Search

AIMS: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies.METHODS AND RESULTS: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers.CONCLUSIONS: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies.TRANSLATIONAL PERSPECTIVE: Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Intra-articular injections are routinely performed to alleviate pain and inflammation associated with osteoarthritis in horses. Intra-articular injections require accurate needle placement to optimize clinical outcomes and minimize complications. This study’s objectives were to develop and validate a three-dimensional (3D) printed model of an equine cervical articular process joint to teach ultrasound-guided injections. Five identical models of an equine cervical articular process joint were 3D printed and embedded in 10% ballistic gelatin. Experts’ and novices’ ability to successfully insert a needle into the joint space of the model using ultrasound guidance was assessed and graded using an objective structured clinical examination (OSCE). Scores from experts and novices were compared to evaluate the construct validity of the model. Participants also answered a survey assessing the face and content validity of the model. Experts required less time (22.51 seconds) for correct needle placement into the model joint space than novices (35.96 seconds); however, this difference was not significant ( p = .53). Experts’ median total OSCE score (14) was significantly higher ( p = .03) than novices’ (12), supporting the model’s construct validity. Participants agreed on the face and content validity of the model by grading all survey questions greater than 7 on a 10-point Likert-type scale. In summary, we successfully developed a 3D printed model of an equine cervical articular process joint, partially demonstrated the construct validity of the model, and proved the face and content validity of this new training tool.

Background Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce. Methods In the VRONI study, children aged 5–14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members. Results Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024. Conclusions VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020).

Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab Importance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P

Purpose To report real-world complications associated with femtosecond laser-assisted cataract surgery (FLACS). Setting De-identified database. Design Retrospective review of adverse events associated with FLACS reported to the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. Methods The MAUDE database was culled for adverse events involving ophthalmic femtosecond laser during cataract surgery from January 2010 to January 2020. Reports in which the narrative description was inadequate to determine the nature of the complication were excluded. Each report was reviewed for complications, which were subsequently assigned to a complication category as determined by these authors. The number of events per year was determined and compared. Results Between January 2010 and January 2020, the MAUDE database search yielded 2,927 reports involving femtosecond laser, of which 1,927 met inclusion criteria and were included for analysis. These reports revealed 2,704 complications: 1,115 capsule tears (41.2%), 329 of which required vitrectomy, 372 instances of suction loss, 321 other capsulotomy-related complications, and 432 corneal or incisional complications. Rare complications included 54 reports of miosis, 16 reports of endophthalmitis, and 4 reports of toxic anterior segment syndrome. The number of events in the MAUDE database increased year over year between 2011 and 2017, peaking in 2017 at 303 events. Conclusions By drawing on real-world data in the MAUDE database, this study identifies the complications of greatest importance in clinical practice. Surgeons should be aware of the spectrum of possible complications in order to best prepare for all potential outcomes and to effectively counsel patients.

Background Following the publication of 2014 consensus statement regarding mass critical care during public health emergencies, much has been learned about surge responses and the care of overwhelming numbers of patients during the COVID-19 pandemic.1 Gaps in prior pandemic planning were identified and require modification in the midst of ongoing surge throughout the world. Methods The Task Force for Mass Critical Care (TFMCC) adopted a modified version of established rapid guideline methodologies from the World Health Organization2 and the Guidelines International Network-McMaster Guideline Development Checklist.3 With a consensus development process incorporating expert opinion to define important questions and extract evidence, TFMCC developed relevant pandemic surge suggestions in a structured manner, incorporating peer-reviewed literature, “gray” evidence from lay media sources, and anecdotal experiential evidence. Results Ten suggestions were identified regarding staffing, load-balancing, communication, and technology. Staffing models are suggested with resilience strategies to support critical care staff. Intensive care unit (ICU) surge strategies and strain indicators are suggested to enhance ICU prioritization tactics to maintain contingency level care and avoid crisis triage, with early transfer strategies to further load-balance care. We suggest intensivists and hospitalists be engaged with the incident command structure to ensure two-way communication, situational awareness, and the use of technology to support critical care delivery and families of patients in intensive care units (ICUs). Conclusions A subcommittee from the Task Force for Mass Critical Care offers interim evidence-informed operational strategies to assist hospitals and communities to plan for and respond to surge capacity demands from COVID-19.

We report on the development of a two-channel digital coherent optics (DCO) module, based on a monolithic InP photonic integrated circuit (PIC) transceiver and SiGe application-specific integrated circuit (ASIC), paired with a real-time 7 nm digital signal processing (DSP) ASIC. The high-performance coherent optical engine, which utilizes digital Nyquist subcarriers and probabilistic constellation shaping (PCS) techniques, enables long-haul and ultra-long-haul transmission distances over mixed fiber and amplifier types. This work discusses the performance of a DCO unit operating at multiple data rates over three practical real-world-like network distances. 800 Gb/s data transmission over a 1,000 km standard single mode fiber link was achieved using a 96 GBd, PCS-64QAM modulation format. Results of extended reaches of over 2,400 km and 5,000 km are also presented with data rates of 600 Gb/s and 400 Gb/s, respectively.

A high level of information asymmetry is characterizing for venture capital investments making new information about entrepreneurial companies especially valuable for a venture capitalist’s valuation process. This paper uses text classification and text mining methodology to extract structured data about capital allocation plans in a unique sample of 1,550 European funding rounds that serves as proxy for the private informational updates shared with investors by entrepreneurs. We show that venture capitalists incorporate the content and specificity of information into their valuation process. Further, results confirm that the value of new information is dependent on the prevailing level of information asymmetry.

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P

Aims The aim of this study was to investigate the efficacy and safety of ticagrelor monotherapy in patients undergoing percutaneous coronary intervention (PCI) stratified according to the baseline white blood cell (WBC) count. Methods and results This is a post hoc analysis of the GLOBAL LEADERS trial, a multi-centre, open-label, randomized all-comer trial in patients undergoing PCI, comparing the experimental strategy (23-month ticagrelor monotherapy following 1-month dual anti-platelet therapy [DAPT]) with the reference strategy (12-month aspirin monotherapy following 12-month DAPT). Patients were stratified into two WBC groups, either < or ≥median WBC count of 7.8 × 109 cells/L (lower or higher WBC group, respectively). The primary endpoint was a composite of all-cause mortality or new Q-wave myocardial infarction at 2 years. Of 14 576 patients included in the present study, 7212 patients (49.5%) were classified as the lower WBC group, who had a significantly lower risk of both ischaemic and bleeding outcomes at 2 years. At 2 years, the experimental strategy was associated with a significant lower incidence of the primary endpoint compared with the reference strategy in the lower WBC group [2.8% vs. 4.2%; hazard ratio (HR): 0.67; 95% confidence interval (CI): 0.52–0.86] but not in the higher WBC group (4.8% vs. 4.7%; HR: 1.01; 95% CI: 0.82–1.25; Pinteraction=0.013). There were no significant differences in the risks of Bleeding Academic Research Consortium type 3 or 5 bleeding between two anti-platelet strategies regardless of the WBC groups. Conclusion Increased WBC counts, which may reflect degree of inflammation, at the time of index procedure may attenuate the anti-ischaemic benefits of ticagrelor monotherapy observed in patients with lower WBC counts.

Background The Surgeon General oversees the Commissioned Corps of the U.S. Public Health Service (USPHS) and is viewed as the “Nation’s Doctor,” responsible for providing the public with information on living healthier and safer lives. The Surgeon General’s influence is seen through public health initiatives such as warning labels on tobacco and alcohol products. The objectives of this paper are to describe the tradition of the Office of the Surgeon General as created by Dr John M. Woodworth and to describe the careers of Dr C. Everett Koop and Dr Richard H. Carmona—the only 2 surgeons by training to hold the role. Methods This is a historical literature review using a combination of primary and secondary sources. Results Dr Woodworth set the priorities and responsibilities of the Surgeon General’s Office: education, public service, sanitation, and public health. Dr Koop is widely regarded as the most influential Surgeon General of all time. He was both a pioneer in pediatric surgery and a highly influential public figure, issuing landmark reports on smoking, violence, and AIDS. Dr Carmona is a trauma surgeon by training and focused on the dangers of second-hand smoke as Surgeon General. Dr Carmona served in a more political role as Surgeon General, eventually running for Senate at the end of his term. Conclusion This brief review of the history of the Surgeon General’s Office highlights the contributions of the first Surgeon General and the only 2 surgeons who have held the position.

Objective: The objective of this study was to examine postpartum, inpatient mother-lactation educator (LE) breastfeeding education, resulting perceptions, and patient-reported worries and outcomes. In the breastfeeding literature, there is inadequate insight into the mother-LE relationship, and specifically, the extent to which contextual factors are elicited and information is tailored accordingly. In this study, we were specifically interested in maternal contextual factors. Materials and Methods: Using a mixed methods approach, we (1) captured 20 postpartum, inpatient mother-LE breastfeeding education sessions and analyzed them for the presence of maternal contextual factors, (2) administered separate perception questions to mothers and LEs, and (3) conducted 13 follow-up interviews with mothers after being discharged from the hospital. Results: Inpatient breastfeeding education is delivered in dynamic and busy clinical settings, characterized by potential distractions such as delivery of medical care. Maternal contextual factors are infrequently elicited during the education. Although both LEs and mothers rate the sessions positively, potential gaps remain as highlighted by the analyses of semistructured interviews with mothers. Conclusion: Human factors perspective, theories, and methods are relevant to the characterization of facilitators and barriers of current breastfeeding education, as well as to the development of interventions to support the delivery of human-centered, effective, and timely breastfeeding education.

While religion and spirituality (R/S) have been linked to positive mental health outcomes, most studies have employed cross-sectional designs, which do not allow one to evaluate the utility of R/S in predicting these outcomes. To address this gap, this study analyzed data from a 7-year nationally representative, prospective cohort study of U.S. military veterans to examine the effects of R/S on the development of incident mental health outcomes in this population. Specifically, we examined the association between organizational religious activity (ORA), non-organizational religious activity (NORA), and intrinsic religiosity (IR), and the risk of incident PTSD, suicidal ideation (SI), and hazardous drinking (HD). Multivariable logistic regression analyses revealed that ORA predicted a lower incidence of PTSD and SI; NORA a greater risk of developing HD; and IR a lower risk of developing HD. These results suggest that religion and spirituality, assessed in a nationally representative sample of military veterans, predict risk of developing PTSD, SI, and HD, over and above sociodemographic factors and perceived social support. Clinical implications and strategies for incorporating R/S into mental health assessment and interventions in this population are discussed.

Access to high-quality health care, including mental health care, remains a high priority for the Department of Veterans Affairs and civilian health care systems. Increased access to mental health care is associated with improved outcomes, including decreased suicidal behavior. Multiple policy changes and interventions are being developed and implemented to improve access to mental health care. The Perceived Access Inventory (PAI) is a patient-centered questionnaire developed to understand the veteran perspective about access to mental health services. The PAI is a self-report measure that includes 43 items across 5 domains: Logistics (6 items), Culture (4 items), Digital (9 items), Systems of Care (13 items), and Experiences of Care (11 items). This article is a preliminary examination of the concurrent and convergent validity of the PAI with respect to the Hoge Perceived Barriers to Seeking Mental Health Services scale (concurrent) and the Client Satisfaction Questionnaire (CSQ; convergent). Telephone interviews were conducted with veterans from 3 geographic regions. Eligibility criteria included screening positive for posttraumatic stress disorder, alcohol use disorder, or depression in the past 12 months. Data from 92 veterans were analyzed using correlation matrices. PAI scores were significantly correlated with the Hoge total score (concurrent validity) and CSQ scores (convergent validity). The PAI items with the strongest correlation with CSQ were in the Systems of Care domain and the weakest were in the Logistics domain. Future efforts will evaluate validity using larger data sets and utilize the PAI to develop and test interventions to improve access to care. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

We present Golden Gate, an FPGA-based simulation tool that decouples the timing of an FPGA host platform from that of the target RTL design. In contrast to previous work in static time-multiplexing of FPGA resources, Golden Gate employs the Latency-Insensitive Bounded Dataflow Network (LI-BDN) formalism to decompose the simulator into subcomponents, each of which may be independently and automatically optimized. This structure allows Golden Gate to support a broad class of optimizations that improve resource utilization by implementing FPGA-hostile structures over multiple cycles, while the LI-BDN formalism ensures that the simulator still produces bit- and cycle-exact results. To verify that these optimizations are implemented correctly, we also present LIME, a model-checking tool that provides a push-button flow for checking whether optimized subcomponents adhere to an associated correctness specification, while also guaranteeing forward progress. Finally, we use Golden Gate to generate a cycle-exact simulator of a multi-core SoC, where we reduce LUT utilization by up to 26% by coercing multi-ported, combinationally read memories into simulation models backed by time-multiplexed block RAMs, enabling us to simulate 50% more cores on a single FPGA.

Purpose To report the clinical and refractive outcomes of a modified Yamane technique for scleral fixation of the CT Lucia 602 lens. Design Retrospective case series. Patients One hundred twenty-one eyes with dislocated posterior chamber lens implants, surgical aphakia, subluxed crystalline lenses, capsular tear, anterior chamber, or iris sutured posterior chamber lens intolerance were included. Methods Secondary implantation of the Zeiss CT Lucia 602 lens was performed by a single surgeon using a modified Yamane technique employing a single needle, rather than the double-needle approach. One hundred twelve eyes underwent simultaneous 3 port pars plana vitrectomy and 9 eyes had previously undergone posterior vitrectomy surgery. Exclusion criteria were age

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

The editorial of this second issue of the Journal of Awareness-Based Systems Change is entitled "Moving from Transactional to Relational," which we read as one of the central themes running through all of the contributions in this issue. In amplifying the voices of the authors, we contend that we have been confined and restrained by western and hegemonic notions of rationalism, reductionism, empiricism, mechanism, dualism, and causality for too long. Speaking from a relational body of knowing the various contributions assembled here represent attempts to reevaluate the ontological and epistemological positions and foundations that make up the fabric of social institutions and systems. They also suggest ways forward that hold the potential to tap into and activate the transformative potential that lies within people and systems.

Background Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI‐PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI‐PEG 20 and PLD in patients with metastatic solid tumors. Methods Patients with advanced ASS1‐deficient solid tumors were enrolled in this phase 1 trial of ADI‐PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI‐PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. Results Of 15 enrolled patients, 9 had metastatic HER2‐negative breast carcinoma. We observed no dose‐limiting toxicities or treatment‐related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression‐free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti‐ADI‐PEG 20 antibodies by week 8 in one third of patients. Conclusion Concurrent IM injection of ADI‐PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1‐deficient solid tumors. Further evaluation of this combination is under discussion., This combination therapy with ADI‐PEG 20 and Doxil had a reversible and manageable toxicity profile, and patients tolerated the treatment. Tumor shrinkage and prolonged duration of therapy were observed in several patients.

There is a continuing debate concerning “adjustments” to heart period variability [i.e., heart rate variability (HRV)] for the heart period [i.e., increases inter-beat-intervals (IBI)]. To date, such arguments have not seriously considered the impact a demographic variable, such as gender, can have on the association between HRV and the heart period. A prior meta-analysis showed women to have greater HRV compared to men despite having shorter IBI and higher heart rate (HR). Thus, it is plausible that men and women differ in the association between HRV and HR/IBI. Thus, the present study investigates the potential moderating effect of gender on the association between HRV and indices of cardiac chronotropy, including both HR and IBI. Data from 633 participants (339 women) were available for analysis. Cardiac measures were assessed during a 5-min baseline-resting period. HRV measures included the standard deviation of inter-beat-intervals, root mean square of successive differences, and autoregressive high frequency power. Moderation analyses showed gender significantly moderated the association between all HRV variables and both HR and IBI (each p

BackgroundThe COVID-19 pandemic brought rapid changes to the work and personal lives of clinicians.ObjectiveTo assess clinician burnout and well-being during the COVID-19 pandemic and guide healthcare system improvement efforts.DesignA survey asking about clinician burnout, well-being, and work experiences.ParticipantsSurveys distributed to 8141 clinicians from June to August 2020 in 9 medical groups and 17 hospitals at Sutter Health, a large healthcare system in Northern California.Main MeasuresBurnout was the primary outcome, and other indicators of well-being and work experience were also measured. Descriptive statistics and multivariate logistic regression analyses were performed. All statistical inferences were based on weighted estimates adjusting for response bias.Key ResultsA total of 3176 clinicians (39.0%) responded to the survey. Weighted results showed 29.2% reported burnout, and burnout was more common among women than among men (39.0% vs. 22.7%,ppConclusionsThis large survey found the pandemic disproportionally impacted women, younger clinicians, and those whose caregiving responsibilities impacted their work. These results highlight the need for a holistic and targeted strategy for improving clinician well-being that addresses the needs of women, younger clinicians, and those with caregiving responsibilities.

Lissencephaly represents a spectrum of rare malformations of cortical development including agyria, pachygyria and subcortical band heterotopia. The progress in molecular genetics has led to identification of 31 lissencephaly-associated genes with the overall diagnostic yield over 80%. In this review, we focus on clinical and molecular diagnosis of lissencephaly and summarize the current knowledge on histopathological changes and their correlation with the MRI imaging. Additionally we provide the overview of clinical follow-up recommendations and available data on epilepsy management in patients with lissencephaly.

Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Data about the influence of short-term lifestyle intervention in children with obesity on long-term follow-up body weight, adipokines and cardiometabolic risk parameters is scarce.In a subgroup of the LOGIC-trial (Long-term Effects of Lifestyle Intervention in Obesity and Genetic Influence in Children), we assessed anthropometry (BMI, BMI-SDS (Standard Deviation Score), adipokines (omentin-1, chemerin, leptin, adiponectin) and cardiometabolic risk parameters, (e.g. hsCRP) in children with overweight/obesity after 4 weeks of lifestyle intervention (n = 156, 14.0 ± 1.8 yrs) and after one year follow-up (n = 50). Data were compared to normal weight children (JuvenTUM school cohort; n = 152, 13.3 ± 0.7 yrs).Short-term lifestyle intervention was associated with a significant reduction in BMI and BMI-SDS (p 0.001), with significant reductions in hsCRP, leptin, and chemerin levels, and an increase in adiponectin and omentin-1 levels (p 0.001 for all). After one year follow-up a significant reduction in BMI and BMI-SDS was observed in children from the LOGIC-trial (p 0.001). Improvements in adiponectin (p = 0.025) and chemerin levels (p = 0.027) were seen in children with clear weight loss success (BMI-SDS reduction ≥ 0.2), whereas children with no or only mild weight loss success showed an increase in leptin levels (p 0.001). An increase in omentin-1 levels was observed after 1 year independent of weight change (p 0.001).Effects of short-term weight reduction on mean BMI and BMI-SDS persist over one year. Improvements in omentin-1 levels were independent of short-term or long-term weight loss.ClinicalTrials.gov: LOGIC-trial: NCT01067157, JuvenTUM-trial: NCT00988754.

Background Adequate neuromuscular control of the knee could be one element to prevent secondary injuries after an anterior cruciate ligament (ACL) injury. To assess neuromuscular control in terms of time, amplitude and activity, electromyography (EMG) is used. However, it is unclear which assessments using EMG could be used for a safe return to sports (RTS). Therefore, we aimed to summarize EMG-related assessments for neuromuscular control of the knee in adult patients after an ACL injury to decide upon readiness for RTS. Methods This systematic review followed guidelines of Preferred Reporting of Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane recommendations. MEDLINE/PubMed, EMBASE, CINAHL, Cochrane Library, Physiotherapy Evidence Database (PEDro), SPORTDiscus and the Web of Science were searched from inception to March 2019 and updated in November 2020. Studies identifying electromyographic assessments for neuromuscular control during dynamic tasks in adult, physically active patients with an anterior cruciate ligament injury were eligible and qualitatively synthesized. Two independent reviewers used a modified Downs and Black checklist to assess risk of bias of included studies. Results From initially 1388 hits, 38 mainly cross-sectional, case-controlled studies were included for qualitative analysis. Most studies provided EMG outcomes of thigh muscles during jumping, running or squatting. Outcomes measures described neuromuscular control of the knee in domains of time, amplitude or activity. Risk of bias was medium to high due to an unclear description of participants and prior interventions, confounding factors and incompletely reported results. Conclusions Despite a wide range of EMG outcome measures for neuromuscular control, none was used to decide upon return to sports in these patients. Additional studies are needed to define readiness towards RTS by assessing neuromuscular control in adult ACL patients with EMG. Further research should aim at finding reliable and valid, EMG-related variables to be used as diagnostic tool for neuromuscular control. Moreover, future studies should aim at more homogenous groups including adequately matched healthy subjects, evaluate gender separately and use sport-specific tasks. Registration The protocol for this systematic review was indexed beforehand in the International Prospective Register of Systematic Reviews (PROSPERO) and registered as CRD42019122188.

Point-of-Care Ultrasonography POCUS is performed by the treating clinician at the bedside, with immediate interpretation and clinical integration of the imaging results. This review discusses POCUS...

Background Among people with musculoskeletal disorders, much of the variation in magnitude of incapability and pain intensity is accounted for by mental and social health opportunities rather than severity of pathology. Current questionnaires seem to combine distinct aspects of mental health such as unhelpful thoughts and distress regarding symptoms, and they can be long and burdensome. To identify personalized health strategies, it would be helpful to measure unhelpful thoughts and distress regarding symptoms at the point of care with just a few questions in a way that feels relevant to a person's health. Questions/purposes (1) Do questions that address unhelpful thoughts and distress regarding symptoms independently account for variation in accommodation of pain? (2) Which questions best measure unhelpful thoughts and distress regarding symptoms? Methods This is a cross-sectional questionnaire study of people seeking care regarding upper and lower extremity conditions from one of eight specialist clinicians (one upper extremity, one arthroplasty, and one sports surgeon and their three nurse practitioners and two physician assistants) in one urban office. Between June 2020 and September 2020, 171 new and returning patients were approached and agreed to participate, and 89% (153) of patients completed all questionnaires. The most common reason for noncompletion was the use of a pandemic strategy allowing people to use their phone to finish the questionnaire, with more people leaving before completion. Women and divorced, separated, or widowed people were more likely to not complete the survey, and we specifically account for sex and marital status as potential confounders in our multivariable analysis. Forty-eight percent (73 of 153) of participants were women, with a mean age 48 ± 16 years. Participants completed demographics and the validated questionnaires: Pain Catastrophizing Scale, Negative Pain Thoughts Questionnaire, Tampa Scale of Kinesiophobia, Intolerance of Uncertainty Scale, and Pain Self-Efficacy Questionnaire (a measure of accommodation to pain). In an exploratory factor analysis, we found that questions group together on four topics: (1) distress about symptoms (unhelpful feelings of worry and despair), (2) unhelpful thoughts about symptoms (such as worst-case thinking and pain indicating harm), (3) being able to plan, and (4) discomfort with uncertainty. We used a multivariable analysis, accounting for potential confounding demographics, to determine whether the identified question groupings account for variation in accommodation of pain-and thus are clinically relevant. Then, we used a confirmatory factor analysis to determine which questions best represent clinically relevant groupings of questions. Results After accounting for sex, marital status, work, and income, we found that distress and unhelpful thoughts about symptoms were independently associated with accommodation of pain, and together, they explained 60% of its variation (compared with 52% for distress alone and 40% for unhelpful thoughts alone). Variation in symptoms of distress was best measured by the question "I feel I can't stand it anymore" (76%). Variation in unhelpful thoughts was best addressed by the question "I wouldn't have this much pain if there wasn't something potentially dangerous going on in my body" (64%). Conclusion We found that distress (unhelpful feelings) and unhelpful thoughts about symptoms are separate factors with important and comparable associations with accommodation to pain. It also appears that these two factors can be measured with just a few questions. Being attentive to the language people use and the language of influential questions might improve clinician identification of mental health opportunities in the form of distress and unhelpful thoughts about symptoms, which in turn might contribute to better accommodation and alleviation of symptoms. Level of evidence Level II, prognostic study.

Objectives: Point of care ultrasound (POCUS) in adult critical care environments has become the standard of care in many hospitals. A robust literature shows its benefits for both diagnosis and delivery of care. The utility of POCUS in the pediatric intensive care unit (PICU), however, is understudied. This study describes in a series of PICU patients the clinical indications, protocols, findings and impact of pediatric POCUS on clinical management. Design: Retrospective analysis of 200 consecutive POCUS scans performed by a PICU physician. Patients: Pediatric critical care patients who required POCUS scans over a 15-month period. Setting: The pediatric and cardiac ICUs at a tertiary pediatric care center. Interventions: Performance of a POCUS scan by a pediatric critical care attending with advanced training in ultrasonography. Measurement and Main Results: A total of 200 POCUS scans comprised of one or more protocols (lung and pleura, cardiac, abdominal, or vascular diagnostic protocols) were performed on 155 patients over a 15-month period. The protocols used for each scan reflected the clinical question to be answered. These 200 scans included 133 thoracic protocols, 110 cardiac protocols, 77 abdominal protocols, and 4 vascular protocols. In this series, 42% of scans identified pathology that required a change in therapy, 26% confirmed pathology consistent with the ongoing plans for new therapy, and 32% identified pathology that did not result in initiation of a new therapy. Conclusions: POCUS performed by a trained pediatric intensivist provided useful clinical information to guide patient management.

Ahmed Hussein Subki,1 Abdullah Khaled Agabawi,2 Muhab Mohammed Hindi,2 Nadeem Shafique Butt,3 Mohammed Saad Alsallum,4 Rawan Ali Alghamdi,2 Siham Hussein Subki,2 Fahad Alsallum,2 Abdulaziz Ahmed Alharbi,5 Yousif Ibrahim Lodhi,6 Sultan Alandijani,1 Faten Al-Zaben,7 Harold G Koenig,7,8 Ayman M Oraif2 1Department of Internal Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; 2Department of Obstetrics and Gynecology, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Biostatistics, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Neurology, King Abdulaziz Medical City, Jeddah, Saudi Arabia; 5‏Department of Emergency Medicine, King Fahad General Hospital, Jeddah, Saudi Arabia; 6Department of Internal Medicine, East Jeddah Hospital, Jeddah, Saudi Arabia; 7Department of Psychiatry, King Abdulaziz University, Jeddah, Saudi Arabia; 8Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USACorrespondence: Ayman M OraifDepartment of Obstetrics and Gynecology, King Abdulaziz University, Jeddah, Saudi ArabiaTel +966 53 806 2000Email ayman_oraif@yahoo.comBackground: The patient–doctor relationship is one of the most important factors in determining the outcome of healthcare. The first step in establishing this relationship is choosing a physician. This study sought to identify patient preferences concerning the gender of their obstetrics and gynecology (OB-GYN) physician and the effect of religion and society on these choices.Methods: A cross-sectional study was conducted at the OB-GYN outpatient clinics at King Abdulaziz University Hospital in Jeddah between February 2017 and June 2017. A total of 227 female patients were recruited. Eligible were women ages 18 years or older who had attended the clinic at least three times. A 30-item questionnaire was administered.Results: Significantly, more female doctors were preferred for pelvic examination in lower income group (p=0.003), while male doctors were preferred for surgery (p=0.010) in higher income group. Significantly more male doctors were preferred for pelvic examination and gynecological surgery in > 35-year age group (p=0.015 and p=0.017, respectively). With regard to predictors, embarrassment was the most significant factor reported for not choosing a male obstetrician/gynecologist (OB-GYN) in the younger age group. Nearly three-quarters (71.2%) of respondents with age ≤ 35 reported embarrassment as a factor for not choosing a male OB-GYN; 79.7% of this subgroup indicated that female doctors were more knowledgeable about women’s health issues.Conclusion: Participants expressed a strong preference for female providers overall, although some women preferred male providers during certain circumstances (gynecologic surgery). Despite these gender preferences, more important to women in their choice of OB-GYN provider was the doctor’s experience, qualifications, and reputation. Such trends are consistent with those culturally similar countries and in line with trends worldwide. These findings have the potential to significantly impact the personal health for women in Saudi Arabia and elsewhere in the Middle East where religious and cultural traditions are so important in decision-making.Keywords: gender, preference, obstetrics, gynecologist, patient care

Do firearm purchase delay laws reduce aggregate homicide levels? Using variation from a 6-month countrywide gun demand shock in 2012/2013, we show that U.S. states with legislation preventing immediate handgun purchases experienced smaller increases in handgun sales. Our findings indicate that this is likely driven by comparatively lower purchases among impulsive consumers. We then demonstrate that states with purchase delays also witnessed comparatively 2% lower homicide rates during the same period. Further evidence shows that lower handgun sales coincided primarily with fewer impulsive assaults and points towards reduced acts of domestic violence.

Research in the field of “Spirituality and Health” has been growing, with spirituality/religiousness (S/R) being consistently related to both physical and mental health. The objective of this article is to provide an updated review of the current scientific evidence on the relationship between S/R and mental health, highlighting the most important studies. As a secondary objective, the mechanisms that explain this relationship and the interventions that utilize this information in treating mental disorders will be discussed. The findings reveal a large body of evidence across numerous psychiatric disorders. Although solid evidence is now available for depression, suicidality, and substance use, other diagnosis, such as post-traumatic stress disorder, psychosis, and anxiety, have also shown promising results. The effects of S/R on mental health are likely bidirectional, and the manner in which religious beliefs are used to cope with distress (i.e. negative and positive), may affect mental health outcomes. Despite these findings, the mechanisms that explain these associations and the role of S/R interventions need further study. Concerning clinical practice, mental health providers should ask patients about S/R that are important in their lives to provide holistic and patient-centered care.

As fetal gene therapies move from experimental animal models to human in utero phase I clinical trials, there is a need to consider the ethical, legal, and social implications. While fetal gene therapies are attracting more regulatory oversight than previous fetal interventions such as fetal surgery, old sociological questions should be applied to this new context. As health care pathways around fetal therapy are shaped by the ways in which a pregnant person and the fetus are constituted, and as risks and benefits are evaluated, we cannot afford to lose sight of long-term consequences, especially those pertaining to social inclusion.

Aim Very preterm infants are exposed to an atypical environment that could alter their developmental trajectory. We aimed to examine neonatal imitation, a foundation of social cognition, in very preterm and full-term infants. Methods In Strasbourg, France, between 2015 and 2018, we prospectively investigated the development of imitation skills. Very preterm (27 to 33 weeks of gestational age, n = 20) and full-term infants (n = 20) were enrolled using four gestures: tongue protrusion, mouth opening, sequential finger movements and hand movements. All testing were performed in infants at term-equivalent age. Two independent and blinded observers coded the behaviour of each infant on video recording. Facial expressions or hand movements, similar to the one presented, were quantified and classified according to their timing. Results A total of 37 out of 40 infants imitated at least one gesture. The very preterm and term infants did not differ in the presence of imitation or its timing for the four gestures tested. The very preterm infants displayed more imitation abilities for sequential finger movement. Tongue protrusion and sequential finger movement were the particularly strong imitated gesture in both groups. Conclusion These findings are the first to show similar neonatal imitation in term and very preterm infants. Our results may support early parent-infant social interactions.

MRI is an essential diagnostic imaging modality for many knee conditions; however, it is not indicated in the setting of advanced knee arthritis. Inappropriate MRI imaging adds to health care costs and may delay definitive management for many patients. The primary purpose of this study was to ascertain the frequency of inappropriate MRI scans performed at one Veterans' Administration Medical Center (VAMC). We performed a retrospective chart review of all knee MRIs ordered over a 6-month period. Inappropriate MRI was defined as MRI performed prior to radiographs (XRs), or in the presence of XRs demonstrating severe osteoarthritis, without leading to a nonarthroplasty procedure of the knee. Of the 304 cases reviewed, 36.8% (112) of the MRIs were deemed inappropriate, 33 were ordered by orthopedists, and 79 were ordered by other health care providers. Of the 33 ordered by orthopedists, 25 were ordered by retired/nonsurgical orthopedists. Obtaining an MRI delayed care by an average of 29.2 days. Of the 252 cases that had XR prior to MRI, none included all four views in the standard knee XR series and only four had weightbearing images. Over a third of knee MRIs performed at this VAMC were inappropriate and delayed care. Additionally, no XRs in our study contained all the necessary views to properly assess knee arthritis. These concerning findings signify a potential opportunity for education in diagnostic strategies, to better patient care and resource utilization in the VAMC.