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OBJECTIVE: To determine the frequency of concurrent cervical and lumbar spinal stenosis (i.e., 'tandem spinal stenosis' [TSS]) in a 10-yr review of hospital admissions. DESIGN: In a retrospective study of 460,964 hospital admissions to our 1,000-bed academic community hospital, we identified a base population of 54 patients with TSS. These patients presented with multiple complaints, including neurogenic claudication, progressive gait disturbances, and neurologic signs of both upper and lower motor neuron dysfunction, among others. Since 1964 when TSS was first described, estimates of its frequency have varied widely, ranging from a low of 5% to a high of 28%. RESULTS: Of the 54 cases of TSS identified among the 460,964 patient admissions during a 10-yr period, 36 were men and 18 were women. A total of 51 were >51 yrs of age. For all ages, the frequency rate of TSS in this series was 12 per 100,000 admissions. CONCLUSION: With TSS, the symptoms of either the cervical or the lumbar type initially predominate. Often, only after the primary pathology is treated does the secondary problem become evident. Although TSS occurred relatively infrequently in this series, its potential presence should not be overlooked. [ABSTRACT FROM AUTHOR]

A 10-yr retrospective review of 460,964 admissions to a 1,000-bed community teaching hospital identified 555 patients with a diagnosis of cervical spinal stenosis. Of this number, 118 were classified as 'young.' With an occurrence rate of 26 per 100,000, in this series there was not a significant difference in sex throughout the decade. During the first 5 yrs of this study, 186 patients with cervical spinal stenosis were identified, of whom 37 were <51 yrs of age. Of 369 patients in the remaining 5-yr period with cervical spinal stenosis, 81 were <51 yrs of age. The proportion of those <51 yrs old between the two 5-yr periods was not statistically different. Although spinal stenosis, both cervical and lumbar, has been regarded as a disorder of the elderly, 21% of those with cervical spinal stenosis and 10% with lumbar spinal stenosis can be anticipated to be <51 yrs of age. [ABSTRACT FROM AUTHOR]

Objective: To assess 1) the health values and health ratings of seriously ill hospitalized patients, their surrogate decision makers, and their physicians; 2) the determinants of health values; and 3) whether health values change over time.Design: Prospective, longitudinal, multicenter study.Setting: 5 academic medical centers.Participants: 1438 seriously ill patients with at least one of nine diseases who had a projected overall 6-month mortality rate of 50%; their surrogates; and their physicians.Measurements: Time-tradeoff utilities (reflecting preferences for a shorter but healthy life) and health ratings.Results: At study day 3, patients had a mean time-tradeoff utility of 0.73 +/- 0.32 (median [25th, 75th percentile], 0.92 [0.63, 1.0]), indicating that they equated living 1 year in their current state of health with living 8.8 months in excellent health. However, scores varied widely; 34.8% of patients were unwilling to exchange any time in their current state of health for a shorter life in excellent health (utility, 1.0), and 9.0% were willing to live 2 weeks or less in excellent health rather than 1 year in their current state of health (utility, 0.04). Health rating scores averaged 57.8 +/- 24.0 (median [25th percentile, 75th percentile], 60 [50, 75]) on a scale of 0 (death) to 100 (perfect health). The patients' mean time-tradeoff score exceeded that of their paired surrogates (n = 1041) by 0.08 (P < 0.0001). Time-tradeoff scores were related to psychosocial well-being; health ratings; desire for resuscitation and extension of life rather than relief of pain and discomfort; degree of willingness to live with constant pain; and perceived prognosis for survival and independent functioning. Scores of surviving patients increased by an average of 0.06 after 2 months (P < 0.0001) and 0.08 after 6 months (P < 0.0001).Conclusions: Health values of seriously ill patients vary widely, are higher than patients' surrogates believe, are related to few other preference and health status measures, and increase over time. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this literature review is to document the contributions dental hygienists have made over the past 3 decades to improve the nation's oral health. This historical review encompasses selected literature that acknowledged dental Hygienists' direct involvement in U.S. school-based or school-linked oral health programs from 1970-1999. METHODS: Five researchers independently searched MEDLINE, PubMed, and other electronic databases to identify relevant literature for the years 1970-1999. The search aimed to locate articles authored by or that documented dental Hygienists' involvement as 'service provider' in U.S. school-based oral health programs. For the purpose of this review, service provider was defined as educator, administrator, clinician, examiner, or any other unspecified service performed by a dental hygienist. RESULTS: Fifty-seven articles were retrieved, of which 36 (63%) directly linked dental hygienists to U.S. school-based activities. Twenty-seven articles specifically identified dental hygienists as service providers. Dental hygienists were listed as either primary or contributing author on 19 of these articles. CONCLUSION: The decade of the 1970s revealed very little literature documenting dental Hygienists' involvement in U.S. school-based oral health programs. The 1970s, however, were instrumental in laying the foundation for service in the years that followed. As public health initiatives expanded in the 1980s, dental hygienists were identified in the largest number of papers as key personnel in the areas of education, management, service provider, and author. The decade of the 1990s yielded less literature than the 1980s, yet recognized dental Hygienists' involvement in all aspects of oral health care delivery, program development and management, and authorship. The authors of this review theorize that dental hygienists were engaged in more school-based programs than reported and were involved in the authorship process more frequently than documented. Due to lack of credentials, or the omission of the words 'dental hygienist,' 'RDH,' or 'LDH,' in favor of 'health care provider,' 'auxiliary,' or 'trained health care educator,' it is unknown what portion of contributions made by dental hygienists remain undocumented. [ABSTRACT FROM AUTHOR]

Abstract: Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-2017) and letermovir prophylaxis (2018-2021) eras. CMV DNA polymerase chain reaction (PCR) surveillance was routinely performed during the pre-HCT workup period, and antiviral therapy was recommended according to risk of progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized, and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified, and 11% had pre-HCT CMV reactivation 14 days (median; interquartile range [IQR], 6-23) before HCT. Lymphopenia (≤0.3 × 103/μL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year after HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV end points were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates, and antiviral therapy may be indicated to prevent post-HCT CMV reactivation., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Maternal investment theory is the study of how breeding females allocate resources between offspring size and brood size to achieve reproductive success. In classical trade-off models, r/K-selection and bet-hedging selection, the primary predictors of maternal investments in offspring are population density and resource stability. In crowded, stable environments, K-selected females invest in large offspring at an equivalent cost in brood size. In uncrowded, unstable environments, r-selected females invest in large broods at an equivalent cost in offspring size. In unpredictable resource environments, bet-hedging females invest moderately in brood size and offspring size. The maternal risk-management model represents a profound departure from classical trade-off models. Maternal investments in offspring size, brood size, and brood number are shaped independently by autonomous risk factors: the duration of gaps in resources during seasonal cycles, rates of predation, and unpredictable catastrophic events. To date, no single model has risen to a position of preeminence. Here in sharks, we show that maternal investments within and across species do not agree with the predictions of trade-off models and instead agree with the predictions of the maternal risk-management model. Within and across shark species, offspring size and brood size were independent maternal investment strategies. The risk of starvation favored investments in larger offspring. The risk of predation favored investments in larger broods. If empirical studies continue to confirm its predictions, maternal-risk management may yet emerge as a unifying model of diverse reproductive adaptations by means of natural selection., (© 2024. The Author(s).)

Background: Herpes simplex viruses (HSVs) frequently reactivate during immunosuppression and may be a risk factor for adverse outcomes after solid organ transplant (SOT). While suppressive antiviral therapy reduces the risk of symptomatic HSV reactivation, the kinetics of asymptomatic viral shedding with chronic immunosuppression after transplant are not well understood. We report the characteristics of oral HSV shedding among 15 HSV-1 seropositive SOT recipients (n = 8 liver, n = 7 kidney, median age 58.5 years, median 20 months post-transplant) who were not taking daily antiviral suppressive therapy., Methods: Participants self-collected oral swabs three times daily for 6 weeks for HSV quantification and recorded the presence of oral symptoms or lesions in a diary., Results: Sample collection adherence was high (median 122 swabs/person, range: 85.7%-101.6% of expected swabs). Most participants (n = 12, 80%) experienced at least one shedding episode, with a median shedding rate of 8.9% (range: 0%-33.6%). There were 32 total shedding episodes, 24 (75%) of which occurred without symptoms or lesions. For episodes of known duration, the median length was 21.8 hrs (interquartile range: 10.8-46.1 hrs)., Conclusion: Most shedding episodes (78.1%) lasted >12 hrs, suggesting that twice-daily sampling may be sufficient to detect most episodes. These data show that self-collection of oral swabs is feasible for patients who have undergone SOTs and can provide insight into the frequency of oral HSV reactivation, which can be used to design future studies in this population., (© 2024 Wiley Periodicals LLC.)

Abstract: Preemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (HESI-DART) group held a hybrid in-person and virtual workshop in Washington, DC, in 2022. The workshop was entitled, "Interpretation of DART in Regulatory Contexts and Frameworks." There were 154 participants (37 in person and 117 virtual) across 9 countries. The purpose of the workshop was to capture key consensus approaches used to assess DART risks associated with chemical product exposure when a nonclinical finding is identified. The decision-making process for determining whether a DART endpoint is considered adverse is critical because the outcome may have downstream implications (e.g., increased animal usage, modifications to reproductive classification and pregnancy labeling, impact on enrollment in clinical trials and value chains). The workshop included a series of webinar modules to train and engage in discussions with federal and international regulators, clinicians, academic investigators, nongovernmental organizations, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART and new approach methodologies in the context of regulatory requirements and processes. Despite the differences in regulatory frameworks between the chemical and pharmaceutical sectors, the same foundational principles for data interpretation should be applied. The discussions led to the categorization of principles, which offer guidance for the systematic interpretation of data. Step 1 entails identifying any hazard by closely analyzing the data at the study endpoint level, while Step 2 involves assessing risk using weight of evidence. These guiding principles were derived from the collective outcomes of the workshop deliberations., (© 2024 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Venous access is a key component of managing haemorrhagic shock. Obtaining intravenous access in trauma patients is challenging due to circulatory collapse in shock. This literature review examines the feasibility of direct puncture and cannulation of the brachiocephalic veins (BCVs) for intravenous access in shocked adult trauma patients. Three literature searches were conducted. OVID Medline was searched for articles on the use of the BCVs for venous access in adults and on the BCVs in shock. A third systematic search of OVID Medline, OVID Embase and Cochrane Library was conducted on the use of the BCVs for access in shocked trauma patients. After full-text review, 18 studies were selected for inclusion for the search on the use of the BCVs for access in adults. No studies met the inclusion criteria for the search on the BCVs in shock and BCV access in shocked trauma patients. The BCVs are currently used for central venous access, haemodialysis and totally implantable venous access devices (TIVADs) in adults. There is a preference for the right BCV (RBCV) over the left as the RBCV is more superficial, straighter, larger, has less anatomical variation and avoids the risk of thoracic duct puncture. The BCVs appear to be stabilised in shock by surrounding bony structures. The BCVs may provide a site for initial, rapid access in trauma resuscitation. Further research is required to determine if the BCVs collapse in shock and if venous access using the BCVs is feasible in a trauma resuscitation setting., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Background: With the elimination in 2021 of the United States Medical Licensing Examination Step 2 Clinical Skills test, it is incumbent upon U.S. medical schools to develop local validated assessments of clinical reasoning. While much attention has been paid to summative exams for graduating students, formative exams for pre-clerkship students have not been well studied., Methods: We applied the University of Illinois at Chicago College of Medicine (UIC-COM) Patient Note (PN) Scoring Rubric to templated PNs written by 103 pre-clerkship students for two cases in an objective structured clinical examination (OSCE) at the Yale School of Medicine. The rubric consists of four section scores (Documentation, Differential Diagnosis, Justification, and Workup, each scored 1 to 4) and a composite score (scaled 23 to 100). We calculated item discrimination for each section score and Cronbach's alpha for each case. We surveyed students about their experience writing the templated PN., Results: Mean Documentation, Differential Diagnosis, Justification, Workup, and composite scores for case A were 2.16, 1.80, 1.65, 2.29, and 47.67, respectively. For case B, the scores were 2.13, 1.21, 1.60, 1.67, and 40.54, respectively. Item discrimination ranged from 0.41 to 0.80. Cronbach's alpha for cases A and B was 0.48 and 0.25, respectively. A majority of the students felt that the exercise was useful and appropriate to their level of training., Conclusions: Despite performing poorly, pre-clerkship students found the note-writing task beneficial. Reliability of the scoring rubric was suboptimal, and modifications are needed to make this exercise a suitable measure of clinical reasoning., (© 2023. The Author(s).)

Bacterial superinfection and antibiotic prescribing in the setting of the current mpox outbreak are not well described in the literature. This retrospective observational study revealed low prevalence (11%) of outpatient antibiotic prescribing for bacterial superinfection of mpox lesions; at least 3 prescriptions (23%) were unnecessary., Competing Interests: R.J. serves as a clinical consultant for Wolters-Kluwer for their online content. All other authors report no conflicts related to this article., (© The Author(s) 2023.)

Purpose of Review: This review summarizes current literature pertaining to fluid management for critically ill children. It includes an overview on crystalloid fluid used throughout the critical illness course, management of fluid output and complications with fluid overload., Recent Findings: Observational paediatric studies and adult randomized trials show mixed results regarding risk of mortality and kidney injury with 0.9% saline and crystalloid fluid. A recent adult randomized trial suggests that a fluid restrictive strategy may be well tolerated in critically ill adults with septic shock, but further randomized trials are needed in paediatrics. Fluid overload has been associated with increased morbidity and mortality. Trials exploring ways to decrease fluid accumulation must be done in paediatrics., Summary: Additional high-quality studies are needed to precisely define the type, timing and rate of intravenous fluid critically ill children should receive throughout their clinical illness course., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

People vary in their performance on visual working memory tasks, and these individual differences covary with a wide range of higher-level cognitive processes including fluid intelligence. Performance also varies across study displays, purportedly driven by both low- and higher-level processes. Understanding what causes these sources of systematic variability has been crucial for developing theories of working memory. However, here we find that all such variability in performance on a test of visual working memory can be accounted for by concurrent variability in visual iconic memory: A person with relatively high working memory capacity will have high iconic memory capacity, and a particularly easy working memory display will also be easy under iconic memory conditions. These results are supported by a nonparametric factor analysis and hierarchical Bayesian model comparison. In a second experiment the relationship between iconic and working memory holds even when they are measured with substantially different experimental paradigms, and a third experiment suggests that the relationship between tests of iconic and working memory is driven by mechanisms other than iconic or working memory storage, such as variation in perceptual or attentional processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background and Objectives: Because of the coronavirus disease 2019 pandemic and recommendations from a range of leaders and organizations, the pediatrics subspecialty 2020 recruitment season was entirely virtual. Minimal data exist on the effect of this change to guide future strategies. The aim of this study was to understand the effects of virtual recruitment on pediatric subspecialty programs as perceived by program leaders., Methods: This concurrent, triangulation, mixed-methods study used a survey that was developed through an iterative (3 cycles), consensus-building, modified Delphi process and sent to all pediatric subspecialty program directors (PSPDs) between April and May 2021. Descriptive statistics and thematic analysis were used, and a conceptual framework was developed., Results: Forty-two percent (352 of 840) of PSPDs responded from 16 of the 17 pediatric (94%) subspecialties; 60% felt the virtual interview process was beneficial to their training program. A majority of respondents (72%) reported cost savings were a benefit; additional benefits included greater efficiency of time, more applicants per day, greater faculty involvement, and perceived less time away from residency for applicants. PSPDs reported a more diverse applicant pool. Without an in-person component, PSPDs worried about programs and applicants missing informative, in-person interactions and applicants missing hospital tours and visiting the city. A model based upon theory of change was developed to aid program considerations for future application cycles., Conclusions: PSPDs identified several benefits to virtual recruitment, including ease of accommodating increased applicants with a diverse applicant pool and enhanced faculty involvement. Identified limitations included reduced interaction between the applicant and the larger institution/city., (Copyright © 2022 by the American Academy of Pediatrics.)

Prior to registering and marketing any new pharmaceutical, (agro)chemical or food ingredient product manufacturers must, by law, generate data to ensure human safety. Safety testing requirements vary depending on sector, but generally repeat-dose testing in animals form the basis for human health risk assessments. Dose level selection is an important consideration when designing such studies, to ensure that exposure levels that lead to relevant hazards are identified. Advice on dose level selection is provided in test guidelines and allied guidance documents, but it is not well harmonised, particularly for selection of the highest dose tested. This paper further builds on concepts developed in a technical report by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) which recommends pragmatic approaches to dose selection considering regulatory requirements, animal welfare and state of the art scientific approaches. Industry sectors have differing degrees of freedom to operate regarding dose level selection, depending on the purpose of the studies and the regulatory requirements/legislation, and this is reflected in the overall recommended approaches. An understanding of systemic exposure should be utilised where possible (e.g., through toxicokinetic approaches) and used together with apical endpoints from existing toxicity studies to guide more appropriate dose level selection. The highest dose should be limited to a reasonable level, causing minimal but evident toxicity to the test animals without significantly compromising their well-being. As the science of predictive human exposure further develops and matures, this will provide exciting and novel opportunities for more human-relevant approaches to dose level selection., (© 2022. The Author(s).)

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents., (© 2022 Global Blood Therapeutics, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD., (© 2022 Global Blood Therapeutics, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To develop a population pharmacokinetics (PPK) model for rucaparib, an oral poly(ADP-ribose) polymerase inhibitor., Methods: The PPK analysis used PK data from patients in Study 1014 (NCT01009190, n = 35), Study 10 (NCT01482715, n = 123), and ARIEL2 (NCT01891344, n = 300), including intensive intravenous data (12-40 mg), intensive and sparse oral data (12-360 mg single-dose, 40-500 mg once daily, and 240-840 mg twice daily [BID]), and intensive single-dose oral data under fasted conditions and after a high-fat meal (40, 300, and 600 mg)., Results: Rucaparib PK was well described by a two-compartment model with sequential zero-order release and first-order absorption and first-order elimination. A high-fat meal slightly increased bioavailability at 600 mg but not at lower doses; this is not considered clinically significant, and rucaparib can be taken with or without food. Covariate effects of baseline creatinine clearance and albumin on rucaparib clearance were identified. Despite numerical increases in exposure with renal impairment, no dose adjustment is recommended for patients with mild or moderate renal impairment. No statistically significant relationships were detected for demographics, hepatic function (normal versus mild impairment), CYP1A2 and CYP2D6 phenotypes, or strong CYP1A2 or CYP2D6 inhibitors. Concomitant proton pump inhibitors showed no clinically significant effect on absorption. External validation of the model with data from ARIEL3 (NCT01968213) and TRITON2 (NCT02952534) studies showed no clinically meaningful PK differences across indications or sex., Conclusion: The PPK model adequately described rucaparib PK, and none of the covariates evaluated had a clinically relevant effect., Clinicaltrials: GOV: Study 1014 (NCT01009190), Study 10 (NCT01482715), ARIEL2 (NCT01891344), ARIEL3 (NCT01968213), and TRITON2 (NCT02952534)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: In 2014, the Association of American Medical Colleges defined 13 Core Entrustable Professional Activities (EPAs) that all graduating students should be ready to do with indirect supervision upon entering residency and commissioned a 10-school, 5-year pilot to test implementing the Core EPAs framework. In 2019, pilot schools convened trained entrustment groups (TEGs) to review assessment data and render theoretical summative entrustment decisions for class of 2019 graduates. Results were examined to determine the extent to which entrustment decisions could be made and the nature of these decisions., Method: For each EPA considered (4-13 per student), TEGs recorded an entrustment determination (ready, progressing but not yet ready, evidence against student progressing, could not make a decision); confidence in that determination (none, low, moderate, high); and the number of workplace-based assessments (WBAs) considered (0->15) per determination. These individual student-level data were de-identified and merged into a multischool database; chi-square analysis tested the significance of associations between variables., Results: The 2,415 EPA-specific determinations (for 349 students by 4 participating schools) resulted in a decision of ready (n = 997/2,415; 41.3%), progressing but not yet ready (n = 558/2,415; 23.1%), or evidence against student progression (n = 175/2,415; 7.2%). No decision could be made for the remaining 28.4% (685/2,415), generally for lack of data. Entrustment determinations' distribution varied across EPAs (chi-square P < .001) and, for 10/13 EPAs, WBA availability was associated with making (vs not making) entrustment decisions (each chi-square P < .05)., Conclusions: TEGs were able to make many decisions about readiness for indirect supervision; yet less than half of determinations resulted in a decision of readiness to perform this EPA with indirect supervision. More work is needed at the 10 schools to enable authentic summative entrustment in the Core EPAs framework., (Copyright © 2021 by the Association of American Medical Colleges.)

Perceiving the motion of an object is thought to involve two stages: Local motion energy is measured at each point in space, and these signals are then pooled across space to build coherent global motion. There are several theories of how local-to-global pooling occurs, but they all predict that global motion perception is a continuous process, such that increasing the strength of motion energy should gradually increase the precision of perceived motion directions. We test this prediction against the alternative that global motion perception is discrete: Motion is either perceived with high precision or fails to be perceived altogether. Data from human observers provides clear evidence that, whereas pooling local motion energy is continuous, the segmentation of local signals into coherent global motion patterns is a discrete process. This result adds motion perception to the growing list of processes that exhibit evidence of all-or-none visual awareness. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

This Personal View is about our experience with preclinical education as medical students. We discuss the problem with current medical education in light of an ever-growing body of medical knowledge and increasing student disengagement with preclinical lectures. We briefly review the concept of retrieval practice as an effective, evidence-based learning strategy that helped us retain knowledge for longer periods and propose that medical educators should adopt this strategy to best prepare medical students to navigate the vastly expanding scope of modern medicine.

Remnants of native tallgrass prairie experience elevated atmospheric nitrogen (N) deposition in urban areas, with potential effects on species traits that are important for N cycling and species composition. We quantified bulk (primarily wet) inorganic N (NH4+-N + NO3--N) deposition at six sites along an urban development gradient (6-64% urban) in the Dallas-Fort Worth metropolitan area from April 2014 to October 2015. In addition, we conducted a phytometer experiment with two common native prairie bunchgrass species--one well studied (Schizachyrium scoparium) and one little studied (Nasella leucotricha)--to investigate ambient N deposition effects on plant biomass and tissue quality. Bulk inorganic N deposition ranged from 6.1-9.9 kg ha-1 yr-1, peaked in spring, and did not vary consistently with proportion of urban land within 10 km of the sites. Total (wet + dry) inorganic N deposition estimated using bulk deposition measured in this study and modeled dry deposition was 12.9-18.2 kg ha-1 yr-1. Although the two plant species studied differ in photosynthetic pathway, biomass, and tissue N, they exhibited a maximum 2-3-fold and 2-4-fold increase in total biomass and total plant N, respectively, with 1.6-fold higher bulk N deposition. In addition, our findings indicate that while native prairie grasses may exhibit a positive biomass response to increased N deposition up to ~18 kg ha-1 yr-1, total inorganic N deposition is well above the estimated critical load for herbaceous plant species richness in the tallgrass prairie of the Great Plains ecoregion and thus may negatively affect these plant communities., Competing Interests: The authors have declared that no competing interests exist.

Background: Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management., Methods: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death., Results: One hundred five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years, and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%), and diabetes (33%) being the most prevalent. Most (63%) had symptoms for ≥5 days prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation, and the overall mortality rate was 33%., Conclusions: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19)., Objective: The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this., Methods: In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9, 2020, and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation., Results: A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62 ± 16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant corrected QT (QTc) prolongation was observed in a minority (n = 5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in prespecified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors., Conclusions: In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy., (© 2020 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

Background: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2., Methods: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day., Results: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation., Conclusions: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.)., (Copyright © 2020 Massachusetts Medical Society.)

Objectives: To characterise the mortality and neurological outcomes of paediatric cardiac patients requiring cardiopulmonary resuscitation for more than 30 minutes prior to extracorporeal membrane oxygenation cannulation and to identify risk factors associated with adverse outcomes in this population., Materials and Methods: Observational retrospective cohort study in paediatric cardiac patients undergoing cardiopulmonary resuscitation for greater than 30 minutes prior to cannulation in a tertiary children's hospital, from July 2000 to July 2013., Results: Seventy-three paediatric cardiac patients requiring cardiopulmonary resuscitation for more than 30 minutes prior to cannulation were included in the study. Survival to hospital discharge was 43.8%, with 75% of survivors having either normal neurologic function or only mild disability. Multivariable logistic regression analysis demonstrated that increased use of calcium during resuscitation (odds ratio 14.5, p 0.01), cardiopulmonary resuscitation duration >50 minutes (odds ratio 4.12, p 0.03), >6 interruptions of chest compressions during cannulation (odds ratio 6.40, p 0.03), the need for continuous renal replacement therapy (odds ratio 11.1, p 0.001), and abnormal pupillary response during extracorporeal membrane oxygenation (odds ratio 33.9, p 0.006) were independent predictors for hospital mortality., Conclusion: Survival after cardiopulmonary resuscitation for more than 30 minutes prior to extracorporeal membrane oxygenation cannulation in our paediatric cardiac cohort was 43.8%. Factors associated with mortality included calcium use during resuscitation, longer cardiopulmonary resuscitation, increased chest compression pauses during cannulation, the use of continuous renal replacement therapy, and abnormal pupils during extracorporeal membrane oxygenation support. A prospective assessment of these factors in paediatric cardiac patients may be beneficial in improving outcomes.

Background: The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood., Methods: To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR)., Results: There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm)., Conclusions: This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Due to their potentially unique properties, beryllium carbide materials have been the subject of many theoretical studies. However, experimental validation has been lacking due to the difficulties of working with Be. Neutral beryllium dicarbide has been predicted to have a T-shaped equilibrium structure ( C 2 v ), while previous quantum chemistry calculations for the structure of the anion had not yielded consistent results. In this study, we report photoelectron velocity map imaging spectra for the BeC 2 - X 2 A 1 → BeC 2 X 1 A 1 transition. These data provide vibrational frequencies and the electron affinity of BeC 2 . Ab initio electronic structure calculations, validated against the experimental data, show that both the anion and the neutral form have C 2 v equilibrium geometries with polar covalent bonding between Be and the C 2 subunit. Computed vibrational frequencies and the electron affinity, obtained at the CCSD(T) level of theory, were found to be in good agreement with the measurements.

This is a review of the first 50 patients attending a colocated continuity clinic with harm reduction services to women experiencing homelessness in north Seattle. Among those tested, patients had high rates of curable sexually transmitted infections (44%), injection opioid use (36%), transactional sex (69%), unintended pregnancy (10%), and human immunodeficiency virus infections (10%).

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Prepackaged leafy green vegetables represent one of the fastest growing segments of the fresh-produce industry in the United States. Several steps in the production process have been mechanized to meet the downstream demand for prebagged lettuces. The growth in this market, however, has come with drawbacks, and chief among them are consumers finding wild animals in prepackaged crops. These incidents may signal an overburdened produce supply chain, but we currently lack the information needed to determine if this is a food-safety problem or food-quality concern. Here, we address this gap by reviewing online media coverage of wild vertebrates found in prepackaged produce items by customers in the United States. We discovered 40 independent incidents since 2003 with 95% having occurred during 2008-2018, suggesting that the frequency of incidents may have increased during the last decade. The minority of incidents included wild animals found in organic produce (27.5%), whereas the majority involved conventionally grown crops (72.5%). Most incidents involved amphibians (52.5%) and reptiles (22.5%), while fewer contained mammals (17.5%) and birds (7.5%). Frogs and toads made up all of the amphibian-related incidents, with more than 60% comprising small-bodied treefrogs found in various types of fresh leafy greens. At least seven incidents involved Pacific Treefrogs (Hyliola regilla) and three comprised Green Anoles (Anolis carolinensis). One lizard and nine frogs were found alive, and at least two frogs were released into non-native areas. This is the first review quantifying incidents of vertebrates found by customers in prepackaged produce, yet it remains unclear whether these occurrences indicate a food-safety crisis or a complaint against food quality. Nevertheless, wild animals can spread diseases to humans via contaminated produce, therefore we contend that industry professionals can reduce the potential health risk to their consumers and negative economic consequences to themselves through increased attention to this matter., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. With regards to human risk assessment practices for developmental toxicity, the analysis showed that, after excluding lenalidomide and pomalidomide data in rats, all available AUC margins at the NOAEL for the induction of malformations or embryofetal lethality were <4-fold of the exposure at the MRHD for all 22 therapeutics. These data support the proposed general approach of increased level of concern for human risk when exposure margins of the NOAEL to the MRHD are <10-fold, reduced concern when the exposure margins are 10- to 25-fold, and minimal concern when the exposure margin is > 25-fold., (Copyright © 2019 Elsevier Inc. All rights reserved.)

High-throughput experimental (HTE) techniques are an increasingly important way to accelerate the rate of materials research and development for many technological applications. However, there are very few publications on the reproducibility of the HTE results obtained across different laboratories for the same materials system, and on the associated sample and data exchange standards. Here, we report a comparative study of Zn-Sn-Ti-O thin films materials using high-throughput experimental methods at National Institute of Standards and Technology (NIST) and National Renewable Energy Laboratory (NREL). The thin film sample libraries were synthesized by combinatorial physical vapor deposition (cosputtering and pulsed laser deposition) and characterized by spatially resolved techniques for composition, structure, thickness, optical, and electrical properties. The results of this study indicate that all these measurement techniques performed at two different laboratories show excellent qualitative agreement. The quantitative similarities and differences vary by measurement type, with 95% confidence interval of 0.1-0.2 eV for the band gap, 24-29 nm for film thickness, and 0.08 to 0.37 orders of magnitude for sheet resistance. Overall, this work serves as a case study for the feasibility of a High-Throughput Experimental Materials Collaboratory (HTE-MC) by demonstrating the exchange of high-throughput sample libraries, workflows, and data.

Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by polymerase chain reaction in breastmilk, vaginal, and saliva samples from nine healthy CMV-seropositive postpartum women for 28 days. CMV was found in seven of nine women and 171 of 253 breastmilk samples (67.6%). In four women, all breastmilk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral, and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted., (© 2018 Wiley Periodicals, Inc.)