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RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.

Objective: Examine trends in e-cigarette use, and Juul use specifically, among U.S. college students.Participants: In 2016, we established a cohort of 529 incoming first-year students to a large Midwestern University. In 2018, these students (now third-years) were re-contacted, and a new sample of 611 incoming first-year students was enrolled.Methods: First-year students in 2016 completed a survey assessing their e-cigarette use; in 2018, first- and second-year students reported on e-cigarette use, and use of Juul specifically.Results: From 2016 to 2018, past 30-day e-cigarette use rose from 5.9% to 27.7%. In 2018, for Juul alone, ever use was above 35% and past 30-day use was above 20% for both cohorts. Juul use did not differ by gender, but was associated with higher socioeconomic status (SES) and being White.Conclusions: Findings present disturbing possibilities for long-term nicotine addiction among the next generation, and underscore the need for a rapid public health response.

BACKGROUND Weakness and disuse of intrinsic foot muscles contributes to dysfunction in foot and toe alignment and sensory input, which may lead to instability and falls in older adults. The aim of this systematic review was to report the effects of intrinsic foot muscle strengthening (IFMS) interventions on functional mobility in adults aged ≥65 years. METHODS A systematic review was performed with searches from December 2019-February 2021 using MEDLINE, CINAHL, SPORTDiscus, Rehab and Sports Medicine Source, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. Additional sources were sought using reference scanning. Eligible sources analyzed adults aged ≥65 years (n = 1674) who were ambulatory, used a functional mobility outcome measure, and contained foot and ankle interventions that included IFMS. Literature studies regarding neurological, vestibular, cognitive, amputation, or post-surgical conditions were excluded. Studies that did not specify intrinsic foot muscle involvement were excluded. Two authors extracted relevant studies and appraised them using the Physiotherapy Evidence Database (PEDro) scale. RESULTS A total of 1420 articles were screened for relevance, and 16 were extracted. Five additional sources were obtained through reference scanning. Nine articles were eligible for review. PEDro scores ranged from 3 to 7 (out of 10), indicating "fair" quality of evidence. Heterogeneity of methods and data did not allow for statistical comparison. Themes extracted from sources were types of intrinsic foot strengthening interventions and parameters; outcomes on falls, balance, functional mobility; and subjective reports regarding functional mobility. CONCLUSION Evidence reviewed was of fair quality. IFMS interventions contributed to improvements in strength, balance, mobility, and possibly reduced fall risk. There was little effect on gait. Subjective reports indicate a possible mechanism for improved mobility may be from increased proprioception and sensation.

INTRODUCTION: Motor skills, an important foundation for language and communication, are considerably delayed in children with Down syndrome (DS) and fragile X syndrome (FXS). However, the impact of these impairments on expressive and receptive communication and phenotypic specificity of these associations remains unknown. METHOD: Study participants included 37 children with DS (chronological age(M) (CA(M))=20.38; nonverbal mental age(M) (NVMA(M))=13.19) and 37 children with FXS (CA(M)=19.; NVMA(M)=13.16) matched on chronological and nonverbal mental age. RESULTS: Results showed syndrome-specific profiles across motor and communication domains, where children with DS scored significantly higher than children with FXS on communication domains, but lower on gross motor. Findings revealed significant associations between domains of motor and communication for both groups, but phenotypic specificity in the magnitude of association between fine motor and receptive communication in that the strength of the association was significantly stronger for children with DS. DISCUSSION: Findings demonstrate the importance of early motor abilities for the development of communication for both children with DS and those with FXS. Implications for phenotypic specificity and targeted intervention are discussed.

An external ventricular drain (EVD) training module may improve the knowledge and proficiency of perioperative health care providers (HCPs).We examined knowledge gaps, self-reported comfort in managing EVDs, and improvement in self-assessment scores among HCPs from 7 academic medical centers based on an online EVD training module.Of the 326 HCPs who completed the module, 207 (70.6%) reported being uncomfortable managing EVDs. The median pretest scores were 6 (interquartile range=2), and posttest scores were 8 (interquartile range=1), out of a maximum possible score of 9. The most frequent incorrectly answered questions were: (a) maximum allowed hourly cerebrospinal fluid volume drainage (51%), (b) the components of a normal intracranial pressure waveform (41%), and (c) identifying the correct position of the stopcock for accurate measurement of intracranial pressure (41%). The overall gain in scores was 2 (interquartile range=2) and highest among HCPs who had managed 1 to 25 EVDs (2.51, 95% confidence interval: 2.23-2.80), and without self-reported comfort in managing EVDs (2.26, 95% confidence interval: 1.96-2.33, P0.0001). The majority of participants (312, 95.7%) reported that the training module helped them understand how to manage EVDs, and 276 (84.7%) rated the module 8 or more out of 10 in recommending it to their colleagues.This online EVD training module was well-received by participants. Overall, improved scores reflect enhanced knowledge among HCPs following completion of the module. The greatest benefit was observed in those reporting less experience and feeling uncomfortable in managing EVDs. The impact on the reduction in EVD-associated adverse events deserves further examination.

Purpose: The study purpose was to compare suicide risk between lesbian, gay, bisexual, transgender, queer, and/or questioning (LGBTQ) and non-LGBTQ adolescents in a psychiatric hospital. Methods: D...

Objective To investigate the incidence and risk factors for hypogammaglobulinaemia and infectious complications associated with rituximab treatment in childhood-onset rheumatic diseases. Methods We performed a single-centre retrospective study of patients (n = 85) treated at Boston Children’s Hospital (BCH) from 2009 to 2019. Study subjects included patients (ages 6–24 years) who received rituximab for the treatment of a childhood-onset rheumatic disease. Results New-onset hypogammaglobulinaemia developed in 23 (27.1%) patients within 18 months of rituximab induction treatment. Twenty-two patients (25.9%) developed at least one infectious complication in the 18 months following the first rituximab infusion; of these, 11 (50%) had serious infections requiring inpatient treatment. After adjusting for potential confounders, exposure to pulse corticosteroid therapy in the month prior to rituximab use was a significant predictor of both new-onset hypogammaglobulinaemia (odds ratio [OR] 3.94; 95% CI: 1.07, 16.0; P = 0.044) and infectious complications (OR 15.3; 95% CI: 3.04, 126.8; P = 0.003). Post-rituximab hypogammaglobulinaemia was the strongest predictor of serious infectious complications (OR 7.89; 95% CI: 1.41, 65.6; P = 0.028). Younger age at rituximab use was also a significant predictor of new-onset hypogammaglobulinaemia (OR 0.83; 95% CI: 0.70, 0.97; P = 0.021). Compared with other rheumatic diseases, patients with vasculitis had a higher likelihood of developing infectious complications, including serious infections. Conclusion Although rituximab was well tolerated in terms of infectious complications in the majority of patients with childhood-onset rheumatic diseases, a substantial proportion developed new-onset hypogammaglobulinaemia and infectious complications following treatment. Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinaemia and infections in paediatric patients with rheumatic conditions.

Purpose of review To review diagnosis, clinical characteristics and treatment of multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings MIS-C emerged in spring 2020 as a hyperinflammatory syndrome following SARS-CoV-2 exposure in children. Despite growing awareness of MIS-C, diagnosis remains challenging due to the range of phenotypes and severity. Fever accompanied by shock, cardiac dysfunction, gastrointestinal symptoms, or mucocutaneous signs suggestive of Kawasaki disease, especially in the presence of known or suspected coronavirus disease 2019 exposure, should trigger consideration of MIS-C. However, clinical presentations are highly varied and may overlap with other infectious diseases. Clinicians must maintain a high index of suspicion for MIS-C and be aware that patients may develop coronary artery aneurysms and myocarditis even with few or no Kawasaki disease symptoms. More precise diagnostic criteria and specific biomarkers are needed to aid diagnosis. Intravenous immunoglobulin (IVIG) is first-line therapy, and steroids should be considered as initial adjunctive treatment for patients with severe manifestations or other risk factors. Prompt treatment is essential, as patients may worsen acutely, though overall prognosis is reassuring. Summary MIS-C associated with SARS-CoV-2 has varied clinical manifestations. Clinicians must be aware of the common presentation and potential for decompensation and cardiac sequalae to guide appropriate evaluation and treatment.

ObjectiveThe objectives of this study were to develop and refine EMPOWER (Enhancing and Mobilizing the POtential for Wellness and Resilience), a brief manualized cognitive-behavioral, acceptance-based intervention for surrogate decision-makers of critically ill patients and to evaluate its preliminary feasibility, acceptability, and promise in improving surrogates’ mental health and patient outcomes.MethodPart 1 involved obtaining qualitative stakeholder feedback from 5 bereaved surrogates and 10 critical care and mental health clinicians. Stakeholders were provided with the manual and prompted for feedback on its content, format, and language. Feedback was organized and incorporated into the manual, which was then re-circulated until consensus. In Part 2, surrogates of critically ill patients admitted to an intensive care unit (ICU) reporting moderate anxiety or close attachment were enrolled in an open trial of EMPOWER. Surrogates completed six, 15–20 min modules, totaling 1.5–2 h. Surrogates were administered measures of peritraumatic distress, experiential avoidance, prolonged grief, distress tolerance, anxiety, and depression at pre-intervention, post-intervention, and at 1-month and 3-month follow-up assessments.ResultsPart 1 resulted in changes to the EMPOWER manual, including reducing jargon, improving navigability, making EMPOWER applicable for a range of illness scenarios, rearranging the modules, and adding further instructions and psychoeducation. Part 2 findings suggested that EMPOWER is feasible, with 100% of participants completing all modules. The acceptability of EMPOWER appeared strong, with high ratings of effectiveness and helpfulness (M= 8/10). Results showed immediate post-intervention improvements in anxiety (d= −0.41), peritraumatic distress (d= −0.24), and experiential avoidance (d= −0.23). At the 3-month follow-up assessments, surrogates exhibited improvements in prolonged grief symptoms (d= −0.94), depression (d= −0.23), anxiety (d= −0.29), and experiential avoidance (d= −0.30).Significance of resultsPreliminary data suggest that EMPOWER is feasible, acceptable, and associated with notable improvements in psychological symptoms among surrogates. Future research should examine EMPOWER with a larger sample in a randomized controlled trial.

BACKGROUND: Fruits of Crataegus songarica are commonly used for the treatment of vascular insufficiency and heart problems. OBJECTIVE: Our aim was to determine the effect of C. songarica on vascular tone and to determine the mechanisms underlying the vasorelaxant properties. METHODS: Extracts of C. songarica were tested for vasodilator activity of porcine coronary artery after pre-contraction with the thromboxane mimetic U46619 in the presence or absence of inhibitors of intracellular signaling cascades. Reactive oxygen species were assessed by dihydroethidine staining and the level of eNOS and AKT phosphorylation was measured by immunohistochemical staining. RESULTS: Extracts of C. songarica berries produced endothelium dependent vasorelaxation, with most significant effect induced by aqueous fraction (AS-CS). This vasorelaxant effect of AS-CS was reduced by inhibition of nitric oxide pathways and inhibition of potassium channels. Inhibition of phosphatidylinositol 3- kinase and Src tyrosine kinase, as well as scavenging of reactive oxygen species, produced an attenuation of the relaxation response. Estrogen receptor antagonists (tamoxifen and ICI 182,782) reduced the AS-CS mediated vasorelaxation. AS-CS also stimulated the endothelial formation of ROS and phosphorylation of Akt and eNOS. CONCLUSION: The data indicated that C. songarica produces an endothelium-dependent vasorelaxation, which is partly dependent upon estrogen receptors, and sensitive to inhibition of ROS/Src/PI3K/NO pathways.

Background: Coeliac disease is one of the most prevalent immune-mediated gastrointestinal disorders in children. Aim: To review the incidence and prevalence of paediatric coeliac disease, and their trends, regionally across Europe, overall and according to age at diagnosis. Methods: Systematic review and meta-analysis from January 1, 1950 to December 31, 2019, based on PubMed, CINAHL and the Cochrane Library, searches of grey literature and websites and hand searching of reference lists. A total of 127 eligible studies were included. Results: The prevalence of previously undiagnosed coeliac disease from screening surveys (histology based) ranged from 0.10% to 3.03% (median = 0.70%), with a significantly increasing annual trend (P = 0.029). Prevalence since 2000 was significantly higher in northern Europe (1.60%) than in eastern (0.98%), southern (0.69%) and western (0.60%) Europe. Large increases in the incidence of diagnosed coeliac disease across Europe have reached 50 per 100 000 person-years in Scandinavia, Finland and Spain. The median age at diagnosis increased from 1.9 years before 1990 to 7.6 since 2000. Larger increases in incidence were found in older age groups than in infants and ages

Misrepresenting Race Medical education and practice have not evolved to reflect advances in understanding of the relationships among race, racism, and health. Instead, race remains one of the most ...

Early identification of behavioral risk markers for anxiety is essential to optimize long-term outcomes in children with neurodevelopmental disorders. This study analyzed attentional avoidance and its relation to anxiety and autism spectrum disorder (ASD) symptomatology during social and nonsocial fear conditions in toddlers with fragile X syndrome (FXS) and Down syndrome (DS). Toddlers with FXS and DS exhibited increased nonsocial attentional avoidance relative to typically developing (TD) toddlers. Attentional avoidance was not related to anxiety symptom severity in any group; however, higher ASD symptom severity was related to more social attentional avoidance in the FXS and TD groups. Findings suggest that there may be different underlying mechanisms driving attentional avoidance across neurodevelopmental disorders.

Acute graft-versus-host disease (aGVHD) is a significant complication of allogeneic hematopoietic stem cell transplant (HSCT) and negatively affects T cell reconstitution. Extracorporeal photopheresis (ECP) reduces aGVHD, but the mechanisms remain incompletely understood. Our objective was to examine the impact of ECP on thymopoiesis in pediatric aGVHD and the mechanisms at a cellular and transcriptional level. Sixteen pediatric HSCT patients were recruited: 6 with ECP-treated aGVHD, 5 without aGVHD, and 5 with aGVHD treated with corticosteroids only. Thymopoiesis was evaluated by measuring naive T cells, TRECs, IL-7, and T cell receptor repertoire diversity. Regulatory T cell (Treg) enumeration and function and dendritic cell (DC) enumeration and phenotype were analyzed using flow cytometry. T cell transcriptome analysis was performed on ECP patients after treatment and responders pre- and post-treatment. Four ECP responders demonstrated thymic-dependent T cell recovery, and superior median naïve T cell numbers at 8 and 12 months post-HSCT compared to the aGVHD corticosteroid group. Increased Tregs and Treg suppressive function, reduced cDC/pDC and DC co-stimulatory marker expression in ECP responders suggest upregulated peripheral tolerance; these findings were not observed in partial responders. Responder post-ECP CD3+ T cell transcriptional profile demonstrated 3333 downregulated and 364 upregulated genes, with significant downregulation of ERRα and GαS pathways, and reduced expression of pro-inflammatory and adhesion proteins. Thymic function improves with successful ECP treatment. ECP reduces T cell activation and impacts peripheral tolerance via DCs and Tregs. Differences in thymic recovery, DC, and Treg cellular patterns and the T cell transcriptome were observed between ECP responders and partial responders and require further validation and investigation in additional patients. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-00991-y.

OBJECTIVE To provide a framework for effective mentorship of residents underrepresented in medicine (UIM) situated in the context of their experiences in healthcare teams. DESIGN A perspective summarizing the important elements for the effective mentorship of UIM residents. CONCLUSION Mentorship of trainees is of profound importance in medical education as it provides tangible benefits for professional and personal development. However, given their unique experiences and position in our teams as well as the larger healthcare construct, the mentorship of UIM residents requires special consideration and focus. Implementing programs that foster diversity, cross-cultural mentorship, and sponsorship are imperative.

Introduction Colorectal cancer is the second leading cause of cancer deaths in the USA, and screening tests are underutilized. The aim of this study was to determine the proportion of individuals at average risk who utilized a recommended initial screening test in a universal healthcare coverage system. Materials and Methods This is a retrospective cohort study of active duty and retired military members as well as civilian beneficiaries of the Military Health System. Individuals born from 1960 to 1962 and eligible for full benefits on their 50th birthday were evaluated. Military rank or rank of benefits sponsor was used to determine socioeconomic status. Adherence to the U.S. Preventive Services Task Force guidelines for initial colorectal cancer screening was determined using “Current Procedural Terminology” and “Healthcare Common Procedure Coding System” codes for colonoscopy, sigmoidoscopy, fecal occult blood test, and fecal immunohistochemistry test. Average risk individuals who obtained early screening ages 47 to 49 were also identified. Results This study identified 275,665 individuals at average risk. Of these, 105,957 (38.4%) adhered to screening guidelines. An additional 19,806 (7.2%) individuals were screened early. Colonoscopy (82.7%) was the most common screening procedure. Highest odds of screening were associated with being active duty military (odds ratio [OR] 3.63, 95% confidence interval [CI] 3.43 to 3.85), having highest socioeconomic status (OR 2.37, 95% CI 2.31 to 2.44), and having managed care insurance (OR 4.36, 95% CI 4.28 to 4.44). Conclusions Universal healthcare coverage does not ensure initial colorectal cancer screening utilization consistent with guidelines no does it eliminate disparities.

Fragile X syndrome (FXS) is the most common identifiable cause of inherited intellectual disability and autism spectrum conditions, and is associated with a range of physical, cognitive and behavioural characteristics. Alongside intellectual disability, heightened rates of autism spectrum disorder, anxiety disorders, attention-deficit-hyperactivity disorder, self-injury and aggression are reported. Timely identification of FXS as well as assessments of common co-morbid psychological conditions and underlying health problems are essential to ensure individuals with FXS receive appropriate support. This article provides an overview for clinicians of current literature on the cause of FXS as well as the key physical, cognitive, and behavioural characteristics with a focus on children and adolescents.

This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) for pediatric life support is based on the most extensive evidence evaluation ever performed by the Pediatric Life Support Task Force. Three types of evidence evaluation were used in this review: systematic reviews, scoping reviews, and evidence updates. Per agreement with the evidence evaluation recommendations of the International Liaison Committee on Resuscitation, only systematic reviews could result in a new or revised treatment recommendation. Systematic reviews performed for this 2020 CoSTR for pediatric life support included the topics of sequencing of airway-breaths-compressions versus compressions-airway-breaths in the delivery of pediatric basic life support, the initial timing and dose intervals for epinephrine administration during resuscitation, and the targets for oxygen and carbon dioxide levels in pediatric patients after return of spontaneous circulation. The most controversial topics included the initial timing and dose intervals of epinephrine administration (new treatment recommendations were made) and the administration of fluid for infants and children with septic shock (this latter topic was evaluated by evidence update). All evidence reviews identified the paucity of pediatric data and the need for more research involving resuscitation of infants and children.

OBJECTIVE: This qualitative study sought to obtain feedback from stakeholder cancer caregivers and bereaved family members on the implementation of bereavement risk screening in oncology. METHODS: Semi-structured interviews were conducted with 38 family members of patients with advanced cancer (n=12) and bereaved family members (n=26) on when and how to effectively implement bereavement risk screening. Data was analyzed using thematic analysis. RESULTS: Many participants indicated that they would be open to completing a self-report screening measure before and after the patient's death. Several suggested screening at multiple timepoints and the importance of follow-up. Participants viewed screening as an opportunity to connect to psychosocial support. CONCLUSIONS: The findings suggest that family members appear supportive of sensitively-approached bereavement risk screening before and after a patient's death as an important component of quality psychosocial care. To optimize implementation, bereavement risk screening would involve screening at multiple timepoints and include follow-up. Findings suggest standardized risk screening using a brief, validated self-report tool would be a pragmatic approach to increasing access to bereavement care. This article is protected by copyright. All rights reserved.

Background and Aims: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Approach and Results: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm −5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure

Measure effect of late-afternoon communication and patient planning (CAPP) rounds to increase early electronic discharge orders (EDO).We enrolled 4485 patients discharged from six subspecialty medical services. We implemented late-afternoon CAPP rounds to identify patients who could have morning discharge the subsequent day. After an initial successful implementation of the intervention, we identified lack of sustainability. We made changes with sustained implementation of the intervention. This is a before-after study of a quality improvement intervention.Primary measures of intervention effectiveness were percentage of patients who received EDO by 11 am and patients discharged by noon. Additional measure of effectiveness were percent of patients admitted to the correct ward, emergency department (ED)-to-ward transfer time compared between intervention and nonintervention periods. We compared the overall expected LOS and the average weekly discharges to assess for comparability across the control and intervention time periods. We used the readmission rate as balancing measure to ensure that the intervention was not have unintended negative patients consequences.Expected length of stay based upon discharge diagnosis/comorbidities and readmission rates were similar across the intervention and control time periods. The average weekly discharges were not statistically significant. Percentage of EDO by 11 am was higher in the first intervention period, second intervention period and combined intervention periods (28.9% vs. 21.8%,Afternoon CAPP rounds to identify early patient discharges the following day led to increase in EDO entered by 11 am and discharges by noon without an adverse change in readmission rates and LOS.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is notable for the fusion of chromosomes 9 and 22, forming the BCR-ABL1 gene [1]. This fusion is observed in 20–40% of adult...

Background Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting A total of 48 hospitals in the UK. Participants Women aged 16–39 years with early pregnancy bleeding. Interventions Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. Trial registration Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

ObjectiveThe aim of this study was to identify the rate of 30-day postoperative complications after the use of epidural in women undergoing hysterectomy for gynecologic malignancy. Secondary outcome was the impact of epidural on hospital length of stay.MethodsA retrospective cohort study was conducted using the American College of Surgeons’ National Surgical Quality Improvement Program database. This large dataset includes perioperative risk factors and 30-day post-operative outcomes from more than 680 hospitals. Women who underwent abdominal hysterectomy for a gynecologic malignancy from January 2014 to December 2017 were included. Adult patients (18 years or older) who underwent abdominal hysterectomy were identified using common procedure terminology and international classification of diseases codes. Only laparotomy cases were included, and minimally invasive cases (laparoscopy, transvaginal) were excluded due to the small prevalence of epidural cases in this cohort. All patients received general anesthesia. If patients were noted to have “epidural anesthesia” they were included in the epidural cohort and those receiving other adjuvant techniques (regional blocks or spinal anesthesia) were excluded. The primary outcome of interest was the 30-day occurrence of a pulmonary embolism, deep-vein thrombosis, pneumonia, and urinary tract infection. Those who received epidural analgesia were matched in a 1:1 ratio with a similar group of patients who did not receive epidural analgesia using a calculated propensity score to control for confounding factors.ResultsA total of 2035 (13.8%) patients undergoing abdominal hysterectomy for a gynecologic malignancy received epidural analgesia. 1:1 propensity-matched samples included 2035 patients in both epidural and no-epidural groups. Patient characteristics between groups were similar. Overall 30-day complication rates were higher in the epidural group (75.9% vs 62.0%, PDiscussionThe rate of 30-day complications and length of stay among women undergoing an abdominal hysterectomy for gynecologic malignancy was higher for those who received epidural analgesia, but there was no difference in 30-day mortality. Although epidural analgesia can provide a number of benefits when used for postoperative pain control, the possible association with increased 30-day morbidity and length of stay needs to be considered.

Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically relevant procedures for repair of long segmental lesions (≥ 5 cm) – the deep peroneal nerve repaired using a sural nerve autograft and the common peroneal nerve repaired using a saphenous nerve autograft – each featuring ultra-long total regenerative distances (up to 20 cm and 27 cm, respectively) to reach distal targets. This paper includes a detailed characterization of the relevant anatomy, surgical approach/technique, functional/electrophysiological outcomes, and nerve morphometry for baseline and autograft repaired nerves. These porcine models of major peripheral nerve injury are suitable as preclinical, translatable models for evaluating the efficacy, safety, and tolerability of next-generation artificial nerve grafts prior to clinical deployment.

OBJECTIVES: The purpose of this study was to evaluate quality and safety of care in acute pediatric settings from the perspectives of nurses working at the bedside and to investigate hospital-level factors associated with more favorable quality and safety. METHODS: Using data from a large survey of registered nurses in 330 acute care hospitals, we described nurses’ assessments of safety and quality of care in inpatient pediatric settings, including freestanding children’s hospitals (FCHs) (n = 21) and general hospitals with pediatric units (n = 309). Multivariate logistic regression models were used to estimate the effects of being a FCH on favorable reports on safety and quality before and after adjusting for hospital-level and nurse characteristics and Magnet status. RESULTS: Nurses in FCHs were more likely to report favorably on quality and safety after we accounted for hospital-level and individual nurse characteristics; however, adjusting for a hospital’s Magnet status rendered associations between FCHs and quality and safety insignificant. Nurses in Magnet hospitals were more likely to report favorably on quality and safety. CONCLUSIONS: Quality and safety of pediatric care remain uneven; however, the organizational attributes of Magnet hospitals explain, in large part, more favorable quality and safety in FCHs compared with pediatric units in general acute care hospitals. Modifiable features of the nurse work environment common to Magnet hospitals hold promise for improving quality and safety of care. Transforming nurse work environments to keep patients safe, as recommended by the National Academy of Medicine 20 years ago, remains an unfinished agenda in pediatric inpatient settings.

Background The UK has low levels of breastfeeding initiation and continuation, with evident socioeconomic disparities. To be inclusive, peer-support interventions should be woman-centred rather than breastfeeding-centred. Assets-based approaches to public health focus on the positive capabilities of individuals and communities, rather than their deficits and problems. The Assets-based feeding help Before and After birth (ABA) intervention offers an assets-based approach based on behaviour change theory. Objective To investigate the feasibility of delivering the ABA infant feeding intervention in a randomised controlled trial. Design This was an individually randomised controlled feasibility trial; women were randomised in a 1 : 1 ratio to either the intervention group or the comparator (usual care) group. Setting Two separate English sites were selected because they had an existing breastfeeding peer support service, relatively high levels of socioeconomic disadvantage and low rates of breastfeeding. Participants Women aged ≥ 16 years who were pregnant with their first child, irrespective of feeding intention (n = 103), were recruited by researchers in antenatal clinics. Interventions Proactive, woman-centred support, using an assets-based approach and including behaviour change techniques, was provided by an infant-feeding helper (a breastfeeding peer supporter trained in the ABA intervention) and delivered through face-to-face contact, telephone conversations and text messages. The intervention commenced at around 30 weeks’ gestation and could continue until 5 months postnatally. Main outcome measures The main outcome measures were feasibility of intervention delivery with the requisite intensity and duration; acceptability to women, infant-feeding helpers and maternity services; and feasibility of a future randomised controlled trial. Outcomes included recruitment rates and follow-up rates at 3 days, 8 weeks and 6 months postnatally, and outcomes for a future full trial were collected via participant questionnaires. A mixed-methods process evaluation included qualitative interviews with women, infant-feeding helpers and maternity services; infant-feeding helper logs; and audio-recordings of antenatal contacts to check intervention fidelity. Results Of the 135 eligible women approached, 103 (76.3%) agreed to participate. The study was successful in recruiting teenagers (8.7%) and women living in areas of socioeconomic disadvantage (37.3% resided in the most deprived 40% of small areas in England). Postnatal follow-up rates were 68.0%, 85.4% and 80.6% at 3 days, 8 weeks and 6 months, respectively. Feeding status at 8 weeks was obtained for 95.1% of participants. Recruitment took place from February 2017 until August 2017. It was possible to recruit and train existing peer supporters to the infant-feeding helper role. The intervention was delivered to most women with relatively high fidelity. Among the 50 women in the intervention group, 39 received antenatal visits and 40 received postnatal support. Qualitative data showed that the intervention was acceptable. There was no evidence of intervention-related harms. Limitations Birth notification delays resulted in delays in the collection of postnatal feeding status data and in the offer of postnatal support. In addition, the intervention needs to better consider all infant-feeding types and did not adequately accommodate women who delivered prematurely. Conclusion It is feasible to deliver the intervention and trial. Future work The intervention should be tested in a fully powered randomised controlled trial. Trial registration Current Controlled Trials ISRCTN14760978. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 7. See the NIHR Journals Library website for further project information.

Visual Abstract, Highlights • Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes. • Mutations affecting genes coding for the WAVE2 protein complex and small GTPase-mediated signaling are associated with LVOTO lesions. • WAVE2 complex genes brk1, nckap1, and wasf2 and regulators of small GTPase signaling cul3a and racgap1 are critical to zebrafish heart development., Summary Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

Trial design A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne®, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. Methods Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 μg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. Results A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. Limitations The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. Future work Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. Conclusions Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. Trial registration Current Controlled Trials ISRCTN17405024. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

GBS2 was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (13/82/04). The funder had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. JJD is supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. KSK is a Distinguished Investigator funded by the Beatriz Galindo (senor modality) Program grant given to the University of Granada by the Ministry of Science, Innovation, and Universities of the Spanish Government., Background: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-ofcare rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. Methods: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. Results: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. Conclusion: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits., National Institute for Health Research (NIHR) 13/82/04, NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust University of Birmingham, Beatriz Galindo (senor modality) Program

Highlights • Peer support specialists effectively screen patients for substance use disorder. • Utilizing peer support specialists enhanced feasibility medication initiation. • Emergency room-initiated medication connects patients to treatment., Introduction Evidence suggests emergency department (ED)-initiated buprenorphine as efficacious in connecting ED patients to Medications for Opioid Use Disorder (MOUD) utilizing peer support specialists (PSS). However, there are no reports of implementation of ED-initiated buprenorphine in practice. Such information is crucial to support the adoption of ED-initiated buprenorphine. Methods In this quality improvement pilot study, a PSS screened ED patients over age 18 with the Tobacco, Alcohol, Prescription medication, and other Substance use – 1 (TAPS-1). The PSS considered the patient a positive screen if the patient met the following criteria: risky weekly alcohol use, illicit drugs, or prescription drugs. For patients who screened positive, the PSS delivered a brief intervention and assessed interest in treatment. An ED clinician assessed patients who screened positive for heroin/opioid use and were interested in treatment for buprenorphine induction. Results From January through June 2019, 1037 patients were screened for risky substance use, and, of these, 238 (23%) screened positive. The distribution of primary substance used was: 51% alcohol, 26% cannabis, 7.5% cocaine, 7.5% heroin, and 3.3% prescription opioids. Of the 23 patients who screened positive for heroin/opioid use and requested treatment, seven were admitted to the hospital. Of the remaining 16 patients, 14 patients wanted buprenorphine treatment, seven were provided buprenorphine in the ED, and four of these attended their intake appointments for community-based MOUD treatment. Conclusion ED-initiated buprenorphine facilitated by a PSS is feasible and requires coordination and planning. Approaches to ED-initiated buprenorphine that screen only for opioid use will miss many patients interested in substance use treatment.1

Objectives Eighteen years ago, the Institute of Medicine estimated that medical errors in hospital were a major cause of mortality. Since that time, reducing patient harm and improving the culture of patient safety have been national health care priorities. The study objectives were to describe the current state of patient safety in pediatric acute care settings and to assess whether modifiable features of organizations are associated with better safety culture. Methods An observational cross-sectional study used 2015-2016 survey data on 177 hospitals in four U.S. states, including pediatric care in general hospitals and freestanding children's hospitals. Pediatric registered nurses providing direct patient care assessed hospital safety and the clinical work environment. Safety was measured by items from the Agency for Healthcare Research and Quality's Culture of Patient Safety survey. Hospital clinical work environment was measured by the National Quality Forum-endorsed Practice Environment Scale. Results A total of 1875 pediatric nurses provided an assessment of safety in their hospitals. Sixty percent of pediatric nurses gave their hospitals less than an excellent grade on patient safety; significant variation across hospitals was observed. In the average hospital, 46% of nurses report that mistakes are held against them and 28% do not feel safe questioning authority regarding unsafe practices. Hospitals with better clinical work environments received better patient safety grades. Conclusions The culture of patient safety varies across U.S. hospital pediatric settings. In better clinical work environments, nurses report more positive safety culture and higher safety grades.

Fragile X syndrome (FXS) is the leading known genetic cause of autism spectrum disorder (ASD) with 60–74% of males with FXS meeting diagnostic criteria for ASD. Infants with FXS have demonstrated atypical neural responses during face processing that are unique from both typically developing, low-risk infants and infants at high familial risk for ASD (i.e., infants siblings of children with ASD). In the current study, event-related potential (ERP) responses during face processing measured at 12 months of age were examined in relation to ASD symptoms measured at ~48 months of age in participants with FXS, as well as siblings of children with ASD and low-risk control participants. Results revealed that greater amplitude N290 responses in infancy were associated with more severe ASD symptoms in childhood in FXS and in siblings of children with ASD. This pattern of results was not observed for low-risk control participants. Reduced Nc amplitude was associated with more severe ASD symptoms in participants with FXS but was not observed in the other groups. This is the first study to examine ASD symptoms in childhood in relation to infant ERP responses in FXS. Results indicate that infant ERP responses may be predictive of later symptoms of ASD in FXS and the presence of both common and unique pathways to ASD in etiologically-distinct high-risk groups is supported (i.e., syndromic risk vs. familial risk).

This chapter discusses hallucinogen-related disorders, a set of conditions and disorders described within the Substance-Related Disorders section of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. The DSM-5 differentiates between phencyclidine-like substances (e.g., phencyclidine [PCP], ketamine, etc.) and other hallucinogens. The latter includes a number of substances with similar cognitive, perceptual, and psychological effects, despite having different chemical structures and molecular mechanisms (e.g., mescaline, psilocybin, lysergic acid diethylamide [LSD], and 3,4-methylenedioxymethamphetamine [MDMA]). The clinical vignettes presented highlight a broad range of possible clinical manifestations of hallucinogen use, including acute intoxication and substance-specific use disorders, as well as unique features that distinguish hallucinogens from other psychoactive substances of clinical interest. Acute management and long-term treatment considerations are discussed. The growing body of scientific literature associated with hallucinogen-assisted psychotherapy will be briefly noted but is beyond the scope of this chapter and the nosology presented in the DSM-5.

Background Fractional laser treatment was introduced in 2004 as a non-invasive technique to treat sun-damaged and aging skin. Since then, numerous ablative and non-ablative photothermolysis technologies and devices have been introduced, increasing the options for clinicians and patients but also increasing the complexity regarding which system to use and the techniques to optimize outcomes. No two devices are the same and the user-manuals preset dosimetry does not address many clinical situations, which can create confusion for new and inexperienced users. Methods An online survey addressing use of a 1550 nm /1927 nm dual wavelength, non-ablative, fractional laser was sent to eight (8) US board certified dermatologists with extensive experience in the use of the device. The survey included 39 questions, addressing experience, best practices and recommendations for use. Results The survey data suggests that the device can be used to treat patients of all ages and skin types for indications including photoaging and photodamage, periorbital wrinkles, freckles, (ephelides), solar lentigines, poikiloderma, scarring due to acne or surgery. It can be used on both facial and non-facial areas, including neck, chest, hands, arms, abdomen, legs, and buttocks. Unexpected and adverse effects were rarely reported and those that did were mild and transient. Conclusions This position paper provides practical real-world guidelines resulting from a small survey of experienced users, for new and early uses of the novel 1550 nm /1927 nm dual wavelength, non-ablative, fractional laser. J Drugs Dermatol. 2021;20(11):1150-1157. doi:10.36849/JDD.6181.

Wnt signalling is an evolutionary conserved signal transduction pathway heavily implicated in normal development and disease. The central mediator of this pathway, β-catenin, is frequently overexpressed, mislocalised and overactive in acute myeloid leukaemia (AML) where it mediates the establishment, maintenance and drug resistance of leukaemia stem cells. Critical to the stability, localisation and activity of β-catenin are the protein-protein interactions it forms, yet these are poorly defined in AML. We recently performed the first β-catenin interactome study in blood cells of any kind and identified a plethora of novel interacting partners. This study shows for the first time that β-catenin interacts with Wilms tumour protein (WT1), a protein frequently overexpressed and mutated in AML, in both myeloid cell lines and also primary AML samples. We demonstrate crosstalk between the signalling activity of these two proteins in myeloid cells, and show that modulation of either protein can affect expression of the other. Finally, we demonstrate that WT1 mutations frequently observed in AML can increase stabilise β-catenin and augment Wnt signalling output. This study has uncovered new context-dependent molecular interactions for β-catenin which could inform future therapeutic strategies to target this dysregulated molecule in AML.Article summaryβ-Catenin is frequently dysregulated in acute myeloid leukemia (AML) and protein interactions govern its stability, localization and activity, but these are poorly defined in AML.This study shows for the first time that β-catenin and Wilms tumour protein (WT1) interact and influence each other’s expression level and signalling activity in AML cells, which could inform future therapeutic strategies.

PurposeThe Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar.ResultsUpdated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications.ConclusionThe development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.

Introduction: Fear of cancer recurrence (FCR) is a prevalent and persistent challenge that many cancer survivors endure. While the role of interpretation bias, a tendency to perceive ambiguous situations as threatening, has been established in the onset and maintenance of FCR, few studies have examined cancer-related interpretation bias specifically. Grounded in the cognitive formulation of FCR, the current study aimed to fill this gap by investigating the relationship between cancer-related interpretation bias, FCR, and somatic symptoms, and examining whether bias mediates the relationship between somatic symptoms and FCR.Materials and Methods: This study used baseline data from a randomized controlled trial of a cognitive bias modification intervention. Breast cancer survivors (n = 110) provided demographic and medical background information as well as self-report measures of FCR and severity of somatic symptoms. A computer-based assessment of interpretation bias was used to measure cancer-related interpretation bias on several bias indices: percentage of cancer-related threat endorsement, and percentage of benign endorsement; mean reaction time (RT) for threat, and mean RT for benign endorsement.Results: Higher threat endorsement was linked to higher Overall Fear and emerged as a mediator of the relationship between overall somatic symptoms and Overall Fear. We also found that older age was related to longer benign endorsement RT.Conclusion: This study contributes understanding of factors related to cancer-related interpretation bias and provides evidence that bias may influence the relationship between somatic symptoms and FCR in cancer survivors.

Insulin-like growth factor (IGF)-1 plays important role in tissue repair through its ability to stimulate wound cell activity. While IGF-1 is expressed locally by wound cells, liver-derived IGF-1 is also present at high levels in the circulation, and the contributions of local vs circulating IGF-1 to wound levels remain undefined. The hypothesis of this study was that liver is a primary source of IGF-1 during skin wound healing. To test this hypothesis, we utilized a model that allows inducible ablation of IGF-1 specifically in liver of adult mice. We demonstrate that ablation of liver IGF-1 leads to >85% loss of circulating IGF-1 and ~60% decrease in wound IGF-1 during the proliferative phase of healing in both male and female mice. This reduction of liver-derived IGF-1 did not alter local mRNA expression of Igf1 in wounds. Knockdown of liver IGF-1 significantly delayed wound re-epithelialization and reduced granulation tissue formation and collagen deposition. Knockdown of liver IGF-1 also significantly reduced angiogenesis and resulted in persistent macrophage accumulation. In summary, liver is a primary source of IGF-1 in skin wounds and contributes to many aspects of both epithelial and dermal healing.

Background:HeterozygousTTNtruncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of the splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized asTTNtruncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain.Methods:Rare variants of unknown significance located in the splice regions of highly expressedTTNexons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay.Results:Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (P=0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance inTTNsplice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site (P=4.4×107) and position -3 of the acceptor site (P=0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%–95%) but poor sensitivity (15%–50%) for the detection of splice-altering variants. Alternate exons spliced out of mostTTNtranscripts frequently lacked the consensus base at +5 donor and −3 acceptor positions.Conclusions:Noncanonical splice-altering variants inTTNexplain 1-2% of DCM and offer a 10-20% increase in the diagnostic power ofTTNsequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternateTTNexons.

Multisystem inflammatory syndrome in children following severe acute respiratory syndrome coronavirus 2 infection is characterized by fever, elevated inflammatory markers, and multisystem organ involvement. Presentations are variable but often include gastrointestinal symptoms. We describe 5 children with fever and gastrointestinal symptoms initially concerning for multisystem inflammatory syndrome in children who were ultimately diagnosed with bacterial enteritis, highlighting the diagnostic challenges presented by the severe acute respiratory syndrome coronavirus 2 pandemic.

[Figure][1] Jaqueline A. Noonan, MD, passed away on July 23, 2020, at age 91 years. Over those years, she led a fulfilling life in the care for children. She was born on October 28, 1928, in Burlington, Vermont, but moved to Hartford, Connecticut, at age 9 months. At age 5 years, she

Background and objective Nitrous oxide has long been used recreationally for its ability to induce euphoria and other deliriant effects. In modern times, it remains a popular, legal, and widely available option for those seeking altered states. Though substance-induced psychotic symptoms have been mentioned in the literature, the potential long-term negative neuropsychiatric effects related to its use have not been well established. Methods and results This is a patient case report of a young man (N = 1) who initially presented with acute neurological symptoms requiring hospitalization due to heavy nitrous oxide inhalant use, and went on to present with symptoms concerning for a primary psychotic illness over multiple inpatient admissions. He provided both verbal and written consent to share his story for this case report. Discussion and conclusions It is important to consider nitrous oxide use as a possible contributing factor to the development of primary psychotic illness. Scientific significance Current literature suggests that psychosis associated with nitrous oxide use is transient and resolves upon cessation and treatment of vitamin B12 deficiency. Here, we present a patient with risk factors for psychotic illness developing psychotic illness following extensive nitrous oxide use. This report offers a unique perspective of longitudinal follow-up (often not provided with reports on this topic), and illustrates the importance of healthcare providers inquiring about nitrous oxide abuse in patients presenting with early psychotic symptoms. (Am J Addict 2020;00:00-00).

Photodynamic therapy [dye-light therapy] is an excellent technique for use in detection and treatment of cancerous tissues. While this therapy is effective, it is limited by the phototoxic reactions that can occur in the surrounding normal tissues. These damaging side effects are of particular importance when treating neurosensory organs, such as the human eye. We report here new treatment strategies to enhance photodynamic effectiveness while limiting side effects to normal tissues.

ObjectiveTo date, nearly 10,000 World Trade Center (WTC) responders have been diagnosed with at least one type of WTC-related cancer, and over 70 types of cancer have been related to WTC occupational exposure. Due to the observed latency period for malignancies, the WTC Health Program anticipates increases in rates of new cancer diagnoses. Given the growing number of cancer diagnoses in this population, there is an urgent need to develop a novel intervention to address the psychosocial needs of WTC responders with cancer. Meaning-centered psychotherapy (MCP) is a structured psychotherapeutic intervention originally developed to help patients with advanced cancer find and sustain meaning in life despite illness-related limitations. Existential distress and loss of meaning are critical and understudied elements of psychological health that have been widely overlooked among WTC responders with cancer.MethodWe have adapted MCP for WTC responders (MCP-WTC) for the treatment of WTC responders who have been diagnosed with WTC-certified cancers. MCP-WTC aims to target the complex crisis in meaning faced by those responders who responded to the 9/11 attacks and subsequently were diagnosed with cancer as a result of their service.ResultsWe describe the adaptation of MCP-WTC and the application of this intervention to meet the unique needs of those exposed to the terrorist attacks of September 11, 2001 (9/11), participated in the rescue, recovery, and clean-up effort at Ground Zero, and were diagnosed with WTC-related cancer. We highlight the novel aspects of this intervention which have been designed to facilitate meaning-making in the context of the patient's response to 9/11 and subsequent diagnosis of cancer.Significance of resultsThis work provides a rationale for MCP-WTC and the potential for this intervention to improve the quality of life of WTC responders and help these patients navigate life after 9/11 and cancer.

Working with research animals exposes employees to emotionally demanding work and moral stressors. The emotional impact of animal research is similar to that of working with human patients, and is similarly associated with burnout (BNO) or compassion fatigue (CF), which can lead to psychosomatic symptoms, pervasive states of stress, workplace conflict, and at its most extreme, suicidal ideation. One remedy for such feelings is increasing the satisfaction one feels from performing one's job well, known as compassion satisfaction (Csat). To address these occupational health concerns in an academic research setting, the Ohio State University's Lab Animal Resources (ULAR) study team reviewed existing preventative programing both internal and external to the university. Subsequently, a survey was distributed to all staff members to assess the following factors: employee awareness of free resources already available to them, association between staff demographics and the experience of BNO and/or CF, and the employee's own mitigation recommendations. Respondents were mostly female, in 20 to 49 age range, with 0 to 4 y in the field. Of those responding, 81.6% specified that they had experienced BNO and CF alone, together, or in combination with CSat. Factors statistically associated (P < 0.05) with BNO and CF were age, number of years in the field, and number of animals euthanized per year. A relative risk analysis was also used to identify protective factors. Only the age of respondents appeared to be a protective factor— the 50+ age group had 88.57% (RR = 0.1143) reduction in risk for experiencing BNO and/or CF. Participant suggestions indicated that employees would like improvements to the work environment, more novel work experiences, and more positive feedback from department leadership. The social ecological model, a public health model for program interventions, was used as a framework for the development of recommendations to mitigate BNO and CF while increasing CSat. The recommendations were customized for ULAR employees based on the survey findings.

OBJECTIVE: There has been a growth in popularity of hookah (or waterpipes) among American college students, despite the health risks. This study investigated factors that predict hookah susceptibility and whether hookah susceptibility predicts hookah initiation and continued use. METHOD: The study established a cohort of 529 incoming college freshmen (51.6% female) who completed an online survey approximately 1 week before their arrival to a large U.S. university. Students were sent four follow-up surveys throughout the 2016–2017 academic year; 90.5% completed at least one follow-up survey. RESULTS: A total of 13.2% of the sample had used hookah at baseline and 9.9% initiated hookah use over the course of their freshman year. Among the nonusers who had no hookah susceptibility at baseline, 30.0% came to indicate some susceptibility. Multivariable logistic regression indicated that the personality construct conscientiousness was protective against becoming susceptible, whereas coming from a rural part of the state was a risk factor. Susceptibility predicted both continued use among the baseline ever-users and initiation among the baseline never-users. CONCLUSIONS: These findings highlight the role of susceptibility in the trajectory of hookah use among U.S. college students.