Miracle-dz/UniFAR-FTUs huggingface dataset:
Are there different evidence thresholds for genomic vs. clinical precision medicine? A VOI-based framework applied to antiplatelet drug therapy

Objective: To evaluate evidence thresholds for clinically-guided precision medicine (PM) vs. genomically-guided PM. Methods: We develop an “evidence threshold criterion” (ETC) that is the time-weighted difference between expected value of perfect information (EVPI) and incremental net health benefit (INHB) minus the cost of research, and use it as a measure of evidence threshold that is proportional to the upper bound of disutility to a risk-averse decision-maker for adopting a new intervention under decision uncertainty. A larger (more negative) ETC value indicates that only decision makers with low risk aversion would adopt new intervention. We evaluated the ETC plus cost of research (ETCc), assuming the same cost of research for both interventions, over time for a pharmacogenomic (PGx) testing intervention and avoidance of a drug-drug interaction (aDDI) intervention for acute coronary syndrome patients indicated for antiplatelet therapy. We then examined how the ETC may explain incongruous decision-making across different national decision-making bodies. Results: The ETCc for PGx increased over time, while the ETCc for aDDI decreased to a negative value over time, indicating that decision makers with even low risk aversion will have doubts in adopting PGx, while decision makers who are highly risk-averse will continue to have doubts about adopting aDDI. National recommendation bodies appear to be consistent over time within their own decision-making, but had different levels of risk aversion. Conclusion: The ETC may be a useful metric for assessing policy makers’ risk preferences, and in particular understanding differences in policy recommendations for genomic vs. clinical PM. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Formulating evidence thresholds for precision medicine interventions through the time-weighted difference between EVPI and INHB and understanding policy recommendation differences using this formulation.
The Association of Transmission Concerns and Social Distance from Loved Ones with Distress in Healthcare Workers Providing Care during the COVID-19 Pandemic in New York City

Background: Healthcare workers (HCWs) during the COVID-19 pandemic report high levels of psychological distress. We examined whether concerns regarding transmission of COVID-19 to loved ones and social distancing from loved ones were associated with HCWs’ distress. We tested whether living with others modified these associations. Methods: HCWs at a New York City academic medical center (N = 767; 80.7% female, 58.5% white) enrolled in the COVID-19 Healthcare Provider Study and completed a web-based survey between April 9, 2020 and May 11, 2020. Results: Controlling for demographics, distress regarding potential transmission to loved ones and social distancing from loved ones were each significantly associated with higher odds of a positive screen for acute stress, depression, and anxiety (ORs = 1.29 – 1.59, all ps < .01). Living with others was associated with lower odds of a positive screen for depression and anxiety, though the protective effect for anxiety was evident only for HCWs with no distress regarding transmission concerns. Conclusions: Transmission concerns and social distancing from loved ones were associated with greater odds of psychological distress, whereas living with others was associated with lower odds of distress. Interventions should consider ways to facilitate the ability of HCWs to receive social support from loved ones, while simultaneously protecting their family’s health.
STATE OF THE ART Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications

Cystic ﬁ brosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, in ﬂ ammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic ﬁ brosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl 2 and HCO 3 2 transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the to the recent of highly therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.
Artemether Does Not Turn Alpha Cells into Beta Cells

Pancreatic alpha cells retain considerable plasticity and can – under the right circumstances – transdifferentiate into functionally mature beta cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used antimalarial drug artemether suppresses the alpha cell transcription factor Arx to promote transdifferentiation into beta cells. However, key initial experiments in this paper were carried out in islet cell lines and most subsequent validation experiments implied transdifferentiation without direct demonstration of alpha to beta cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary alpha cells into beta cells. Moreover, artemether reduces Ins2 expression in primary beta cells >100-fold, suppresses glucose uptake, and abrogates beta cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote alpha to beta cell transdifferentiation in treating diabetes.
The Pathway from Cognitive Impairment to Dental Caries in Older Adults: A Conceptual Model

Background: Dental caries significantly increases in persons with cognitive impairment (PWCI). However, the interrelationships among cognitive impairment, dentally-related function (DRF), oral hygiene and dental caries remain unclear, increasing difficulties to appropriately care for PWCI. This study tests a conceptual model in which impaired DRF acts as a mediator between cognitive function and oral hygiene, which then leads to dental caries. Methods: 68 elderly dentate participants with normal to severely impaired cognition were recruited from three assisted living communities in North Carolina. Within one week of calibrated oral examination by a geriatric dentist, a trained examiner blind to the oral exam results conducted cognitive and functional assessments. Statistical analyses were conducted to examine the mediating effect of DRF on the relationship between cognitive impairment and oral hygiene or dental caries. Results: Cognitive impairment ( β =0.05, SE=0.02, P=0.017) and DRF ( β =−0.07, SE=0.02, P=0.005) were significantly associated with oral hygiene. However, the association between cognitive impairment and oral hygiene was greatly reduced and became non-significant after controlling for DRF ( β =0.01, SE=0.03, P=0.430), suggesting that the effect of cognitive impairment on oral hygiene may be mediated by DRF. DRF accounted for 80% of the total effect (P M =0.8). Associations between either cognitive impairment or DRF and dental caries were not significant, however oral hygiene was significantly associated with dental caries ( β =0.87, SE=0.28, P<0.001). Conclusion: DRF mediated the association between cognitive impairment and oral hygiene. It accounted for 80% of the total impact of cognitive impairment on oral hygiene, which was associated with increased dental caries in PWCI.
Powertrain Modeling and Model Predictive Longitudinal Dynamics Control for Hybrid Electric Vehicles

This paper discusses modeling of a power-split hybrid electric vehicle and the design of a longitudinal dynamics controller for the University of Waterloo’s self-driving vehicle project. The powertrain of Waterloo’s vehicle platform, a Lincoln MKZ Hybrid, is controlled only by accelerator pedal actuation. The vehicle’s power management strategy cannot be altered, so a novel approach to greybox modeling of the OEM powertrain control architecture and dynamics was developed. The model uses a system of multiple neural networks to mimic the response of the vehicle’s torque control module and estimate the distribution of torque between the powertrain’s internal combustion engine and electric motors. The vehicle’s power-split drivetrain and longitudinal dynamics were modeled in MapleSim, a modeling and simulation software, using a physics-based analytical approach. All model parameters were identified using Controller Area Network (CAN) data and measurements of wheel torque data that were gathered during vehicle road testing. Using the grey-box powertrain model as a framework, a look-ahead linear time-varying (LTV) model predictive controller (MPC) for reference velocity tracking is proposed. Using some simplifying assumptions about the powertrain dynamics, the controloriented model was reformulated in a pseudo-Hammerstein form. Inversion of the nonlinearities allows linear MPC algorithms to be applied directly to the linear portion of the system. The performance of the MPC was tested using multiple model in the loop (MIL) reference velocity tracking scenarios, and benchmarked against a tuned proportional-integral (PI) controller. Using the novel controloriented model of the OEM powertrain, the MPC was found to track the desired velocity trajectory and reject measurable disturbance inputs, such as road slope, better than the PI controller.
Potential Benefits of Integration of Targeted Therapies With Chemoradiation in Rectal Cancer

Improved pelvic control with reduced toxicity and enhanced sphincter preservation has been demonstrated with neoadjuvant chemoradiation compared with postoperative adjuvant chemoradiation in patients with stage II and III rectal cancer. However, analyses from many trials of adjuvant chemoradiation indicate that patients with T3 node-positive and T4 tumors are at high risk of pelvic recurrence even with use of chemoradiation. This limitation could be addressed with treatment intensification strategies, such as increasing the radiotherapy dose using altered fractionation, or incorporation of novel cytotoxic and targeted chemotherapeutic agents. In addition, preliminary evidence suggests that selected patients with clinically staged T2 or T3 node-negative tumors may be candidates for trials evaluating organ-preserving strategies after chemoradiation, thus eliminating the morbidity of radical surgery. These efforts could be enhanced with the availability of more effective chemoradiation regimens. This paper will discuss incorporation of molecular targeted therapy with chemoradiation regimens in the context of current standards, limitations, and new concepts in the combined modality therapy of locally advanced rectal cancer.
Multi‐scale features fusion from sparse LiDAR data and single image for depth completion

Recently deep learning-based methods for dense depth completion from sparse depth data have shown superior performance than traditional techniques. However, sparse depth data lose the details of the scenes, for instance, the spatial and texture information. To overcome this problem, additional single image is introduced and a multi-scale features fusion scheme to learn more correlations of the two different data is proposed. Furthermore, sparse convolution operation to improve feature robustness for sparse depth data is exploited. Experiments demonstrate that the approach obviously improves the performance for depth completion and outperforms all the previous published methods. The authors believe their works also have the guidance significance for stereo images depth estimation fused with sparse LiDAR depth data.
Multi-Descriptor Read Across (MuDRA): a simple and transparent approach for developing accurate QSAR models

Multiple approaches to QSAR modeling using various statistical or machine learning techniques and different types of chemical descriptors have been developed over the years. Oftentimes models are used in consensus to make more accurate predictions at the expense of model interpretation. We propose a simple, fast, and reliable method termed Multi-Descriptor Read-Across (MuDRA) for developing both accurate and interpretable models. The method is conceptually related to the well-known kNN approach, but uses different types of chemical descriptors simultaneously for similarity assessment. To benchmark the new method, we have built MuDRA models for six different endpoints (Ames mutagenicity, aquatic toxicity, hepatotoxicity, hERG liability, skin sensitization, and endocrine disruption) and compared the results with those generated with conventional consensus QSAR modeling. We find that models built with MuDRA show consistently high external accuracy similar to that of conventional QSAR models. However, MuDRA models excel in terms of transparency, interpretability, and computational efficiency. We posit that due to its methodological simplicity and reliable predictive accuracy, MuDRA provides a powerful alternative to a much more complex consensus QSAR modeling. MuDRA is implemented and freely available at the Chembench web portal (https://chembench.mml. unc
Regulation of Nuclear Factor (cid:1) B in the Hippocampus by Group I Metabotropic Glutamate Receptors

An increasing amount of evidence suggests that the family of nuclear factor (cid:1) B (NF- (cid:1) B) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF- (cid:1) B family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist ( S )-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl)pyridine,inhibitedtheDHPG-inducedactivationofNF- (cid:1) B,whereasanantagonistofmGluR1,( S )-( (cid:1) )- (cid:2) -amino-4-carboxy-2-methylbenzeneaceticacid,didnot.Usingaseriesofinhibitors,weinvestigatedthesignalingpathwaysnecessaryforDHPG-inducedactivationofNF- (cid:1) B and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF- (cid:1) B, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel (cid:2) / (cid:2) mice. However, late-phase LTD ( (cid:3) 90 min) was impaired in c-rel (cid:2) / (cid:2) mice. The observations of this deficit in hippocampal synaptic plasticitypromptedustofurtherinvestigatelong-termmemoryformationinc-rel (cid:2) / (cid:2) mice.c-rel (cid:2) / (cid:2) miceexhibitedimpairedperformancein along-termpassiveavoidancetask,providingadditionalevidenceforc-Relinlong-termmemoryformation.TheseresultsdemonstratethattheNF- (cid:1) B transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-termmaintenanceofLTDandformationoflong-termmemory.
Mechanism of oxidative inactivation of human presequence protease (hPreP) by hydrogen peroxide

The mitochondrial presequence protease (PreP) is a member of the pitrilysin class of metalloproteases. It degrades the mitochondrial targeting presequences of mitochondria-localized proteins as well as unstructured peptides such as amyloid- β -peptide. The specific activity of PreP is reduced in Alzheimer patients and animal models of Alzheimer disease. The loss of activity can be mimicked in vitro by exposure to oxidizing conditions, and indirect evidence suggested that inactivation was due to methionine oxidation. We performed peptide mapping analyses to elucidate the mechanism of inactivation. None of the 24 methionine residues in recombinant human PreP was oxidized. We present evidence that inactivation was due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. The most susceptible cysteine residues to oxidation are Cys34, Cys112, and Cys119. Most, but not all, of the activity loss is restored by the reducing agent, dithiothreitol. These findings elucidate a redox mechanism for regulation of PreP and also provide a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.
Presenilin-Dependent (cid:1) -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer’s Disease

Presenilins(PSs)arepartofthe (cid:1) -secretasecomplexthatproducestheamyloid (cid:2) -peptide(A (cid:2) )fromitsprecursor[ (cid:2) -amyloidprecursor protein ( (cid:2) APP)]. Mutations in PS that cause familial Alzheimer’s disease (FAD) increase A (cid:2) production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, (cid:1) -secretase inhibitors, and (cid:2) APP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNAexpression.p53expressionalsoisdiminishedinthebrainsofPS-or (cid:2) APP-deficientmice.The (cid:1) -and (cid:3) -secretase-derivedamyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of (cid:2) APP trigger p53-dependent cell death and increasep53activityandmRNA.Finally,PS1mutationsenhancep53activityinhumanembryonickidney293cellsandp53expressioninFAD-affectedbrains.ThusourstudyshowsthatAICDscontrolp53atatranscriptionallevel, in vitro and in vivo , and that FAD mutations increase p53 expression and activity in cells and human brains.
Who Benefits from Adjuvant Radiotherapy for Gastric Cancer?: A Meta-Analysis

Purpose— Large randomized trials have demonstrated significant survival benefits with the use of adjuvant chemotherapy or chemoradiotherapy for gastric cancer. The importance of adjuvant radiotherapy (RT) remains unclear. Here we perform an up-to-date meta-analysis of randomized trials testing the use of radiotherapy for resectable gastric cancer. Methods— We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant (including neoadjuvant) RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine if the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, and lymph node status. Results— Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR=0.78, 95% CI: 0.70 to 0.86, p<0.001) and DFS (HR=0.71, 95% CI: 0.63 to 0.80, p<0.001). In the five studies that tested adjuvant chemoradiotherapy against adjuvant chemotherapy, similar effects were seen for OS (HR=0.83, 95% CI: 0.67 to 1.03, p=0.087) and DFS (HR=0.77, 95% CI: 0.91 to 0.65, p=0.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusion— In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regards to patient selection and integration with systemic therapy.
Randomized Controlled Trial Testing the Effectiveness of Adaptive “SMART” Stepped-Care Treatment for Adults with Binge-Eating Disorder Co-morbid with Obesity

Objective: This RCT tested effectiveness of an adaptive “SMART” stepped-care approach to “standard” behavioral weight loss (BWL (Standard)) for patients with binge-eating disorder (BED) and obesity. Method: 191 patients with BED/obesity were randomly assigned to six-months BWL (Standard) (N=39) or Stepped-care (N=152). Within Stepped-care, patients started with BWL for one month; treatment-responders continued BWL while non-responders switched to CBT. All patients receiving Stepped-care were additionally randomized to weight-loss medication or placebo (double-blind) for the remaining five months. Independent assessments were performed reliably at baseline, throughout-treatment, and post-treatment. Results: ITT analyses of remission rates (zero binges/month) revealed BWL (Standard) and Stepped-care did not differ significantly overall (74.4% vs 66.5%); within Stepped-care, remission rates ranged 40.0%−83.3% with medication significantly superior to placebo (overall) and among non-responders switched to CBT. Mixed-models analyses of binge-eating frequency revealed significant time-effects but BWL (Standard) and Stepped-care did not differ overall; within Stepped-care, medication was significantly superior to placebo (overall) and among non-responders switched to CBT. Mixed models revealed significant weight loss but BWL (Standard) (5.1% weight-loss) and Stepped-care (5.8% weight-loss) did not differ overall; within Stepped-care (range 0.4%−8.8% BMI loss), medication was significantly superior to placebo (overall) and among both responders continued on BWL and non-responders switched to CBT. Conclusions: Overall, BWL (Standard) and adaptive Stepped-care treatments produced robust improvements in binge-eating (high remission-rates and binge-eating reductions) and weight-loss in patients with BED/obesity but differed little. Within adaptive Stepped-care, weight-loss medication enhanced outcomes for BED/obesity. Implications for clinical practice and future adaptive designs are offered. This study shows that behavioral weight loss treatment can provide substantial benefits to patients with binge-eating disorder who also have excess weight. Behavioral weight loss treatment resulted in 74.4% of patients achieving abstinence from binge eating and an average of 5.1% weight loss. This study also shows that weight-loss medications have potential utility for enhancing outcomes particularly amongst those patients who do not respond initially to behavioral weight loss treatment.