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Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation., Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA)., Results: As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile)., Interpretation: Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Vaccines have historically played a pivotal role in controlling epidemics. Effective vaccines for viruses causing significant human disease, e.g. , Ebola, Lassa fever, or Crimean Congo hemorrhagic fever virus, would be invaluable to public health strategies and counter-measure development missions. Here, we propose coverage metrics to quantify vaccine-induced CD8 + T cell-mediated immune protection, as well as metrics to characterize immuno-dominant epitopes, in light of human genetic heterogeneity and viral evolution. Proof-of-principle of our approach and methods are demonstrated for Ebola virus, SARS-CoV-2, and Burkholderia pseudomallei (vaccine) proteins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest., (Copyright © 2024 Harris, Shanker, Montoya, Llewellyn, Matuszak, Lohar, Kubicek-Sutherland, Li, Wilding, Mcmahon, Gnanakaran, Ribeiro, Perelson and Molina-París.)

Objectives: In 2016, the Department of Veterans Affairs (VA) and the Department of Energy (DOE) established an Interagency Agreement (IAA), the Million Veteran Program-Computational Health Analytics for Medical Precision to Improve Outcomes Now (MVP-CHAMPION) research collaboration., Materials and Methods: Oversight fell under the VA Office of Research Development (VA ORD) and DOE headquarters. An Executive Committee and 2 senior scientific liaisons work with VA and DOE leadership to optimize efforts in the service of shared scientific goals. The program supported centralized data management and genomic analysis including creation of a scalable approach to cataloging phenotypes. Cross-cutting methods including natural language processing, image processing, and reusable code were developed., Results: The 79.6 million dollar collaboration has supported centralized data management and genomic analysis including a scalable approach to cataloging phenotypes and launched over 10 collaborative scientific projects in health conditions highly prevalent in veterans. A ground-breaking analysis on the Summit and Andes supercomputers at the Oak Ridge National Laboratory (ORNL) of the genetic underpinnings of over 2000 health conditions across 44 million genetic variants which resulted in the identification of 38 270 independent genetic variants associating with one or more health traits. Of these, over 2000 identified associations were unique to non-European ancestry. Cross-cutting methods have advanced state-of-the-art artificial intelligence (AI) including large language natural language processing and a system biology study focused on opioid addiction awarded the 2018 Gordon Bell Prize for outstanding achievement in high-performance computing. The collaboration has completed work in prostate cancer, suicide prevention, and cardiovascular disease, and cross-cutting data science. Predictive models developed in these projects are being tested for application in clinical management., Discussion: Eight new projects were launched in 2023, taking advantage of the momentum generated by the previous collaboration. A major challenge has been limitations in the scope of appropriated funds at DOE which cannot currently be used for health research., Conclusion: Extensive multidisciplinary interactions take time to establish and are essential to continued progress. New funding models for maintaining high-performance computing infrastructure at the ORNL and for supporting continued collaboration by joint VA-DOE research teams are needed., Competing Interests: None declared., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2024.)

Objective: No study has examined outcomes derived from blood flow restriction exercise training interventions using regulated compared with unregulated blood flow restriction pressure systems. Therefore, we used a systematic review and meta-analyses to compare the chronic adaptations to blood flow restriction exercise training achieved with regulated and unregulated blood flow restriction pressure systems., Data Sources: The electronic database search included using the tool EBSCOhost and other online database search engines. The search included Medline, SPORTDiscus, CINAHL, Embase and SpringerLink., Methods: Included studies utilised chronic blood flow restriction exercise training interventions greater than two weeks duration, where blood flow restriction was applied using a regulated or unregulated blood flow restriction pressure system, and where outcome measures such as muscle strength, muscle size or physical function were measured both pre- and post-training. Studies included in the meta-analyses used an equivalent non-blood flow restriction exercise comparison group., Results: Eighty-one studies were included in the systematic review. Data showed that regulated ( n  = 47) and unregulated ( n  = 34) blood flow restriction pressure systems yield similar training adaptations for all outcome measures post-intervention. For muscle strength and muscle size, this was reaffirmed in the included meta-analyses., Conclusion: This review indicates that practitioners may achieve comparable training adaptations with blood flow restriction exercise training using either regulated or unregulated blood flow restriction pressure systems. Therefore, additional factors such as device quality, participant comfort and safety, cost and convenience are important factors to consider when deciding on appropriate equipment to use when prescribing blood flow restriction exercise training., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. We present GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks when GWAS thresholds are relaxed. GRIN was validated on both simulated interrelated gene sets as well as multiple GWAS traits. From multiple GWAS summary statistics of suicide attempt, a complex phenotype, GRIN identified additional genes that replicated across independent cohorts and retained biologically interrelated genes despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways that may influence suicidal behavior, and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate GRIN's utility in boosting GWAS results by increasing the number of true positive genes identified from GWAS results., (© 2024. The Author(s).)

Issue Addressed: Australian veterans suffer higher rates of both mental and physical health conditions than civilians, yet many do not seek treatment. Computerised Interventions (CIs) may provide an alternative approach to management, which can overcome some barriers to treatment uptake. We aim to evaluate the scope and quality of CIs designed specifically for Australian veterans and their families., Methods: A manual search of the Department of Veterans' Affairs and other Ex-service organisation websites was performed to map and describe CIs for Australian veterans and their families, followed by a scoping review of four databases to identify evaluations of relevant CIs., Results: Our search identified 10 CIs specific to Australian veterans and their families. The majority were structured, self-guided CIs, designed to elicit cognitive/behavioural change that addressed mental health and psychosocial needs during transition. Three evaluations examined previously identified CIs. The results showed mixed reviews from participants and clinicians, in two separate evaluations, regarding user experience, quality and perceived benefit. In addition, positive psychological outcomes, including the reduction of post-traumatic stress disorder (PTSD) symptoms, were demonstrated for participants of the online intervention., Conclusion: While Australian veteran-centric online interventions primarily focus on psychological conditions, the prevalent physical health concerns within the veteran population remain unaddressed. Additionally, despite the documented impact of military experience on family members, there is a lack of specific Australian interventions designed for families. Few tools have been formally evaluated, yet show promise as supportive self-directed resources for veterans with PTSD, and for navigating transition challenges. SO WHAT?: Further development of online interventions addressing prevalent physical and family needs, and conduction of comprehensive evaluations are needed to enhance overall quality, accessibility and holistic effectiveness of interventions for the Australian veteran community., (© 2023 The Authors. Health Promotion Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of Australian Health Promotion Association.)

Background and Objectives: Anxiety related school avoidance can affect up to 5% of a country's students each year. VRET (Virtual Reality Exposure Therapy) is a novel therapy proven to be as effective as conventional approaches for treating many anxiety disorders. The aim of this research is to co-design and evaluate a VRET intervention for students experiencing school related anxiety., Method: Eighteen adolescents participated in design thinking workshops where they developed a script and storyboard for the VRET. Using an iterative approach, a VRET prototype was developed based on this work. Eighteen teenagers were subsequently recruited to engage with the VRET for one session each and provide feedback on their experience via a structured questionnaire (supervised by a study coordinator) particularly focusing on the ability of the VR experience to reduce school related anxiety., Results: Exposure therapy needs to produce an anxiety response to be effective. The VRET was effective in producing an anxiety response in 89% of participants. Results demonstrated that 93% of participants found the simulations immersive, 94% found the scenarios believable, and 83% could relate to 'Dala', the avatar in the videos. 100% of participants believed that VRET would help with school anxiety., Conclusion: This proof-of-concept study demonstrates favourable face validity indicating promise for this mode of intervention for delivering targeted support to anxious students. VRET could be used as a scalable, cost effective early intervention to reduce the severity of anxiety associated with school avoidance.

Background: An electronic health record-based tool could improve accuracy and eliminate bias in provider estimation of the risk of death from other causes among men with nonmetastatic cancer., Objective: To recalibrate and validate the Veterans Aging Cohort Study Charlson Comorbidity Index (VACS-CCI) to predict non-prostate cancer mortality (non-PCM) and to compare it with a tool predicting prostate cancer mortality (PCM)., Design, Setting, and Participants: An observational cohort of men with biopsy-confirmed nonmetastatic prostate cancer, enrolled from 2001 to 2018 in the national US Veterans Health Administration (VA), was divided by the year of diagnosis into the development (2001-2006 and 2008-2018) and validation (2007) sets., Outcome Measurements and Statistical Analysis: Mortality (all cause, non-PCM, and PCM) was evaluated. Accuracy was assessed using calibration curves and C statistic in the development, validation, and combined sets; overall; and by age (<65 and 65+ yr), race (White and Black), Hispanic ethnicity, and treatment groups., Results and Limitations: Among 107 370 individuals, we observed 24 977 deaths (86% non-PCM). The median age was 65 yr, 4947 were Black, and 5010 were Hispanic. Compared with CCI and age alone (C statistic 0.67, 95% confidence interval [CI] 0.67-0.68), VACS-CCI demonstrated improved validated discrimination (C statistic 0.75, 95% CI 0.74-0.75 for non-PCM). The prostate cancer mortality tool also discriminated well in validation (C statistic 0.81, 95% CI 0.78-0.83). Both were well calibrated overall and within subgroups. Owing to missing data, 18 009/125 379 (14%) were excluded, and VACS-CCI should be validated outside the VA prior to outside application., Conclusions: VACS-CCI is ready for implementation within the VA. Electronic health record-assisted calculation is feasible, improves accuracy over age and CCI alone, and could mitigate inaccuracy and bias in provider estimation., Patient Summary: Veterans Aging Cohort Study Charlson Comorbidity Index is ready for application within the Veterans Health Administration. Electronic health record-assisted calculation is feasible, improves accuracy over age and Charlson Comorbidity Index alone, and might help mitigate inaccuracy and bias in provider estimation of the risk of non-prostate cancer mortality., (Published by Elsevier B.V.)

We evaluated factors associated with the presence of hepatitis A virus antibodies 23 years after initiating vaccination at ages 6-15 months. Among 67 participants, 86% (42/49) of those vaccinated at ages 12-15 months and 61% (11/18) of those vaccinated at 6 months remained seropositive at 23 years. Lack of maternal antibodies at enrollment and higher initial vaccine response were independently associated with higher antibody concentrations at 23 years. Further research is needed to assess the duration of hepatitis A vaccine protection and possible need for a booster dose., Competing Interests: Potential conflicts of interest. All authors reported having no conflicts of interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

The hardware for data archiving has expanded capacities for digital storage enormously in the past decade or more. The IUCr evaluated the costs and benefits of this within an official working group which advised that raw data archiving would allow ground truth reproducibility in published studies. Consultations of the IUCr's Commissions ensued via a newly constituted standing advisory committee, the Committee on Data. At all stages, the IUCr financed workshops to facilitate community discussions and possible methods of raw data archiving implementation. The recent launch of the IUCrData journal's Raw Data Letters is a milestone in the implementation of raw data archiving beyond the currently published studies: it includes diffraction patterns that have not been fully interpreted, if at all. The IUCr 75th Congress in Melbourne included a workshop on raw data reuse, discussing the successes and ongoing challenges of raw data reuse. This article charts the efforts of the IUCr to facilitate discussions and plans relating to raw data archiving and reuse within the various communities of crystallography, diffraction and scattering., (open access.)

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Appendicitis typically presents with characteristic symptoms such as right lower quadrant abdominal pain, localizing to McBurney's point, facilitating diagnosis. Here, we report a case of a 19-year-old female who exhibited atypical manifestations, including lower abdominal pain and associated hematochezia. Despite inconclusive findings from imaging modalities and laboratory investigations, persistent pain prompted exploratory laparotomy, revealing appendicitis. This case highlights the diagnostic challenge posed by variant presentations of appendicitis, emphasizing the importance of clinical judgment and vigilance in surgical decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Patel et al.)

Objective: There is a growing consensus that the risks of current pharmacologic analgesics warrant consideration of alternative modalities for acute and chronic pain control. The objective of this study was to evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) in adult emergency department (ED) patients presenting with abdominal pain., Methods: We conducted a patient and observer blinded randomized controlled trial comparing TENS to sham TENS. The study was conducted at a large suburban academic ED. Patients with abdominal pain and a verbal numeric pain scale (VNS) of 5 or greater were randomized to TENS or sham TENS applied via 4 skin pads, one in each abdominal quadrant for 30 min. The primary outcome was change in pain scores 30 min after the intervention. Our study had 80% power to detect a between group difference of 1.5 points on the VNS., Results: 81 patients were randomized to TENS (n = 41) or sham TENS (n = 40). Groups were similar in baseline characteristics. The mean (SD) reductions in pain scores were 1.9 (2.1) and 1.7 (2.6) in patients treated with TENS and sham TENS respectively (P = 0.81). Use of rescue medications in patients with treated with TENS and sham TENS was similar (49 vs 55% respectively, P = 0.66)., Conclusions: Application of TENS to the abdominal wall did not result in more effective pain relief than sham TENS in adult ED patients with abdominal pain., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Interoperability of crystallographic data with other disciplines is essential for the smooth and rapid progress of structure-based science in the computer age. Within crystallography and closely related subject areas, there is already a high level of conformance to the generally accepted FAIR principles (that data be findable, accessible, interoperable and reusable) through the adoption of common information exchange protocols by databases, publishers, instrument vendors, experimental facilities and software authors. Driven by the success within these domains, the IUCr has worked closely with CODATA (the Committee on Data of the International Science Council) to help develop the latter's commitment to cross-domain integration of discipline-specific data. The IUCr has, in particular, emphasized the need for standards relating to data quality and completeness as an adjunct to the FAIR data landscape. This can ensure definitive reusable data, which in turn can aid interoperability across domains. A microsymposium at the IUCr 2023 Congress provided an up-to-date survey of data interoperability within and outside of crystallography, expounded using a broad range of examples., (open access.)

Objective: To apply deep neural networks (DNNs) to longitudinal EHR data in order to predict suicide attempt risk among veterans. Local explainability techniques were used to provide explanations for each prediction with the goal of ultimately improving outreach and intervention efforts., Materials and Methods: The DNNs fused demographic information with diagnostic, prescription, and procedure codes. Models were trained and tested on EHR data of approximately 500 000 US veterans: all veterans with recorded suicide attempts from April 1, 2005, through January 1, 2016, each paired with 5 veterans of the same age who did not attempt suicide. Shapley Additive Explanation (SHAP) values were calculated to provide explanations of DNN predictions., Results: The DNNs outperformed logistic and linear regression models in predicting suicide attempts. After adjusting for the sampling technique, the convolutional neural network (CNN) model achieved a positive predictive value (PPV) of 0.54 for suicide attempts within 12 months by veterans in the top 0.1% risk tier. Explainability methods identified meaningful subgroups of high-risk veterans as well as key determinants of suicide attempt risk at both the group and individual level., Discussion and Conclusion: The deep learning methods employed in the present study have the potential to significantly enhance existing suicide risk models for veterans. These methods can also provide important clues to explore the relative value of long-term and short-term intervention strategies. Furthermore, the explainability methods utilized here could also be used to communicate to clinicians the key features which increase specific veterans' risk for attempting suicide., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2023.)

In a comparison between 50 Alaska Native persons with chronic hepatitis B who cleared HBV surface antigen (HBsAg) and 50 Alaska Native age-, sex-, and HBV genotype-matched controls, we found differences in changes in HBV DNA and HBV RNA levels over time but no difference in hepatitis B core-related antigen. These findings suggest that serial HBV DNA and HBV RNA may be associated with HBV functional cure defined by HBsAg clearance., (© 2023 John Wiley & Sons Ltd.)

Background: In 2014, a change in the water source in Flint, Michigan, exposed residents to dangerous levels of lead in their drinking water. The concern for lead toxicity created the opportunity for pharmacies to provide quick and accessible blood lead testing services., Objective: The primary objective was to create a pharmacy-based blood lead testing program through collaboration with the Michigan Department of Health & Human Services and community pharmacies in Flint, Michigan., Practice Description: The partnership was established in 2016 and Magellan LeadCare II blood analyzers were placed at three pharmacies. Walk-in testing was offered from June 2016 to August 2016., Practice Innovation: Community pharmacists aimed to provide more accessible lead screening services to limit health disparities and medical complications., Evaluation Methods: A retrospective analysis using descriptive statistics was conducted to assess the benefits of early blood lead screening and to determine when a patient should seek further evaluation. Blood lead screening values were based on the Center for Disease Control (CDC) and Prevention's blood lead reference value (BLRV). The BLRV at the time of the study was ≥ 5 μg/dL, but this was eventually changed to ≥3.5 μg/dL., Results: A total of 77 individuals were screened in the pharmacies. Four (5%) individuals had lead levels ≥5 μg/dL. Of these, two patients were <6 years of age. Fifteen (19%) patients had lead levels ≥3.5 μg/dL. The highest lead level detected was 24.2 μg/dL in a 70-year-old patient. If the result was ≥5 μg/dL, patients were instructed to follow up with their physician or the Genesee County Health Department. All patients with elevated blood levels were referred to the appropriate health care provider., Conclusion: This model demonstrates the feasibility of a public health/community pharmacy collaborative lead testing program. This program can serve as a template for future crisis-focused collaborative models., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Despite a recent global decrease in suicide rates, death by suicide has increased in the United States. It is therefore imperative to identify the risk factors associated with suicide attempts to combat this growing epidemic. In this study, we aim to identify potential risk factors of suicide attempt using geospatial features in an Artificial intelligence framework., Methods: We use iterative Random Forest, an explainable artificial intelligence method, to predict suicide attempts using data from the Million Veteran Program. This cohort incorporated 405,540 patients with 391,409 controls and 14,131 attempts. Our predictive model incorporates multiple climatic features at ZIP-code-level geospatial resolution. We additionally consider demographic features from the American Community Survey as well as the number of firearms and alcohol vendors per 10,000 people to assess the contributions of proximal environment, access to means, and restraint decrease to suicide attempts. In total 1,784 features were included in the predictive model., Results: Our results show that geographic areas with higher concentrations of married males living with spouses are predictive of lower rates of suicide attempts, whereas geographic areas where males are more likely to live alone and to rent housing are predictive of higher rates of suicide attempts. We also identified climatic features that were associated with suicide attempt risk by age group. Additionally, we observed that firearms and alcohol vendors were associated with increased risk for suicide attempts irrespective of the age group examined, but that their effects were small in comparison to the top features., Discussion: Taken together, our findings highlight the importance of social determinants and environmental factors in understanding suicide risk among veterans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (At least a portion of this work is authored by David W. Oslin, Jean C. Beckham and Nathan A. Kimbrel on behalf of the U.S. Government and as regards Dr Oslin, Dr. Beckham, Dr. Kimbrel and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

Background and Aim: High autoimmune hepatitis (AIH) and overlap syndrome (OS) prevalence have been previously documented among Alaska Native people. The purpose of this project is to report changes in AIH/OS prevalence over time, clinical characteristics, and factors associated with biochemical remission., Methods: We reviewed medical records for Alaska Native/American Indian (AN/AI) patients diagnosed with AIH/OS between 1984 and 2021. Point prevalence was calculated based on AIH/OS patients alive at the end of 2021 and at 5-year intervals from July 1, 2000, to July 1, 2020., Results: We identified 189 AN/AI persons diagnosed with AIH or OS (157 AIH, 32 OS). Of these 189, 137 were alive at the end of 2021 for a point prevalence of 91.2 per 100 000 (95% confidence interval [CI]: 77.2-107.8)-75.9 (95% CI: 63.2-91.2) for AIH and 15.3 (95% CI: 10.2-23.0) for OS. Prevalence for both AIH and OS has risen steadily since 2000. Eighty-nine consented participants (62.7%) achieved biochemical remission with a median time from diagnosis to start of remission of 1.9 years (IQR 0.5-5.0 years). Consented patients with fatty liver were less likely to achieve remission, but their time to remission was shorter than for patients without fatty liver., Conclusion: The AN/AI population in Alaska continues to have the highest reported prevalence of AIH/OS in the world, with prevalence rising steadily since 2000. High reported AIH/OS prevalence is likely due in part to strong referral networks for liver disease. Detection and treatment can lead to biochemical remission and improved health outcomes., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, analyzed the entire expressed transcriptome in whole blood from children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25). Analyses revealed 3,420 up-regulated and 3,442 down-regulated transcripts, signifying impairments in host inflammasome activation, cell death, innate immune responses, and cellular stress responses in SMA. Immune cell profiling showed a decreased antigenic and immune priming response in children with SMA, favoring polarization toward cellular proliferation and repair. Enrichment analysis further identified altered neutrophil and autophagy-related processes, consistent with neutrophil degranulation and altered ubiquitination and proteasome degradation. Pathway analyses highlighted SMA-related alterations in cellular homeostasis, signaling, response to environmental cues, and cellular and immune stress responses. Validation with a qRT-PCR array showed strong concordance with the sequencing data. These findings identify key molecular themes in SMA pathogenesis, providing potential targets for new malaria therapies., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines., Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas., Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up., Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued., (©2023 American Association for Cancer Research.)

Background There is a Registered Nurse (RN) shortage across the United States that is predicted to intensify in the upcoming years. RNs are an integral part of Emergency Departments (EDs) and perform many vital tasks, including IV placement, blood draws, medication administration, acute assessments, and patient hand-offs. Thus, RN staffing is a crucial part of ED operations, and ED initiatives should account for RN workforce shortages. Given the increase in ED visits and crowding, throughput initiatives that can expedite patient care are integral to the functioning of an ED. Team Triage is a throughput initiative that has been shown to improve ED time to provider, length of stay, and left without being seen rates. In our institution, we created a Team Triage model where advanced practice providers (APPs) perform a patient's initial evaluation in triage and place orders for labs, intravenous (IV) catheters, and imaging. Given the RN staffing shortage, we incorporated Licensed Practical Nurses (LPNs) in Team Triage to place IV catheters and draw blood work for laboratory tests. The objective of this investigation was to describe a Team Triage model that incorporated LPNs and to report the patient safety and productivity of this model. Methods This was a single-site retrospective study at a large, academic, tertiary care center with over 100,000 annual visits. Adult patients who self-presented to the ED and went through Team Triage (11 am-11 pm) between Jan 1, 2020, and Jan 31, 2020, were included in this study. LPNs staffed the Team Triage, along with APPs. LPNs placed IV catheters and drew blood specimens for the Team Triage patients. The primary outcomes studied were the proportion of specimens mislabeled by LPNs, the proportion of patients receiving IV catheters, the proportion of patients receiving blood work, blood tubes drawn per hour, and IVs inserted per hour in Team Triage. Results During the study period, 1355 patients went through Team Triage. Of these patients, 1075 (79%) were ordered for blood work, and 1017 (75%) were ordered for an IV catheter. All Team Triage blood work and IV catheter placements were completed by LPNs, who staffed 372 hours of Team Triage. A total of 2558 blood tubes were collected by LPNs. The LPNs cared for 2.9 patients per hour, collected 6.9 blood tubes per hour, inserted 2.7 IV catheters per hour, and collected 2.4 blood tubes per patient. The LPNs had a 0% specimen mislabeling rate. Conclusion Due to the significant RN workforce shortage impacting Emergency Medicine coupled with increased ED crowding, there is a significant need to evaluate the integration of LPNs into Team Triage to place IV catheters and perform blood draws. This study shows that incorporating LPNs in Team Triage is a productive and safe way to address nursing shortages in Emergency Medicine., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Heslin et al.)

HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework's 5 domains (biological, behavioral, physical/built environment, sociocultural environment, and health care system) and 4 levels (individual, interpersonal, community, and societal) of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies., (© The Author(s) 2023. Published by Oxford University Press.)

A 35-Year-Old Man with FeverA 35-year-old man presented for evaluation of fever for 2 weeks with left-sided abdominal pain. How do you approach the evaluation, and what is the diagnosis?

The risk of developing venous thromboembolism (VTE) is four to seven times higher in patients with cancer than in those without. At JADPRO Live 2022, presenters discussed risk factors and assessing patients for VTE, as well as how to protect patients against VTE in both the inpatient and outpatient clinic settings. They reviewed selecting an appropriate anticoagulation treatment, including the choice of agent and duration of treatment for the patient with cancer, and finally the steps needed to assess and treat patients experiencing therapeutic anticoagulation failure., Competing Interests: Ms. Halsema has no relevant financial relationships to disclose. Dr. McMahon has served as a consultant for CTI Biopharma and Curio Science., (© 2023 Harborside™.)

The COVID-19 pandemic has highlighted a need for better understanding of countries' vulnerability and resilience to not only pandemics but also disasters, climate change, and other systemic shocks. A comprehensive characterization of vulnerability can inform efforts to improve infrastructure and guide disaster response in the future. In this paper, we propose a data-driven framework for studying countries' vulnerability and resilience to incident disasters across multiple dimensions of society. To illustrate this methodology, we leverage the rich data landscape surrounding the COVID-19 pandemic to characterize observed resilience for several countries (USA, Brazil, India, Sweden, New Zealand, and Israel) as measured by pandemic impacts across a variety of social, economic, and political domains. We also assess how observed responses and outcomes (i.e., resilience) of the COVID-19 pandemic are associated with pre-pandemic characteristics or vulnerabilities, including (1) prior risk for adverse pandemic outcomes due to population density and age and (2) the systems in place prior to the pandemic that may impact the ability to respond to the crisis, including health infrastructure and economic capacity. Our work demonstrates the importance of viewing vulnerability and resilience in a multi-dimensional way, where a country's resources and outcomes related to vulnerability and resilience can differ dramatically across economic, political, and social domains. This work also highlights key gaps in our current understanding about vulnerability and resilience and a need for data-driven, context-specific assessments of disaster vulnerability in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Beesley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

A prototype application for machine-readable literature is investigated. The program is called pyDataRecognition and serves as an example of a data-driven literature search, where the literature search query is an experimental data set provided by the user. The user uploads a powder pattern together with the radiation wavelength. The program compares the user data to a database of existing powder patterns associated with published papers and produces a rank ordered according to their similarity score. The program returns the digital object identifier and full reference of top-ranked papers together with a stack plot of the user data alongside the top-five database entries. The paper describes the approach and explores successes and challenges., (open access.)

Suicide is a major public health problem affecting US Veterans and the US in general. Many variables (e.g., demographic, clinical, biological, geographic) have been associated with risk for suicide and suicidal behavior, including altitude; however, the exact nature of the relationship between altitude and suicide remains unclear in part due to the fact that previous studies have used either geospatial data or individual-level data, but not both. Prior research has also failed to consider the full range of suicidal thoughts and behaviors, ranging from suicidal ideation to suicide deaths. Accordingly, the objective of the present research was to use both geospatial data (county and zip codes) and individual-level data to comprehensively assess the association between altitude and suicide mortality, suicide attempts, and suicidal ideation among US Veterans between 2000 and 2018. Taken together, our results demonstrate that there is a strong correlation between altitude and suicide rates at all the levels investigated and using different statistical analyses and even after controlling for significant covariates such as percent of age >50yr, percent male, percent white, percent non-Hispanic, median household income, and population density. We show that there is a positive correlation between altitude and suicide attempts especially when controlling by the covariates and a weak correlation between altitude and suicide ideation and the combination of suicide, suicide attempts and suicide ideation., (Published by Elsevier Ltd.)

Many mathematical models have been proposed to predict death following the Coronavirus Disease 2019 (COVID-19); all started with comorbidity subsets for this still-little understood disease. Thus, we derived a novel predicted probability of death model (PDeathDx) upon all diagnostic codes documented in the Department of Veterans Affairs. We present the conceptual underpinnings and analytic approach in estimating the independent contribution of pre-existing conditions. This is the largest study to-date following patients with COVID-19 to predict mortality. Cases were identified with at least one positive nucleic acid amplification test. Starting in 1997, we use diagnoses from the first time a patient sought care until 14 days before a positive nucleic acid amplification test. We demonstrate the clear advantage of using an unrestricted set of pre-existing conditions to model COVID-19 mortality, as models using conventional comorbidity indices often assign little weight or usually do not include some of the highest risk conditions; the same is true of conditions associated with COVID-19 severity. Our findings suggest that it is risky to pick comorbidities for analysis without a systematic review of all those experienced by the cohort. Unlike conventional approaches, our comprehensive methodology provides the flexibility that has been advocated for comorbidity indices since 1993; such an approach can be readily adapted for other diseases and outcomes. With our comorbidity risk adjustment approach outperforming conventional indices for predicting COVID-19 mortality, it shows promise for predicting outcomes for other conditions of interest., (Published by Oxford University Press 2022.)

Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet-induced obesity model in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits that may contribute to the development of diastolic dysfunction in mouse hearts. Cardiomyocyte-specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Waste electrical and electronic equipment (WEEE) presents the dual characteristic of containing both hazardous substances and valuable recoverable materials. Mainly found in WEEE plastics, brominated flame retardants (BFRs) are a component of particular interest. Several actions have been taken worldwide to regulate their use and disposal, however, in countries where no regulation is in place, the recovery of highly valuable materials has promoted the development of informal treatment facilities, with serious consequences for the environment and the health of the workers and communities involved. Hence, in this review we examine a wide spectrum of aspects related to WEEE plastic management. A search of legislation and the literature was made to determine the current legal framework by region/country. Additionally, we focused on identifying the most relevant methods of existing industrial processes for determining BFRs and their challenges. BFR occurrence and substitution by novel BFRs (NBFRs) was reviewed. An emphasis was given to review the health and environmental impacts associated with BFR/NBFR presence in waste, consumer products, and WEEE recycling facilities. Knowledge and research gaps of this topic were highlighted. Finally, the discussion on current trends and proposals to attend to this relevant issue were outlined.

Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe 2+ ) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation. Under chronic hypoxia, oxidative stress drives oxidation of sGC heme (Fe 2+ →Fe 3+ ), rendering it NO-insensitive. We previously showed that cytochrome b5 reductase 3 (CYB5R3) in SMC is a sGC reductase important for maintaining NO-dependent vasodilation and conferring resilience to systemic hypertension and sickle cell disease-associated pulmonary hypertension. To test whether CYB5R3 may be protective in the context of chronic hypoxia, we subjected SMC-specific CYB5R3 knockout mice (SMC CYB5R3 KO) to 3 weeks hypoxia and assessed vascular and cardiac function using echocardiography, pressure volume loops and wire myography. Hypoxic stress caused 1) biventricular hypertrophy in both WT and SMC CYB5R3 KO, but to a larger degree in KO mice, 2) blunted vasodilation to NO-dependent activation of sGC in coronary and pulmonary arteries of KO mice, and 3) decreased, albeit still normal, cardiac function in KO mice. Overall, these data indicate that SMC CYB5R3 deficiency potentiates bilateral ventricular hypertrophy and blunts NO-dependent vasodilation under chronic hypoxia conditions. This implicates that SMC CYB5R3 KO mice post 3-week hypoxia have early stages of cardiac remodeling and functional changes that could foretell significantly impaired cardiac function with longer exposure to hypoxia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The most prevalent mental health diagnosis is anxiety disorder, which remains largely undertreated., Objective: This investigation considered differences in workplace discrimination against adults with anxiety disorders during two eras of legal history: the original Americans with Disabilities Act (ADA, 1990-2008) and the ADA Amendments Act (ADAAA, 2009-present)., Method: Research questions addressed differential (a) numbers and types of allegations, (b) case resolutions, and (c) demographic characteristics of the charging parties., Results: Results indicated substantially more allegations and merit-based resolutions filed by charging parties with anxiety disorders post-ADAAA. Furthermore, the post-ADAAA era revealed increases in allegations from women and people from non-white racial groups., Conclusion: These findings can inform advocacy and counseling and rehabilitation services for clients who experience anxiety.

Hepatitis B virus (HBV) infection remains a global health threat. The World Health Organization (WHO) established a goal to eliminate HBV infection as a public health threat by 2030, and defined targets for key interventions to achieve that goal. We evaluated HBV burden and relevant national recommendations for progress towards WHO targets in circumpolar countries. Viral hepatitis experts of circumpolar countries were surveyed regarding their country's burden of HBV, achievement of WHO targets and national public health authority recommendations for HBV prevention and control. Eight of nine circumpolar countries responded. All countries continue to see new HBV infections. Data about HBV prevalence and progress in reaching WHO 2030 elimination targets are lacking. No country was able to report data for all seven WHO target measures. All countries have recommendations targeting the prevention of mother-to-child transmission. Only the USA and Greenland recommend universal birth dose vaccination. Four countries have recommendations to screen persons at high risk for HBV. Existing recommendations largely address prevention; however, recommendations for universal birth dose vaccination have not been widely introduced. Opportunities remain for the development of trackable targets and national elimination planning to screen and treat for HBV to reduce incidence and mortality.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

Objective: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD., Conclusions: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the least deadly but most infectious coronavirus strain transmitted from wild animals. It may affect many organ systems. Aim of the current guideline is to delineate the effects of SARS-CoV-2 on the liver. Asymptomatic aminotransferase elevations are common in coronavirus disease 2019 (COVID-19) disease. Its pathogenesis may be multifactorial. It may involve primary liver injury and indirect effects such as "bystander hepatitis," myositis, toxic liver injury, hypoxia, and preexisting liver disease. Higher aminotransferase elevations, lower albumin, and platelets have been reported in severe compared with mild COVID-19. Despite the dominance of respiratory disease, acute on chronic liver disease/acute hepatic decompensation have been reported in patients with COVID-19 and preexisting liver disease, in particular cirrhosis. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a higher risk of respiratory disease progression than those without MAFLD. Alcohol-associated liver disease may be severely affected by COVID-19-such patients frequently have comorbidities including metabolic syndrome and smoking-induced chronic lung disease. World Gastroenterology Organization (WGO) recommends that interventional procedures such as endoscopy and endoscopic retrograde cholangiopancreatography should be performed in emergency cases or when they are considered strictly necessary such as high risk varices or cholangitis. Hepatocellular cancer surveillance may be postponed by 2 to 3 months. A short delay in treatment initiation and non-surgical approaches should be considered. Liver transplantation should be restricted to patients with high MELD scores, acute liver failure and hepatocellular cancer within Milan criteria. Donors and recipients should be tested for SARS-CoV-2 and if found positive donors should be excluded and liver transplantation postponed until recovery from infection.

Purpose: The goal of the research was to describe discrimination, both actual and perceived, that has occurred against younger individuals with cancer (i.e., 35 years of age and under) in comparison with older individuals with cancer (i.e., over age 35) through analysis of the US Equal Employment Opportunity Commission (EEOC) Integrated Mission System (IMS) database., Methods: An ex post facto, causal comparative quantitative design was used to examine Americans with Disabilities Act Amendments Act (ADAAA) Title I complaints received by the EEOC from younger people with cancer from 2009 through 2016 (n = 1001) in comparison with older people with cancer over the same time period (n = 8874)., Results: Results revealed statistically significant differences in the patterns of issues alleged by the two groups. When compared with older charging parties with cancer, the younger charging parties with cancer had proportionally more individuals who were male and who identified as African American and proportionally fewer individuals who identified as Caucasian., Conclusions: Younger people with cancer were more likely to allege discrimination in the areas of promotion, training, reinstatement, and referrals to other employers. They were less likely to allege discrimination in the area of benefits. The younger group was also significantly less likely than the older group to find that EEOC investigations of their allegations resulted in merit-based case resolutions, that is, discrimination had indeed occurred., Implications for Cancer Survivors: Psychosocial programs and vocational programming assisting young adults with career development should focus on the types of discrimination that young adults experience, which is unique compared with older adult cancer survivors.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Background: The Pennsylvania Youth Survey (PAYS) is administered biennially to adolescents; it covers knowledge, attitudes, and behaviors about risk and protective factors., Purpose: This study explored 8th, 10th, and 12th grade students' attitudes and beliefs about current trends regarding drugs, alcohol, and mental health., Methods: We asked persons a series of questions in semi-structured focus groups (102 participants) while they were being presented with the PAYS data., Results: Participants expressed significant insight on root causes of risk behaviors. They recommended a decreased emphasis on grades and class rank, and recommended addressing mental health stigma, educating about vaping and marijuana effects, and obtaining support from families, schools, and communities., Conclusion: Youth expressed interest in being an integral part of the planning and decision-making efforts that impact them. Our results support the Whole School, Community, and Child (WSCC) model., (© 2020, American School Health Association.)

To determine the duration of immunity provided by the Hepatitis A vaccination (HepA), we evaluated a cohort of participants in Alaska 20 years after being immunized as infants. At recruitment, participants received two doses of inactivated HepA vaccine on one of three schedules. We conducted hepatitis A antibody (anti-HAV) testing for participants at the 20-year time-point. Seventy-five of the original 183 participants (41%) were available for follow-up. The overall anti-HAV geometric mean concentration was 29.9 mIU/mL (95% CI 22.4 mIU/mL, 39.7 mIU/mL) and 50 participants (68%) remained seropositive (titer ≥ 20 mIU/mL). Using a fractional polynomial model, the predicted percent seropositive at 25 years was 55.3%, 49.8% at 30 years and 45.7% at 35 years, suggesting that the percent sero-positive could drop below 50% earlier than previously expected. Further research is necessary to understand if protection continues after seropositivity diminishes or if a HepA booster dose may become necessary., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Anti-CRISPRs (Acrs) are small proteins that inhibit the RNA-guided DNA targeting activity of CRISPR-Cas enzymes. Encoded by bacteriophage and phage-derived bacterial genes, Acrs prevent CRISPR-mediated inhibition of phage infection and can also block CRISPR-Cas-mediated genome editing in eukaryotic cells. To identify Acrs capable of inhibiting Staphylococcus aureus Cas9 (SauCas9), an alternative to the most commonly used genome editing protein Streptococcus pyogenes Cas9 (SpyCas9), we used both self-targeting CRISPR screening and guilt-by-association genomic search strategies. Here we describe three potent inhibitors of SauCas9 that we name AcrIIA13, AcrIIA14, and AcrIIA15. These inhibitors share a conserved N-terminal sequence that is dispensable for DNA cleavage inhibition and have divergent C termini that are required in each case for inhibition of SauCas9-catalyzed DNA cleavage. In human cells, we observe robust inhibition of SauCas9-induced genome editing by AcrIIA13 and moderate inhibition by AcrIIA14 and AcrIIA15. We also find that the conserved N-terminal domain of AcrIIA13-AcrIIA15 binds to an inverted repeat sequence in the promoter of these Acr genes, consistent with its predicted helix-turn-helix DNA binding structure. These data demonstrate an effective strategy for Acr discovery and establish AcrIIA13-AcrIIA15 as unique bifunctional inhibitors of SauCas9., Competing Interests: Competing interest statement: The Regents of the University of California have patents pending for CRISPR technologies on which the authors are inventors. J.A.D. is a co-founder of Caribou Biosciences, Editas Medicine, Intellia Therapeutics, Scribe Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific advisory board member of Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Synthego, Felix Biosciences, Mammoth Biosciences, and Inari. J.A.D. is a Director at Johnson & Johnson and has sponsored research projects supported by Pfizer and Biogen., (Copyright © 2020 the Author(s). Published by PNAS.)