Search

Michael S Albosta,1 Jelani K Grant,2 Pam Taub,3 Roger S Blumenthal,2 Seth S Martin,2 Erin D Michos2 1Internal Medicine Department, University of Miami Miller School of Medicine/ Jackson Memorial Hospital, Miami, FL, USA; 2Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Division of Cardiology, University of California San Diego, San Diego, CA, USACorrespondence: Erin D Michos, Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Blalock 524-B, 600 N. Wolfe Street, Baltimore, MD, 21287, USA, Tel +1 410-502-6813, Email edonnell@jhmi.eduAbstract: Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic cardiovascular disease (ASCVD). As such, lowering LDL-C is a central tenet in all ASCVD prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as difficulty with long-term adherence to statin therapy and inability to achieve desired LDL-C thresholds with statins alone results in residual elevated ASCVD risk. Non-statin therapies generally provide similar risk reduction per mmol/L of LDL-C reduction and are included by major society guidelines as part of the treatment algorithm for managing LDL-C. Per the 2022 American College of Cardiology Expert Consensus Decision Pathway, patients with ASCVD are recommended to achieve both an LDL-C reduction ≥ 50% and an LDL-C threshold of < 55 mg/dL in patients at very high-risk and < 70 mg/dL in those not at very high risk. Patients with familial hypercholesterolemia (FH) but without ASCVD should lower LDL-C to < 100 mg/dL. For patients who remain above LDL-C thresholds with maximally tolerated statin therapy plus lifestyle changes, non-statin therapy warrants strong consideration. While several non-statin therapies have been granted FDA approval for managing hypercholesterolemia (eg, ezetimibe, Proprotein Convertase Subtilisin/Kexin 9 [PCSK9] monoclonal antibodies, and bempedoic acid), the focus of the current review is on inclisiran, a novel small interfering RNA therapy that inhibits the production of the PCSK9 protein. Inclisiran is currently FDA approved as an adjunct to statin therapy in patients with clinical ASCVD or heterozygous FH who require additional LDL-lowering. The drug is administered by subcutaneous injection twice a year, after an initial baseline and 3 month dose. In this review, we sought to provide an overview of the use of inclisiran, review current trial data, and outline an approach to potential patient selection.Keywords: inclisiran, lipids, cardiovascular disease prevention, LDL-cholesterol

Background Higher cardiac troponin is associated with worse outcomes in patients with acute heart failure. The significance of repeat measurements over hours remains unclear. We assessed whether a repeat measurement and the Δ between measurements of high‐sensitivity cardiac troponin I (hs‐cTnI) were associated with outcomes in hypervolemic patients with acute heart failure without acute coronary syndrome. Methods and Results We analyzed 582 individuals from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase‐Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) with hs‐cTnI measured ≤12 hours from admission and repeated ≤6 hours thereafter. Associations between hs‐cTnI levels and their Δ with short‐term (death, intensive care unit admission, receipt of inotropes, or positive pressure ventilation during hospitalization) and long‐term (death or heart failure readmission within 1 year) outcomes were assessed. The average age was 69±13 years, 62% were men, 65% were White, 46% had coronary artery disease, and 22% had chest pain. Median hs‐cTnI levels were 27 (interquartile range [IQR], 13–62) ng/L initially and 28 (IQR, 14–68) ng/L subsequently, with a Δ of 0 [IQR, −2 to 4] ng/L over 3.4±1 hours. Only the second measurement was associated with short‐term outcomes (odds ratio, 1.14 per 2‐fold higher [95% CI, 1.02–1.28]). Both individual measurements and the Δ were associated with long‐term outcomes (hazard ratios, 1.09, 1.12, and 1.16 for first, second, and Δ, respectively). Associated risk for the first and second measurements were not constant over the year but highest early after being measured and decreased over 1 year. Conclusions Repeat measurements of hs‐cTnI over hours can identify individuals with acute heart failure without acute coronary syndrome at risk for short‐ and long‐term outcomes.

Introduction: There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in in vitro and in a proven animal model of MRONJ. Methods: 3H labelled GGOH (2 mM) was incorporated into a Hydroset bone cement pellet and release from the cement was assessed over time. To assess the effect on bone cell function, the GGOH-loaded cement was placed in a porous filter above cultured osteoclasts treated with bisphosphonate and the effect on osteoclast survival and function were measured. In a pilot study the effect of GGOH on osteotomy microstructure was measured in a rat model of MRONJ using a split mouth design. Results: The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel. Conclusion: These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ.

Background The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients.Methods The 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 GD2BATs/kg/infusion.Results Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2–3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines.Conclusions This study demonstrated the safety of GD2BATs up to 160×106 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.

Abstract Background As well known to any photographer, controlling the “field of view” offers an extremely powerful mechanism by which to adjust target acquisition. Only a few natural sensory systems can actively control their field of view (e.g., dolphins, whales, and bats). Bats are known for their active sensing abilities and modify their echolocation signals by actively controlling their spectral and temporal characteristics. Less is known about bats’ ability to actively modify their bio-sonar field of view. Results We show that Pipistrellus kuhlii bats rapidly narrow their sensory field of view (i.e., their bio-sonar beam) when scanning a target. On-target vertical sonar beams were twofold narrower than off-target beams. Continuous measurements of the mouth gape of free-flying bats revealed that they control their bio-sonar beam by a ~3.6 mm widening of their mouth gape: namely, bats open their mouth to narrow the beam and vice versa. Conclusions Bats actively and rapidly control their echolocation vertical beam width by modifying their mouth gape. We hypothesize that narrowing their vertical beam narrows the zone of ensonification when estimating the elevation of a target. In other words, bats open their mouth to improve sensory localization.

Abstract Background Alcohol use disorder (AUD) accounts for millions of acute care encounters annually in the United States. Hospitalization represents a vital opportunity to intervene pharmacologically, but low medication adherence is a significant barrier. Two single-dose, adherence-independent interventions are well suited for pre-discharge administration: intravenous (IV) ketamine and intramuscular (IM) naltrexone. Their feasibility and readmission-reducing efficacy in hospital settings are not well-established. Methods A 3-arm, open-label randomized trial was conducted at our safety-net medical hospital among high-utilization inpatients with severe AUD. Consented adults (age 18–65) were randomized to (1) IV ketamine (KET) 0.5 mg/kg over 40 min, (2) IM naltrexone (NTX) 380 mg once, or (3) linkage alone (LA). The primary clinical outcome was 30-day all-cause hospital readmission rate. All were provided enhanced linkage to outpatient addiction clinic. Results We consented and randomized 44 participants (n = 13, 14, 17 for KET, NTX, LA, respectively), with a mean of 3.2 past-year hospitalizations. Compared to the LA arm, both the KET arm (RR 0.37, p = 0.17) and NTX arm (RR 0.52, p = 0.27) had a lower 30-day readmission rate, though the differences were nonsignificant. Immediate acceptability ratings of KET and NTX were 9.50 and 9.17 out of 10, respectively. No serious adverse events or illicit ketamine use was reported. Conclusions Both interventions are feasible and showed promise in reducing readmissions for high-utilization AUD inpatients. Despite randomization, baseline characteristics may have differed in ways that biased against the control arm. Additional pragmatic studies—with larger sample size, blinding, and robust follow-up data collection—are needed to verify findings and better understand mediating factors. ClinicalTrials.gov Identifier NCT04562779. Registered 24 September 2020. https://clinicaltrials.gov/ct2/show/NCT04562779

Thoracic outlet syndrome is an umbrella term for compressive pathologies in the supraclavicular and infraclavicular fossae, with the vast majority being neurogenic in nature. These compressive neuropathies, such as pectoralis minor syndrome, can be challenging problems for both patients and physicians. Robust understanding of thoracic outlet anatomy and scapulothoracic biomechanics are necessary to distinguish neurogenic vs. vascular disorders and properly diagnose affected patients. Repetitive overhead activity, particularly when combined with scapular dyskinesia, leads to pectoralis minor shortening, decreased volume of the retropectoralis minor space, and subsequent brachial plexus compression causing neurogenic thoracic outlet syndrome. Combining a thorough history, physical examination, and diagnostic modalities including ultrasound-guided injections are necessary to arrive at the correct diagnosis. Rigorous attention must be paid to rule out alternate etiologies such as peripheral neuropathies, vascular disorders, cervical radiculopathy, and space-occupying lesions. Initial nonoperative treatment with pectoralis minor stretching, as well as periscapular and postural retraining, is successful in the majority of patients. For patients that fail nonoperative management, surgical release of the pectoralis minor may be performed through a variety of approaches. Both open and arthroscopic pectoralis minor release may be performed safely with effective resolution of neurogenic symptoms. When further indicated by the preoperative workup, this can be combined with suprascapular nerve release and brachial plexus neurolysis for complete infraclavicular thoracic outlet decompression.

Abstract Background Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Abstract Background The surgical ciliated cyst of the maxilla was initially reported as a sequela of Caldwell–Luc type open maxillary sinus procedures. Recently, other etiologies have become apparent and cases have been reported outside of the maxilla. They have the potential for local destruction and at times may mimic a locally aggressive tumor or cyst. We aim to elucidate the etiopathogenesis of the surgical ciliated cyst to improve prevention, diagnosis and treatment of these lesions. Body A systematic review of the literature using PubMed and Scopus databases was conducted to assess the presentation, treatment, and outcomes of this disease. Surgical ciliated cysts of the maxillofacial region shows a 1.1:1 female-to-male ratio with a protracted time to diagnosis (range: 4–22 years). Typically, radiology shows a unilocular radiolucency (95%) and histology predominantly shows pseudostratified ciliated columnar epithelium (58%). The most common treatment of these lesions involves enucleation and curettage. In rare instances, transfacial approaches, resection, and reconstruction are required. Recurrence ranges from 6 to 20%. Conclusion Surgical ciliated cyst should be considered in a patient presenting with an orofacial mass or edema who has a history of maxillofacial injury or surgery. Timely diagnosis will decrease the severity and morbidity associated with this entity. Meticulous surgical technique can aid in the prevention of this lesion.

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.

Abstract Background Various mammalian species emit ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interactions. USVs are usually analyzed by manual or semi-automated methodologies that categorize discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders the effective use of USVs as a readout for high-throughput analysis of behavioral changes in animals. Results Here we present a novel automated open-source tool that utilizes a different approach towards USV analysis, termed TrackUSF. To validate TrackUSF, we analyzed calls from different animal species, namely mice, rats, and bats, recorded in various settings and compared the results with a manual analysis by a trained observer. We found that TrackUSF detected the majority of USVs, with less than 1% of false-positive detections. We then employed TrackUSF to analyze social vocalizations in Shank3-deficient rats, a rat model of autism, and revealed that these vocalizations exhibit a spectrum of deviations from appetitive calls towards aversive calls. Conclusions TrackUSF is a simple and easy-to-use system that may be used for a high-throughput comparison of ultrasonic vocalizations between groups of animals of any kind in any setting, with no prior assumptions.

Abstract How do people estimate the time of past events? A prominent hypothesis suggests that there are multiple timing systems which operate in parallel, depending on circumstances. However, quantitative evidence supporting this hypothesis focused solely on short time-scales (seconds to minutes) and lab-produced events. Furthermore, these studies typically examined the effect of the circumstance and the psychological state of the participant rather than the content of the timed events. Here, we provide, for the first time, support for multiple content-based timing systems when estimating the time of real-life events over long time-scales. The study was conducted during the COVID-19 crisis, which provided a rare opportunity to examine real-life time perception when many were exposed to similar meaningful events. Participants (N = 468) were asked to retrospectively estimate the time that has passed since prominent events, that were either related or unrelated to the pandemic. Results showed an overall time-inflation, which was decreased for events related to the pandemic. This indicates that long-term subjective timing of real-life events exists in multiple systems, which are affected not only by circumstances, but also by content.

Background: The purpose of the present study was to evaluate the website pages of integrated plastic and reconstructive surgery resident aesthetic clinics in the United States. Methods: Website pages dedicated to resident aesthetic clinics in all integrated plastic and reconstructive surgery residency programs (n = 79) were accessed between October and November 2019 and evaluated across several criteria, including: number of pages, procedures offered, faculty participation, respective prices, patient photographs, patient testimonials, contact information, and specific recruitment incentives. Results: Seventy-nine integrated and 54 independent residency programs were identified, 31 of which had both an integrated and an independent residency program for a total of 102 distinct programs. Out of these, only 11 programs (10.8%) had a webpage dedicated to their resident aesthetic clinic (Figure 1). Twelve other programs (13.7%) that did not have a dedicated webpage mentioned a resident aesthetic clinic elsewhere on their residency program website. For each of the eleven programs with space for the resident aesthetic clinic, there was exactly one dedicated webpage. None of the programs with dedicated webpages included photographs of before and after cases, nor procedures performed, nor a listing of resident aesthetic clinic prices. Three of the dedicated webpages included information about faculty participation. Out of the 24 ASAPS endorsed aesthetic fellowship programs, 6 (25%) had a webpage dedicated to the fellow aesthetic clinic. Four of these webpages were comprised of a single webpage, while one program had 6 webpages and one program had 8 webpages. Only one program's webpage included before and after pictures. Four programs (16.7%) included information about faculty participation on the webpage. Five out of the 6 programs had a procedure list on the webpage. Discussion: Resident aesthetic clinic websites are an important tool in recruiting patients as well as medical students. Addressing the lack and quality of such websites may improve recruitment of patients and students to plastic and reconstructive surgery residency programs. As a primary source of information for potential future residents and patients, plastic and reconstructive surgery programs need to maximize the content and utility of their websites.

The first known portal system in the mammalian brain was identified in 1933. Here the authors describe a new portal system between the capillary beds of the Suprachiasmatic Nucleus master clock and a circumventricular organ, enabling humoral signals to reach targets without dilution in the systemic circulation.

Abstract Background Learning to adapt to changes in the environment is highly beneficial. This is especially true for echolocating bats that forage in diverse environments, moving between open spaces to highly complex ones. Bats are known for their ability to rapidly adjust their sensing according to auditory information gathered from the environment within milliseconds but can they also benefit from longer adaptive processes? In this study, we examined adult bats’ ability to slowly adapt their sensing strategy to a new type of environment they have never experienced for such long durations, and to then maintain this learned echolocation strategy over time. Results We show that over a period of weeks, Pipistrellus kuhlii bats gradually adapt their pre-takeoff echolocation sequence when moved to a constantly cluttered environment. After adopting this improved strategy, the bats retained an ability to instantaneously use it when placed back in a similarly cluttered environment, even after spending many months in a significantly less cluttered environment. Conclusions We demonstrate long-term adaptive flexibility in sensory acquisition in adult animals. Our study also gives further insight into the importance of sensory planning in the initiation of a precise sensorimotor behavior such as approaching for landing.

IntroductionAccurate assessment of right ventricular (RV) systolic function has prognostic and therapeutic implications in many disease states. Echocardiography remains the most frequently deployed imaging modality for this purpose, but estimation of RV systolic function remains challenging. The purpose of this study was to evaluate the diagnostic performance of a novel measurement of RV systolic function called lateral annular systolic excursion ratio (LASER), which is the fractional shortening of the lateral tricuspid annulus to apex distance, compared to right ventricular ejection fraction (RVEF) derived by cardiac magnetic resonance imaging (CMR).MethodsA retrospective cohort of 78 consecutive patients who underwent clinically indicated CMR and transthoracic echocardiography within 30 days were identified from a database. Parameters of RV function measured included: tricuspid annular plane systolic excursion (TAPSE) by M-mode, tissue Doppler S', fractional area change (FAC) and LASER. These measurements were compared to RVEF derived by CMR using Pearson's correlation coefficients and receiver operating characteristic curves.ResultsLASER was measurable in 75 (96%) of patients within the cohort. Right ventricular systolic dysfunction, by CMR measurement, was present in 37% (n = 29) of the population. LASER has moderate positive correlation with RVEF (r = 0.54) which was similar to FAC (r = 0.56), S' (r = 0.49) and TAPSE (r = 0.37). Receiver operating characteristic curves demonstrated that LASER (AUC = 0.865) outperformed fractional area change (AUC = 0.767), tissue Doppler S' (AUC = 0.744) and TAPSE (AUC = 0.645). A cohort derived dichotomous cutoff of 0.2 for LASER was shown to provide optimal diagnostic characteristics (sensitivity of 75%, specificity of 87% and accuracy of 83%) for identifying abnormal RV function. LASER had the highest sensitivity, accuracy, positive and negative predictive values among the parameters studied in the cohort.ConclusionsWithin the study cohort, LASER was shown to have moderate positive correlation with RVEF derived by CMR and more favorable diagnostic performance for detecting RV systolic dysfunction compared to conventional echocardiographic parameters while being simple to obtain and less dependent on image quality than FAC and emerging techniques.

2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, including the kidney. The tumorigenesis resulting from overproduced 2HG has been attributed to the ability of 2HG alter gene expression by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation (TET) enzymes. Genes that regulate cellular differentiation are reportedly repressed, blocking differentiation of mesenchymal cells into myocytes, and adipocytes. In this report, the expression of the enzyme responsible for L2HG degradation, L-2HG dehydrogenase (L2HGDH), is knocked down, using lentiviral shRNA, as well as siRNA, in primary cultures of normal Renal Proximal Tubule (RPT) cells. The knockdown (KD) results in increased L-2HG levels, decreased demethylation of 5mC in genomic DNA, and increased methylation of H3 Histones. Consequences include reduced tubulogenesis by RPT cells in matrigel, and reduced expression of molecular markers of differentiation, including membrane transporters as well as HNF1α and HNF1β, which regulate their transcription. These results are consistent with the hypothesis that oncometabolite 2HG blocks RPT differentiation by altering the methylation status of chromatin in a manner that impedes the transcriptional events required for normal differentiation. Presumably, similar alterations are responsible for promoting the expansion of renal cancer stem-cells, increasing their propensity for malignant transformation.

Abstract About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Resmetirom (MGL‐3196), a selective thyroid hormone receptor‐β agonist, was evaluated in a 36‐week paired liver biopsy study (NCT02912260) in adults with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI–proton density fat fraction (MRI‐PDFF), and secondary endpoints included histopathology. Subsequently, a 36‐week active treatment open‐label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI‐PDFF reduction at OLE week 36 was −11.1% (1.5%) mean reduction (standard error [SE]; P

Objectives: The purpose of this study is to evaluate clinical outcomes in patients with critical COVID-19 pneumonia requiring invasive mechanical ventilation who were treated with tocilizumab Design: Single-center retrospective cohort study Setting: Stony Brook University Hospital, a 600-bed academic tertiary medical center in Suffolk County, New York Participants: Consecutive patients with COVID-19 confirmed by nasopharyngeal polymerase chain reaction (PCR) who were admitted to Stony Brook University Hospital between March 10 and April 2 2020 and required mechanical ventilation in any intensive care unit during their hospitalization Exposure: Treatment with tocilizumab while intubated Main Outcome: Overall mortality 30 days from the date of intubation Results: Forty-five patients received tocilizumab compared to seventy controls. Baseline demographic characteristics, inflammatory markers, treatment with corticosteroids, and sequential organ failure assessment (SOFA) scores were similar between the two cohorts. Patients who received tocilizumab had significantly lower Charlson co-morbidity index (2.0 vs 3.0,P = 0.01) than controls. There was a trend towards younger mean age in the tocilizumab exposed group (56.2 vs 60.6; P = 0.09). In logistic regression analysis there was no reduction in mortality associated with receipt of tocilizumab (odds ratio (OR) 1.04; 95% CI, 0.27–3.75). There was no observed increased risk of secondary infection in patients given tocilizumab (28.9 vs 25.7; OR 1.17; 95% CI, 0.51–2.71). Conclusion: When controlling for age, severity of illness, and co-morbidities, tocilizumab was not associated with reduction in mortality in this retrospective cohort study of mechanically ventilated patients with COVID-19 pneumonia. Further studies are needed to determine the role of tocilizumab in the treatment of COVID-19.

Background: COVID-19 has infected over 35 million people worldwide and led to over 1 million deaths. Several risk factors that increase COVID-19 severity have emerged, including age and a history of cardiovascular disease, hypertension, or kidney disease. However, a number of outstanding questions persist, including whether the above comorbidities correlate with increased mortality from COVID-19 or whether age is a significant confounding variable that accounts for the observed relationship between COVID-19 severity and other comorbidities. Methods and Findings: We conducted a systematic review and meta-analysis of studies documenting COVID-19 patients with hypertension, cardiovascular disease, cerebrovascular disease, or chronic kidney disease. We classified COVID-19 cases into severe/non-severe or deceased/surviving and calculated the odds ratio (OR) for each of the four comorbidities in these cohorts. 36 studies, comprising 22,573 patients, are included in our meta-analysis. We found that hypertension is the most prevalent comorbidity in deceased COVID-19 patients (55.4%; CI: 49.4–61.3%), followed by cardiovascular disease (30.7%; CI: 22.6–38.8%), cerebrovascular disease (13.4%; CI: 9.12–19.2%), then chronic kidney disease (9.05%; CI: 5.57–15.0%). The risk of death is also significantly higher for patients with these comorbidities, with the greatest risk factor being chronic kidney disease (OR: 8.86; CI: 5.27–14.89), followed by cardiovascular disease (OR: 6.87; CI: 5.56–8.50), hypertension (OR: 4.87; CI: 4.19–5.66), and cerebrovascular disease (OR: 4.28; CI: 2.86–6.41). These risks are significantly higher than previously reported, while correlations between comorbidities and COVID-19 severity are similar to previously reported figures. Using meta-regression analysis with age as a moderating variable, we observed that age contributes to the observed risks but does not explain them fully. Conclusions: In this meta-analysis, we observed that cardiovascular, cerebrovascular, and kidney-related comorbidities in COVID-19 significantly contributes to greater risk of mortality and increased disease severity. We also demonstrated that age may not be a confounder to these associations.

We have used quasielastic and inelastic neutron scattering to investigate the structure, dynamics, and phase transitions of water interacting with superhydrophilic CuO surfaces that not only possess a strong affinity for water but also a “grass-like” topography that is rough on both micro- and nanoscales. Here, we report quasielastic neutron scattering (QENS) measurements on two samples differing in water content at five temperatures below 280 K. The QENS spectra show water undergoing two different types of diffusive motion near the CuO surfaces: a “slow” translational diffusion occurring on a nanosecond time scale and a faster rotational motion. Further from the surfaces, there is “fast” translational diffusion comparable in rate to that of bulk supercooled water and the rotational motion occurring in the interfacial water. Analysis of the QENS spectra supports wetting of water to the CuO blades as seen in electron microscopy images. In addition, we observe an anomalous temperature dependence of the QENS spectra on cooling from 270 to 230 K with features consistent with a liquid–liquid phase transition. We suggest that the solvent-like properties of the coexisting bulk-like water in our CuO samples are a significant factor in determining the temperature dependence of the interfacial water’s dynamics. Our results are compared with those obtained from two well-studied substrate classes: (1) silicas that contain ordered cylindrical nanopores but have weaker hydrophilicity and (2) nanoparticles of other transition-metal oxides, such as TiO2, which share the strong hydrophilicity of our samples but lack their porosity.

Self-regulated learning (SRL) is critical for learning across tasks, domains, and contexts. Despite its importance, research shows that not all learners are equally skilled at accurately and dynamically monitoring and regulating their self-regulatory processes. Therefore, learning technologies, such as intelligent tutoring systems (ITSs), have been designed to measure and foster SRL. This paper presents an overview of over 10 years of research on SRL with MetaTutor, a hypermedia-based ITS designed to scaffold college students’ SRL while they learn about the human circulatory system. MetaTutor’s architecture and instructional features are designed based on models of SRL, empirical evidence on human and computerized tutoring principles of multimedia learning, Artificial Intelligence (AI) in educational systems for metacognition and SRL, and research on SRL from our team and that of other researchers. We present MetaTutor followed by a synthesis of key research findings on the effectiveness of various versions of the system (e.g., adaptive scaffolding vs. no scaffolding of self-regulatory behavior) on learning outcomes. First, we focus on findings from self-reports, learning outcomes, and multimodal data (e.g., log files, eye tracking, facial expressions of emotion, screen recordings) and their contributions to our understanding of SRL with an ITS. Second, we elaborate on the role of embedded pedagogical agents (PAs) as external regulators designed to scaffold learners’ cognitive and metacognitive SRL strategy use. Third, we highlight and elaborate on the contributions of multimodal data in measuring and understanding the role of cognitive, affective, metacognitive, and motivational (CAMM) processes. Additionally, we unpack some of the challenges these data pose for designing real-time instructional interventions that scaffold SRL. Fourth, we present existing theoretical, methodological, and analytical challenges and briefly discuss lessons learned and open challenges.

Background: Therapeutic drug monitoring (TDM) is useful to assess clozapine adherence and optimize treatment. However, analysis of venous blood levels by liquid chromatography tandem mass spectrometry (LC-MS/MS) is often logistically complicated and process time is prolonged. Objective: To assess the feasibility and reliability of a new point-of-care device, (MyCare™ Insite), using capillary blood for clozapine therapeutic monitoring. Methods: Matched venous and capillary blood samples were collected from patients treated with clozapine on a stable dose. Samples were analyzed by LC-MS/MS and MyCare Insite Clozapine Test. Clozapine plasma levels were compared between methods using linear regression model. Both patients and treatment team completed questionnaires about the feasibility of blood sampling. Results: Of the total sample (44 patients, 61% males, mean age 43 ± 12 years), mean daily clozapine dose was 293 ± 134 mg/day. Linear regression model demonstrated high correlation with R 2 = 0.83 ( p

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or “omics,” quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.

Abstract Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

Hilary A Marusak,1– 3 Allesandra S Iadipaolo,4 Cindy Cohen,5 Elimelech Goldberg,5,6 Jeffrey W Taub,6,7 Felicity WK Harper,3,7 Martin H Bluth,5,8 Christine A Rabinak1,2,4,9 1Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, USA; 2Merrill Palmer Skillman Institute, Wayne State University, Detroit, MI, USA; 3Population Studies and Disparities Research Program, Karmanos Cancer Institute, Detroit, MI, USA; 4Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA; 5Kids Kicking Cancer, Southfield, MI, USA; 6Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI, USA; 7Department of Oncology, School of Medicine, Wayne State University, Detroit, MI, USA; 8Department of Pathology, School of Medicine, Wayne State University, Detroit, MI, USA; 9Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USACorrespondence: Hilary A Marusak Tel +1 313-577-1278Fax +1 313-577-6188Email hmarusak@med.wayne.eduObjective: Test whether a martial arts-based therapy, Kids Kicking Cancer (KKC), can reduce pain and emotional distress in children with cancer, other chronic health conditions (e.g., sickle cell), and healthy siblings.Methods: This study surveyed children’s pain and distress levels immediately before and after a 1-hr in-person KKC class. Eligible participants were enrolled in standard KKC classes, were diagnosed with a chronic health condition (e.g., cancer, sickle cell) or were the sibling of a child diagnosed and were between the ages of 5– 17 years (inclusive). Children reported on their pain and distress using Likert-style scales (Coloured Analog Scale and modified FACES scale, respectively). Friedman test was used to test for overall changes in pain and distress, and within subgroups. Age and sex effects were evaluated using Spearman’s rank-order correlation. Additional Yes/No questions were administered regarding KKC satisfaction and use of techniques.Results: Fifty-nine youth (19 cancer patients, 17 non-cancer patients, 23 siblings; 5– 17 yrs, 26 females) completed this study. Overall, there was a significant reduction in pain (p = 0.033) and emotional distress (p < 0.001) after a 1-hr class, with 50% and 89% of youth reporting a reduction in pain and distress, respectively. On average, pain levels remained within the mild/moderate range on average (i.e., pre vs. post levels; pre: M = 1.67, post: M = 1.33) and emotional distress went from mild/moderate to none/mild distress, on average (pre: M = 1.92, post: M = 1.08). Youth with higher pre-class pain and distress reported greater reductions (p = 0.001 and p < 0.001, respectively). The reduction in pain appeared to be most pronounced with cancer and non-cancer patients. In contrast, the reduction in distress appeared to be most pronounced among healthy siblings. However, overall, reductions in pain and distress did not significantly differ among subgroups (i.e., cancer patients, non-cancer patients, siblings), and change in pain and distress was not associated with age or sex. Ninety-six percent of youth would recommend KKC to others and 81% reported using KKC techniques (e.g., the Breath BrakeTM or other martial arts techniques) outside of class, such as at home.Conclusion: Results support the more widespread application of KKC as a psychosocial intervention for reducing pain and distress in various pediatric populations.Keywords: meditation, mindfulness, oncology, psychosocial, sickle cell, leukemia

Introduction: Acute kidney injury (AKI) is strongly associated with poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19), but data on the association of proteinuria and hematuria are limited to non-US populations. In addition, admission and in-hospital measures for kidney abnormalities have not been studied separately. Methods: This retrospective cohort study aimed to analyze these associations in 321 patients sequentially admitted between March 7, 2020 and April 1, 2020 at Stony Brook University Medical Center, New York. We investigated the association of proteinuria, hematuria, and AKI with outcomes of inflammation, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death. We used ANOVA, t test, χ2 test, and Fisher’s exact test for bivariate analyses and logistic regression for multivariable analysis. Results: Three hundred patients met the inclusion criteria for the study cohort. Multivariable analysis demonstrated that admission proteinuria was significantly associated with risk of in-hospital AKI (OR 4.71, 95% CI 1.28–17.38), while admission hematuria was associated with ICU admission (OR 4.56, 95% CI 1.12–18.64), IMV (OR 8.79, 95% CI 2.08–37.00), and death (OR 18.03, 95% CI 2.84–114.57). During hospitalization, de novo proteinuria was significantly associated with increased risk of death (OR 8.94, 95% CI 1.19–114.4, p = 0.04). In-hospital AKI increased (OR 27.14, 95% CI 4.44–240.17) while recovery from in-hospital AKI decreased the risk of death (OR 0.001, 95% CI 0.001–0.06). Conclusion: Proteinuria and hematuria both at the time of admission and during hospitalization are associated with adverse clinical outcomes in hospitalized patients with COVID-19.

Background Despite the Clinical Learning Environment Review’s recommendations of their use, patient safety event reporting systems are underutilized by residents. Objective We aimed to identify perceived barriers to event reporting amongst internal medicine residents and implement a targeted quality improvement initiative to address the identified barriers and increase overall resident event report rates. Methods A total of 94 Internal Medicine (IM) residents participated in the educational intervention in 2018. We measured residents’ perception of barriers to event reporting and employed the results of the questionnaire to create a skill-based educational workshop. We conducted the plan-do-study-act model to test a structured educational intervention and its effectiveness on pre-post IM residents’ event report rates and compared it to report rates of Non-Internal Medicine (Non-IM) residents. Additionally, we assessed pre-post intervention knowledge, skills, and attitudes in event reporting. Results 94/94 (100%) of IM residents had a significantly higher median percent of patient safety event reporting when compared to pre-intervention (23.6% compared to 5.88%, p-value = 0.0030) and when compared to Non-IM residents (23.6% compared to 5.31%, p-value = 0.0002). Residents performed better on the post-test compared to the pre-test (90% compared to 30%, p-value = 0.0001) for knowledge. 100% of the critical action items were completed and 90% of participants reported their perception of the event reporting process improved. Conclusions By elucidating common reasons why residents are not reporting patient safety events, a specific intervention can be created to target the identified impediments and improve resident event reporting. Abbreviations IM: Internal Medicine IM; Non-IM: Non-Internal Medicine; IOM: Institute of Medicine I; ACGME CLER: Accreditation Council for Graduate Medical Education Clinical Learning Environment Review; GME: Graduate Medical Education; IRB: Institutional Review Board; PDSA: Plan, Do, Study, Act

Objective: To assess the personal perspectives of persons with multiple sclerosis (MS) on the acceptability of a novel physical therapy program that is designed to transfer gains from the clinic to their real-world lower extremity (LE) use, termed LE constraint-induced therapy (CIT). The program includes several behavior change techniques (prescribed home exercises, daily structured therapist interviews and problem solving for LE activities, keeping an activity diary) and a concentrated physical treatment schedule. Design: Anonymous internet survey. Setting: Participants accessed the survey from computers in the community. Participants: Five hundred adults (N=500) were recruited from an MS support organization's registry for having indicated from mild to total limb spasticity because they were anticipated to have markedly impaired LE use in the community. Interventions: Not applicable. Main Outcome Measures: Participants were offered the options on a nonnumerical Likert scale of “Very likely,” “Likely,” “Neutral,” “Unlikely,” or “Very unlikely” to indicate their personal acceptability for each of 5 different key treatment procedures after these were explained. Totals for each option within each key procedure were analyzed for their acceptability. Results: Of the 281 persons who responded, 90% expressed interest in participating in LE CIT. A large majority of persons who completed the survey selected either “Very likely” or “Likely” for each key procedure (median=88%, range=65%-90%, P

Success in online and blended courses requires engaging in self-regulated learning (SRL), especially for challenging STEM disciplines, such as physics. This involves students planning how they will navigate course assignments and activities, setting goals for completion, monitoring their progress and content understanding, and reflecting on how they completed each assignment. Based on Winne & Hadwin’s COPES model, SRL is a series of events that temporally unfold during learning, impacted by changing internal and external factors, such as goal orientation and content difficulty. Thus, as goal orientation and content difficulty change throughout a course, so might students’ use of SRL processes. This paper studies how students’ SRL behavior and achievement goal orientation change over time in a large (N = 250) college introductory level physics course taught online. Students’ achievement goal orientation was measured by repeated administration of the achievement goals questionnaire-revised (AGQ-R). Students’ SRL behavior was measured by analyzing their clickstream event traces interacting with online learning modules via a combination of trace clustering and process mining. Event traces were first divided into groups similar in nature using agglomerative clustering, with similarity between traces determined based on a set of derived characteristics most reflective of students’ SRL processes. We then generated causal nets for each cluster of traces via process mining and interpreted the underlying behavior and strategy of each causal net according to the COPES SRL framework. We then measured the frequency at which students adopted each causal net and assessed whether the adoption of different causal nets was associated with responses to the AGQ-R. By repeating the analysis for three sets of online learning modules assigned at the beginning, middle, and end of the semester, we examined how the frequency of each causal net changed over time, and how the change correlated with changes to the AGQ-R responses. Results have implications for measuring the temporal nature of SRL during online learning, as well as the factors impacting the use of SRL processes in an online physics course. Results also provide guidance for developing online instructional materials that foster effective SRL for students with different motivational profiles.

La patología mamaria durante el embarazo y la lactancia representa un desafío debido a que los cambios fisiológicos del tejido mamario durante este periodo pueden afectar la interpretación de los hallazgos clínicos e imagenológicos. El objetivo de esta revisión es conocer el diagnóstico diferencial de las enfermedades mamarias durante el embarazo y la lactancia. La mayoría de las patologías mamarias durante el embarazo y la lactancia son benignas y pueden ser clasificadas en tres categorías: 1) aquellas relacionadas con cambios fisiológicos, 2) enfermedades inflamatorias y 3) tumores benignos. Solo el 3% de los cánceres mamarios se desarrollan durante el embarazo. Los factores de mal pronóstico, como receptores hormonales negativos o HER2/neu positivo, en las mujeres embarazadas tienen una prevalencia similar a la observada en no embarazadas de la misma edad. El diagnóstico precoz es de crucial importancia pronóstica, por lo que es necesario mantener los esquemas de tamizaje recomendados. Es importante estar familiarizado con los cambios fisiológicos durante el embarazo y la lactancia, y conocer las patologías más prevalentes que afectan a las mujeres durante este periodo.

Summary: Background: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach. Methods: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850. Results: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%. Interpretation: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life. Funding: PCORI, NIH

Background:Recent studies suggest movements of speech and gait in patients with Parkinson's Disease (PD) are impaired by a common underlying rhythmic dysfunction. If this being the case, motor deficits in speech and gait should equally benefit from rhythmic interventions regardless of whether it is a speech-specific or step-training-specific approach.Objective:In this intervention trial, we studied the effects of two rhythmic interventions on speech and gait. These rhythmic intervention programs are similar in terms of intensity and frequency (i.e., 3x per week, 45 min-long sessions for 4 weeks in total), but differ regarding therapeutic approach (rhythmic speech vs. rhythmic balance-mobility training).Methods:This study is a cross-over, parallel multi-arms, single blind intervention trial, in which PD patients treated with rhythmic speech-language therapy (rSLT; N = 16), rhythmic balance-mobility training (rBMT; N = 10), or no therapy (NT; N = 18) were compared to healthy controls (HC; N = 17; matched by age, sex, and education: p > 0.82). Velocity and cadence in speech and gait were evaluated at baseline (BL), 4 weeks (4W-T1), and 6 months (6M-T2) and correlated.Results:Parameters in speech and gait (i.e., speaking and walking velocity, as well as speech rhythm with gait cadence) were positively correlated across groups (p < 0.01). Statistical analyses involved repeated measures ANOVA across groups and time, as well as independent and one-samples t-tests for within groups analyses. Statistical analyses were amplified using Reliable Change (RC) and Reliable Change Indexes (RCI) to calculate true clinically significant changes due to the treatment on a patient individual level. Rhythmic intervention groups improved across variables and time (total Mean Difference: 3.07 [SD 1.8]; 95% CI 0.2–11.36]) compared to the NT group, whose performance declined significantly at 6 months (p < 0.01). HC outperformed rBMT and NT groups across variables and time (p < 0.001); the rSLT performed similarly to HC at 4 weeks and 6 months in speech rhythm and respiration.Conclusions:Speech and gait deficits in PD may share a common mechanism in the underlying cortical circuits. Further, rSLT was more beneficial to dysrhythmic PD patients than rBMT, likely because of the nature of the rhythmic cue.

Background Functional mitral regurgitation (FMR) has emerged as a therapeutic target in patients with chronic heart failure and left ventricular systolic dysfunction. The significance of FMR in acute decompensated heart failure remains obscure. We systematically investigated the prevalence and clinical significance of FMR on admission in patients admitted with acute decompensated heart failure and left ventricular systolic dysfunction. Methods and Results The study was a single‐center, retrospective review of patients admitted with acute decompensated heart failure and left ventricular systolic dysfunction between 2012 and 2017. Patients were divided into 3 groups of FMR: none/mild, moderate, and moderate‐to‐severe/severe FMR. The primary outcome was 1‐year post‐discharge all‐cause mortality. We also compared these groups for 6‐month heart failure hospitalization rates. Of 2303 patients, 39% (896) were women. Median left ventricular ejection fraction was 25%. Four hundred and fifty‐three (20%) patients had moderate‐to‐severe/severe FMR, which was independently associated with 1‐year all‐cause mortality. Moderate or worse FMR was found in 1210 (53%) patients and was independently associated with 6‐month heart failure hospitalization. Female sex was independently associated with higher severity of FMR. Conclusions More than half of patients hospitalized with acute decompensated heart failure and left ventricular systolic dysfunction had at least moderate FMR, which was associated with increased readmission rates and mortality. Intensified post‐discharge follow‐up should be undertaken to eliminate FMR amenable to pharmacological therapy and enable timely and appropriate intervention for persistent FMR. Further studies are needed to examine sex‐related disparities in FMR.

In virtually any practical field or application, discovering and implementing near-optimal decision strategies is essential for achieving desired outcomes. Workflow planning is one of the most common and important problems of this kind, as sub-optimal decision-making may create bottlenecks and delays that decrease efficiency and increase costs. Recently, machine learning has been used to attack this problem, but unfortunately, most proposed solutions are “black box” algorithms with underlying logic unclear to humans. This makes them hard to implement and impossible to trust, significantly limiting their practical use. In this work, we propose an alternative approach: using machine learning to generate optimal, comprehensible strategies which can be understood and used by humans directly. Through three common decision-making problems found in scheduling, we demonstrate the implementation and feasibility of this approach, as well as its great potential to attain near-optimal results.

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Background Although widely used in treating severe abdominal trauma, damage control laparotomy (DCL) has not been assessed in any randomized controlled trial. We conducted a pilot trial among patients for whom our surgeons had equipoise and hypothesized that definitive laparotomy (DEF) would reduce major abdominal complications (MAC) or death within 30 days compared with DCL.Methods Eligible patients undergoing emergency laparotomy were randomized during surgery to DCL or DEF from July 2016 to May 2019. The primary outcome was MAC or death within 30 days. Prespecified frequentist and Bayesian analyses were performed.Results Of 489 eligible patients, 39 patients were randomized (DCL 18, DEF 21) and included. Groups were similar in demographics and mechanism of injury. The DEF group had a higher Injury Severity Score (DEF median 34 (IQR 20, 43) vs DCL 29 (IQR 22, 41)) and received more prerandomization blood products (DEF median red blood cells 8 units (IQR 6, 11) vs DCL 6 units (IQR 2, 11)). In unadjusted analyses, the DEF group had more MAC or death within 30 days (1.71, 95% CI 0.81 to 3.63, p=0.159) due to more deaths within 30 days (DEF 33% vs DCL 0%, p=0.010). Adjustment for Injury Severity Score and prerandomization blood products reduced the risk ratio for MAC or death within 30 days to 1.54 (95% CI 0.71 to 3.32, p=0.274). The Bayesian probability that DEF increased MAC or death within 30 days was 85% in unadjusted analyses and 66% in adjusted analyses.Conclusion The findings of our single center pilot trial were inconclusive. Outcomes were not worse with DCL and, in fact, may have been better. A randomized clinical trial of DCL is feasible and a larger, multicenter trial is needed to compare DCL and DEF for patients with severe abdominal trauma.Level of evidence Level II.

Maternal mortality in the United States is a public health crisis of preventable deaths among young women. The role of echocardiography in the evaluation of pregnant women with cardiovascular symptoms or risk factors without known heart disease is unclear. We retrospectively examined the clinical characteristics of consecutive pregnant patients without established heart disease who underwent echocardiography and evaluated associations between abnormal exam findings and obstetric outcomes. Among low-risk women undergoing echocardiography during pregnancy, older age, higher parity and a history of chronic hypertension are associated with a higher likelihood of echocardiographic abnormalities, which in turn are associated with a higher likelihood of adverse obstetric outcomes including caesarean section and preterm delivery.

Purpose: We present an unusual case of a congenital lesion presenting with concomitant chronic dacryocystitis. The clinical presentation, examination, management, and histopathology are reviewed. Observations: A healthy male infant born at 37 weeks gestation presented with an isolated painless 5mm congenital mass of the left medial lower eyelid. Parents also reported episodic epiphora and discharge from the left eye. A surgical excision of the mass revealed an underlying dacryocystitis and the presence of a formed tooth. A dacryocystorhinostomy was performed together with a repair of the soft tissue defect. Histopathology revealed components of disorganized epithelial and mesenchymal tissues including a tooth, skeletal muscle, fat, fibrous tissue, nonkeratinized epithelium, and myelinated nerves. A diagnosis of an odontogenic choristoma of the eyelid was made. Furthermore, a lacrimal sac culture was positive for oxacillin-susceptible Staphylococcus aureus with pathological evidence of chronic dacryocystitis. Conclusions and Importance: Odontogenic choristoma is a very rare finding in the periocular region with only a few cases reported in the literature. Awareness of clinical findings from this case may allow for a more accurate clinical diagnosis and understanding of the embryologic mechanisms underpinning eyelid and nasolacrimal development. Timely management of this condition is critical to ensure normal oculofacial development and prevent future complications.

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts- the most common craniofacial birth defects in humans- are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10-8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10-6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.

Entendiendo la teología política como aquellos actos y conceptos políticos en los que subyace un resto que los sobrepasa y que los vincula con una dimensión que reside más allá de lo humano, el objetivo de este artículo es analizar los avatares de este concepto desde la matriz de la tradición judía. Es por ello que se intentará realizar un corrimiento y una relectura de los debates modernos de la teología política cristiana y la secularización desde el judaísmo. Adentrándonos también por los caminos de la mística judía, nuestro objetivo es comprender de qué manera se produce un fenómeno inverso al de la así llamada secularización, por el cual los conceptos políticos se mueven a la esfera de lo divino y no al inverso. Para conseguir demostrar esta idea, se retomarán las concepciones angelológicas del judaísmo así como, principalmente, la idea antropomórfica de la cábala, buscando construir otra forma de leer nuestra realidad política, entendiéndola como aquello que constituye un “pálido reflejo”, o una “huella residual”, de las formas políticas divinas en este mundo.