Institute of Medicine Report revealed ongoing racial and ethnic health care disparities, spearheading a deeper understanding of the social determinants of health and systemic racism to develop strategies for CV health equity (HE). This article outlines the strategic HE approach of the American College of Cardiology, comprising 6 strategic equity domains: workforce pathway inclusivity, health care, data, science, and tools; education and training; membership, partnership, and collaboration; advocacy and policy; and clinical trial diversity. The American College of Cardiology's Health Equity Task Force champions the improvement of patients' lived experiences, population health, and clinician well-being while reducing health care costs-the Quadruple Aim of Health Equity. Thus, we examine multifaceted HE interventions and provide evidence for scalable real-world interventions to promote equitable CV care.

The Social Comparison Rumination Scale: Development, Psychometric Properties, and Associations With Perfectionism, Narcissism, Burnout, and Distress.

In the current article, we describe the development and validation of the Social Comparison Rumination Scale. This measured was developed as a supplement to existing social comparison measures and to enable us to determine its potential relevance to perfectionism and other personality constructs. The Social Comparison Rumination Scale (SCRS) is a six-item inventory assessing the extent to which an individual is cognitively preoccupied and thinking repetitively about social comparison outcomes and information. Three studies with five samples of university students are described. Psychometric analyses established the SCRS consists of one factor assessed with high internal consistency and the measure is reliable and valid. Analyses showed that elevated levels of social comparison rumination are associated with trait perfectionism, perfectionistic automatic thoughts, perfectionistic self-presentation, ruminative brooding, burnout, depression, and fear of negative evaluation. Links were also established between social comparison rumination and both narcissism and dispositional envy. Overall, our findings support the further use of the SCRS and highlight the tendency of many people to think in deleterious ways about social comparisons long after the actual comparisons have taken place. We discuss social comparison rumination within the context of concerns about excessive social media use and young people being exposed to seemingly perfect lives that became a vexing cognitive preoccupation.

Assessing and Evaluating the Perfectionism Social Disconnection Model: Social Support, Loneliness, and Distress Among Undergraduate, Law, and Medical Students.

The current research evaluates the Perfectionism Social Disconnection Model (PSDM) by considering the links between measures of trait perfectionism and perfectionistic self-presentation and measures of social support, loneliness, and distress in cross-sectional research. A particular focus is on perfectionism and levels of social support as assessed by the Social Provisions Scale. The current study also uniquely evaluates levels of perfectionism and perfectionistic self-presentation in undergraduate students, medical students, and law students. The results across samples provided evidence that loneliness mediates the link between interpersonal perfectionism and distress in keeping with the predictions of the PSDM. Correlational results found robust links between loneliness and low levels of social support. Moreover, socially prescribed perfectionism and perfectionistic self-presentation were associated negatively with social support, and this was especially evident in terms of the facet tapping the nondisclosure of imperfections. Group comparisons of perfectionism yielded few significant differences in accordance with expectations. Levels of perfectionism tended to be lower among medical students. However, the links between perfectionism and distress were clearly evident among undergraduates, medical students, and law students, thus attesting to the vulnerability of perfectionistic students in general. Overall, the results further confirm the relevance of perfectionism in distress among students and applicability of the PSDM in various types of students.

Perfectionism, Self-Image Goals and Compassionate Goals in Health and Mental Health: A Longitudinal Analysis.

This research focuses on ego-focused self-image goals as central to understanding the vulnerability inherent in perfectionism and the link that perfectionism has with poorer health and emotional well-being. The present study expands theory and research on perfectionism from a unique motivational perspective through a longitudinal investigation of perfectionism, the pursuit of self-image goals related to self-improvement, and mental and physical health among 187 university students. Our central finding was that trait and self-presentational perfectionism were associated longitudinally with self-image goals and poorer mental and physical health. Longitudinal analyses showed that perfectionistic self-presentation predicted subsequent self-image goals, controlling for initial self-image goals. Additionally, self-image goals were associated with worse mental and physical health and greater loneliness and social anxiety. Collectively, our results illustrate the benefits of assessing problematic personal goals in perfectionism and the need to revise existing motivational accounts by recognizing the important role ego-involved goals play in guiding much of what perfectionists do and how they act in their daily lives.

Interplay between the Glass Transition Temperature, Analyte Diffusion, and Fluorescence Quenching for Detection of Nitro-Group Containing Explosives Using Organic Semiconducting Films.

Efficient detection of chemical analytes using fluorescence-based sensors necessitates an in-depth understanding of the physical interaction between the analyte molecules and the sensor films. This study explores the interplay between the thermal properties of a series of triphenylamine-centered fluorescent dendrimers with different glass transition temperatures (Tg) for detecting nitroaromatic explosives. When exposed to 4-nitrotoluene (pNT) vapors, biphasic diffusion kinetics were observed for all the dendrimers, corresponding to Super Case II kinetics, suggesting rapid film swelling during initial analyte uptake. The diffusion kinetics were further analyzed using a diffusion-relaxation model, where a strong Tg dependence was observed for both the initial concentration-driven diffusion phase and the slower film relaxation phase. Additionally, a difference in kinetics between analyte uptake and release was observed. The photoluminescence (PL) kinetics also showed a Tg dependence, with more efficient PL recovery observed for films composed of dendrimers that had a lower Tg. Rapid quenching of over 40% with little PL recovery was seen in the dendrimer with the highest Tg (107 °C), while a smaller quench with efficient PL recovery was observed in the dendrimer that had a Tg close to room temperature. The results highlight the critical role of the thermal properties of sensor films in achieving rapid and sensitive detection.

Durability of Motor Learning by Observing.

Information about another person's movement kinematics obtained through visual observation activates brain regions involved in motor learning. Observation-related changes in these brain areas are associated with adaptive changes to feedforward neural control of muscle activation and behavioral improvements in limb movement control. However, little is known about the stability of these observation-related effects over time. Here we used force channel trials to probe changes in lateral force production at various time points (1 min, 10 min, 30 min, 60 min, 24 h) after participants either physically performed, or observed another individual performing upper limb reaching movements that were perturbed by novel, robot-generated forces (a velocity-dependent force-field). Observers learned to predictively generate directionally and temporally specific compensatory forces during reaching, consistent with the idea that they acquired an internal representation of the novel dynamics. Participants who physically practiced in the force-field showed adaptation that was detectable at all time points, with some decay detected after 24 h. Observation-related adaptation was less temporally stable in comparison, decaying slightly after 1 h and undetectable at 24 h. Observation induced less adaptation overall than physical practice, which could explain differences in temporal stability. Visually acquired representations of movement dynamics are retained and continue to influence behavior for at least one hour after observation.

Development of a Sensitive High-throughput Enzymatic Assay Capable of Measuring Sub-nanomolar Inhibitors of SARS-CoV2 Mpro.

The SARS-CoV-2 main protease (Mpro) is essential for viral replication because it is responsible for the processing of most of the non-structural proteins encoded by the virus. Inhibition of Mpro prevents viral replication and therefore constitutes an attractive antiviral strategy. We set out to develop a high-throughput Mpro enzymatic activity assay using fluorescently labeled peptide substrates. A library of fluorogenic substrates of various lengths, sequences and dye/quencher positions was prepared and tested against full length SARS-CoV-2 Mpro enzyme for optimal activity. The addition of buffers containing strongly hydrated kosmotropic anion salts, such as citrate, from the Hofmeister series significantly boosted the enzyme activity and enhanced the assay detection limit, enabling the ranking of sub-nanomolar inhibitors without relying on the low-throughput Morrison equation method. By comparing cooperativity in citrate or non-citrate buffer while titrating the Mpro enzyme concentration, we found full positive cooperativity of Mpro with citrate buffer at less than one nanomolar (nM), but at a much higher enzyme concentration (∼320 nM) with non-citrate buffer. In addition, using a tight binding Mpro inhibitor, we confirmed there was only one active catalytical site in each Mpro monomer. Since cooperativity requires at least two binding sites, we hypothesized that citrate facilitates dimerization of Mpro at sub-nanomolar concentration as one of the mechanisms enhances Mpro catalytic efficiency. This assay has been used in high-throughput screening and structure activity relationship (SAR) studies to support medicinal chemistry efforts. IC50 values determined in this assay correlates well with EC50 values generated by a SARS-CoV-2 antiviral assay after adjusted for cell penetration.

Children and adolescents at risk for seclusion and restraint in inpatient psychiatric treatment: a case control study.

To reduce coercion in acute inpatient child and adolescent psychiatric units, a better understanding of individuals at risk for seclusion and/or restraint (S/R) is needed. We report data on the proportion of patients secluded/restrained and factors associated with higher risk of S/R. Identifying preventative mechanisms through risk stratification upon inpatient admission can aid the training of mental health professionals, and support shaping specific workflows for at-risk populations for example by joint crisis plans or post-coercion review sessions. METHODS: A case-control study included all admissions (n = 782) to a department of child and adolescent psychiatry within 36 months between 2019 and 2022. Data on age, sex, out of home care, primary and comorbid ICD-10 diagnoses, length of stay, prior/multiple admissions were compared between admissions with and without S/R using chi square tests for categorical and t-tests for continuous variables. Uni- and multivariate binary logistic regression models were computed. RESULTS: The overall proportion of S/R was 12.8% (n = 100). Females (p = 0.001), patients in out of home care (p < 0.001), with prior admission (p < 0.001), Post-traumatic stress disorder (PTSD; p < 0.001) and Borderline personality disorder (BPD; p < 0.001) were at a significantly higher risk of S/R. Length of stay in days (OR 1.01), out of home care (OR 3.85), PTSD (OR 6.20), BPD (OR 15.17), Attention deficit hyperactivity disorder (ADHD)/conduct disorder (OR 4.29), and manic episode/bipolar disorder (OR 36.41) were significantly associated with S/R in multivariate regression. CONCLUSIONS: Child and adolescent psychiatric staff should consider risk factors when using coercive measures. Patients with PTSD and/or BPD are the most vulnerable subgroups. Training of professionals and clinical practice need to be adapted in order to prevent the use of S/R and its potential hazards.

Transmediastinal primary pulmonary liposarcoma: Case report and review of management strategies.

Soft tissue sarcomas account for less than 1% of new cancer diagnoses, approximately one in five of which are liposarcomas. These tumors typically arise in the deep tissues of the proximal extremity or retroperitoneum, with just under 3% presenting as primary intrathoracic neoplasms. We present an exceedingly rare and particularly unique presentation of primary lung liposarcoma which traversed the mediastinum into the contralateral hemithorax. This report highlights the primary characteristics of the disease and underscores the importance of a multidisciplinary approach to its successful treatment.

Radiation Therapy for HPV-Positive Oropharyngeal Squamous Cell Carcinoma: An ASTRO Clinical Practice Guideline.

PURPOSE: Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management. METHODS: ASTRO convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and posttreatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or 1 node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins or extranodal extension. Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without positive surgical margins and extranodal extension, 5600 to 6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-dimensional techniques with reduction in dose to critical organs at risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography is recommended approximately 3 months after definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal positron emission tomography-computed tomography findings, either neck dissection or repeat imaging is recommended. CONCLUSIONS: The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

Targeted exome analysis in patients with rare bleeding disorders: data from the Rare Bleeding Disorders in the Netherlands study.

Background: Rare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict. Objectives: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype. Methods: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines. Results: Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% (n = 123) were clearly pathogenic, 19% (n = 40) were likely pathogenic, and 24% (n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear. Conclusion: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.