Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

Recommendations for a Military Health System Auditory Blast Injury Prevention Standard.

INTRODUCTION: Although existing auditory injury prevention standards benefit warfighters, the Department of Defense could do more to understand and address auditory injuries (e.g., hearing loss, tinnitus, and central processing deficits) among service members. The Blast Injury Prevention Standards Recommendation (BIPSR) Process is designed to address the needs of all the Military Services for biomedically valid Military Health System (MHS) Blast Injury Prevention Standards. MATERIALS AND METHODS: Through the BIPSR Process, stakeholders provided their intended uses and requested functionalities for an MHS Blast Injury Prevention Standard. The BIPSR Process established a broad-based, non-advocacy panel of auditory injury Subject Matter Expert (SME) Panel with members drawn from industry, academia, and government. The SME Panel selected evaluation factors, weighted priorities, and then evaluated the resulting candidate MHS Auditory Blast Injury Prevention Standards against the evaluation criteria. The SME Panel members provided rationales for their decisions, documented discussions, and used iterative rounds of feedback to promote consensus building among members. The BIPSR Process used multi-attribute utility theory to combine members' evaluations and compare the candidate standards. RESULTS: The SME Panel identified and collated information about existing auditory injury datasets to identify gaps and promote data sharing and comprehensive evaluations of standards for preventing auditory blast injury. The panel evaluated the candidate standards and developed recommendations for an MHS Blast Injury Prevention Standard. CONCLUSIONS: The BIPSR Process illuminated important characteristics, capabilities, and limitations of candidate standards and existing datasets (e.g., limited human exposure data to evaluate the validity of injury prediction) for auditory blast injury prevention. The evaluation resulted in the recommendation to use the 8-hour Equivalent Level (LAeq8hr) as the interim MHS Auditory Blast Injury Prevention Standard while the community performs additional research to fill critical knowledge gaps.

ß-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that ß-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of ß-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant ß-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.

MmCMS: mouse models' consensus molecular subtypes of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue. METHODS: Using transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n = 577) and mouse (n = 57 across n = 8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers. RESULTS: We developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours. CONCLUSIONS: When applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package enables researchers to select suitable mouse models of human CRC subtype for their experimental testing.

A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients.

PURPOSE: Direct oral anticoagulants (DOACs) are not recommended in adult Fontan patients (Level of Evidence C). We hypothesized that DOACs are comparable to warfarin and do not increase thrombotic and embolic complications (TEs) or clinically significant bleeds. METHODS: We reviewed the medical records of adult Fontan patients on DOACs or warfarin at three major medical centers. We identified 130 patients: 48 on DOACs and 107 on warfarin. In total, they were treated for 810 months on DOACs and 5637 months on warfarin. RESULTS: The incidence of TEs in patients on DOACs compared to those on warfarin was not increased in a statistically significant way (hazard ratio [HR] 1.7 and p value 0.431). Similarly, the incidence of nonmajor and major bleeds in patients on DOACs compared to those on warfarin was also not increased in a statistically significant way (HR for nonmajor bleeds in DOAC patients was 2.8 with a p value of 0.167 and the HR for major bleeds was 2.0 with a p value 0.267). In multivariate analysis, congestive heart failure (CHF) was a risk factor for TEs across both groups (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.3-17.6) and bleed history was a risk factor for clinically significant bleeds (OR = 6.8, 95% CI = 2.7-17.2). CONCLUSION: In this small, retrospective multicenter study, the use of DOACs did not increase the risk of TEs or clinically significant bleeds compared to warfarin in a statistically significant way.

Recurrent Rash in an 11-Year-Old Boy With Pericardial and Pleural Effusions.

An 11-year-old, previously healthy boy presented to the emergency center (EC) for acute respiratory distress in the setting of 5 months of recurrent and worsening rash with progressive fatigue, shortness of breath, chest pain, and cough. At the onset of his rash, he and his younger brothers were diagnosed with roseola. Although his brothers' symptoms resolved, the patient's rash recurred, prompting his primary care provider to prescribe amoxicillin. The rash subsequently worsened, so amoxicillin was stopped; a prednisone course was prescribed which alleviated the rash. Upon completion of the prednisone course, the rash returned more diffusely with associated symptoms of shortness of breath, chest pain, and cough. Because of these symptoms, his mother brought him to the EC, where his vitals were notable for tachypnea and tachycardia. His initial EC imaging workup was remarkable for an echocardiogram with a mild to moderate circumferential pericardial effusion, chest x-ray (CXR) with a large right pleural effusion, and chest computerized tomography significant for prominent and diffuse mediastinal and hilar lymphadenopathy with numerous enlarged axillary lymph nodes. Laboratory results were notable for elevated liver enzymes, inflammatory markers, d-dimer, and brain natriuretic peptide. Differential diagnosis remained broad, including infectious, oncologic, and rheumatologic etiologies. Our panel of experts reviews the evaluation, hospital course, and treatment of this patient presenting with an unusual rash and serositis.

Antihistamines for motion sickness.

BACKGROUND: Motion sickness is a syndrome that occurs as a result of passive body movement in response to actual motion, or the illusion of motion when exposed to virtual and moving visual environments. The most common symptoms are nausea and vomiting. Antihistamines have been used in the management of motion sickness for decades, however studies have shown conflicting results regarding their efficacy. OBJECTIVES: To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness in adults and children. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) in susceptible adults and children in whom motion sickness was induced under natural conditions such as air, sea and land transportation. We also included studies in which motion sickness was induced under experimental conditions (analysed separately). Antihistamines were included regardless of class, route or dosage and compared to no treatment, placebo or any other pharmacological or non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1) the proportion of susceptible participants who did not experience any motion sickness symptoms; 2) the proportion of susceptible participants who experienced a reduction or resolution of existing symptoms. Secondary outcomes were 1) physiological measures (heart rate, core temperature and gastric tachyarrhythmia (electrogastrography)) and 2) adverse effects (sedation, impaired cognition, blurred vision). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included nine RCTs (658 participants). Studies were conducted across seven countries, with an overall age range of 16 to 55 years. Motion sickness was induced naturally in six studies and experimentally in four studies (rotating chair). All the naturally induced studies only evaluated first-generation antihistamines (cinnarizine and dimenhydrinate). Risk of bias across the studies varied, with mostly low risk for random sequence generation and allocation concealment, and mostly high risk for selective reporting. Only the experimentally induced studies measured physiological parameters and only the naturally induced studies evaluated adverse effects. There were no studies that clearly assessed the paediatric population. Antihistamines versus placebo or no treatment Antihistamines are probably more effective than placebo at preventing motion sickness symptoms under natural conditions (symptoms prevented: 25% placebo; 40% antihistamines) (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.23 to 2.66; 3 studies; 240 participants) (moderate-certainty). The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under experimental conditions (standardised mean difference (SMD) 0.32, 95% CI -0.18 to 0.83; 2 studies; 62 participants) (very low-certainty). No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia under experimental conditions (mean difference (MD) -2.2, 95% CI -11.71 to 7.31; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. When compared to placebo, antihistamines may be more likely to cause sedation (sedation: 44% placebo; 66% antihistamines) (RR 1.51, 95% CI 1.12 to 2.02; 2 studies; 190 participants) (low-certainty); they may result in little or no difference in blurred vision (blurred vision: 12.5% placebo; 14% antihistamines) (RR 1.14, 95% CI 0.53 to 2.48; 2 studies; 190 participants) (low-certainty); and they may result in little or no difference in terms of impaired cognition (impaired cognition: 33% placebo; 29% antihistamines) (RR 0.89, 95% CI 0.58 to 1.38; 2 studies; 190 participants) (low-certainty). Antihistamines versus scopolamine The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under natural conditions when compared to scopolamine (symptoms prevented: 81% scopolamine; 71% antihistamines) (RR 0.89, 95% CI 0.68 to 1.16; 2 studies; 71 participants) (very low-certainty). No studies were performed under experimental conditions. No studies reported results on the resolution of existing motion sickness symptoms. The evidence is very uncertain about the effect of antihistamines on heart rate under natural conditions (narrative report, 1 study; 20 participants; "No difference in pulse frequency"; very low-certainty). No studies reported results for any other physiological measures. When compared to scopolamine, the evidence is very uncertain about the effect of antihistamines on sedation (sedation: 21% scopolamine; 30% antihistamines) (RR 0.82, 95% CI 0.07 to 9.25; 2 studies; 90 participants) (very low-certainty) and on blurred vision (narrative report: not a significant difference; 1 study; 51 participants; very low-certainty). No studies evaluated impaired cognition. Antihistamines versus antiemetics Antihistamines may result in little or no difference in the prevention of motion sickness under experimental conditions (MD -0.20, 95% CI -10.91 to 10.51; 1 study; 42 participants) (low-certainty). The evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. No studies assessed the effects of antihistamines versus antiemetics under natural conditions. No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. No studies evaluated sedation, impaired cognition or blurred vision. One study reported physiological data for this outcome, evaluating gastric tachyarrhythmia specifically. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants; low-certainty evidence). This evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. Antihistamines versus acupuncture The evidence is very uncertain about the effects of antihistamines on the prevention of motion sickness under experimental conditions when compared to acupuncture (RR 1.32, 95% CI 1.12 to 1.57; 1 study; 100 participants) (very low-certainty). This study did not assess the prevention of motion sickness under natural conditions, nor the resolution of existing motion sickness symptoms. There was no study performed under natural conditions. Physiological measures and adverse effects were not reported. AUTHORS' CONCLUSIONS: There is probably a reduction in the risk of developing motion sickness symptoms under naturally occurring conditions of motion when using first-generation antihistamines, in motion sickness-susceptible adults, compared to placebo. Antihistamines may be more likely to cause sedation when compared to placebo. No studies evaluated the treatment of existing motion sickness, and there are few data on the effect of antihistamines in children. The evidence for all other outcomes and comparisons (versus scopolamine, antiemetics and acupuncture) was of low or very low certainty and we are therefore uncertain about these effects of antihistamines.

Parent Engagement with an Online, School-Based, Character Strengths Promotion Program.

Schools are increasingly bolstering student character strengths to promote academic success and well-being. Schools' character-promotion efforts would benefit from involving students' caregivers. Online resources may be an accessible way to engage students' families, but further research is needed to maximize accessibility and engagement. A brief character strengths program was developed and integrated within online accounts accessed by parents of kindergarten students. Content analysis of parent focus groups (N = 14, 86% women) indicated that access to and engagement with the program was improved by several factors, including visuals, intuitive navigation, strength-based content, and school-based recruitment. Content analysis of caregivers' (N = 54, 91% women, M age = 36.52, SD age = 4.40) responses to the program's reflection questions indicated that parents prefer highly applicable content, particularly information about noticing and developing character strengths in their child. Finally, exploratory descriptive statistics indicated that single parents, fathers, and parents of racial minority children were less likely to engage with the program which alludes to the additional barriers faced by these socio-demographic groups. The results provide specific suggestions for involving parents in school-based character promotion efforts, as well as highlight the importance of additional research to better understand the needs of diverse families. Supplementary Information: The online version contains supplementary material available at 10.1007/s41042-022-00072-4.

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.

PURPOSE: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. EXPERIMENTAL DESIGN: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. RESULTS: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. CONCLUSIONS: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.

Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.

OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.

Endovascular Repair of a Descending Thoracic Aortic Aneurysm in a Pediatric Patient with Tuberous Sclerosis: A Case Report and Review of the Literature.

Aortic aneurysm in children is rare, but has been described in the tuberous sclerosis complex (TSC) population. While surgical repair has been utilized as the primary means of intervention, we present the first known case reporting exclusion of a descending thoracic aortic aneurysm with percutaneous covered stent implantation in a pediatric patient with TSC. A review of the literature is also included herein.

Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors: Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents.

African and American trypanosomiases are estimated to affect several million people across the world, with effective treatments distinctly lacking. New, ideally oral, treatments with higher efficacy against these diseases are desperately needed. Peroxisomal import matrix (PEX) proteins represent a very interesting target for structure- and ligand-based drug design. The PEX5-PEX14 protein-protein interface in particular has been highlighted as a target, with inhibitors shown to disrupt essential cell processes in trypanosomes, leading to cell death. In this work, we present a drug development campaign that utilizes the synergy between structural biology, computer-aided drug design, and medicinal chemistry in the quest to discover and develop new potential compounds to treat trypanosomiasis by targeting the PEX14-PEX5 interaction. Using the structure of the known lead compounds discovered by Dawidowski et al. as the template for a chemically advanced template search (CATS) algorithm, we performed scaffold-hopping to obtain a new class of compounds with trypanocidal activity, based on 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines chemistry. The initial compounds obtained were taken forward to a first round of hit-to-lead optimization by synthesis of derivatives, which show activities in the range of low- to high-digit micromolar IC50 in the in vitro tests. The NMR measurements confirm binding to PEX14 in solution, while immunofluorescent microscopy indicates disruption of protein import into the glycosomes, indicating that the PEX14-PEX5 protein-protein interface was successfully disrupted. These studies result in development of a novel scaffold for future lead optimization, while ADME testing gives an indication of further areas of improvement in the path from lead molecules toward a new drug active against trypanosomes.

Sizing Up Fontan Failure: Association with Increasing Weight in Adulthood.

Obesity has become increasingly recognized in adults with Fontan palliation, yet the relationship between weight changes in adulthood and Fontan failure is not clearly defined. We hypothesize that increasing weight in adulthood among Fontan patients is associated with the development of Fontan failure. Single-center data from adults with Fontan palliation who were not in Fontan failure at their first clinic visit in adulthood and who received ongoing care were retrospectively collected. Fontan failure was defined as death, transplant, diagnosis of protein losing enteropathy, predicted peak VO2 less than 50%, or new loop diuretic requirement. Anthropometric data including weight and BMI were collected. Change in weight was compared between those that developed Fontan failure, and those that remained failure-free. To estimate the association between weight change during adulthood and the risk of developing Fontan failure, a survival analysis using multiple Cox's proportional hazards regression model was performed. Overall, 104 patients were included in the analysis. Those that developed Fontan failure had a larger associated median weight gain than those who remained failure-free (7.8 kg vs. 4.9 kg, respectively; p = 0.011). In multivariable Cox regression analysis, increased weight during adulthood was associated with increased likelihood of developing Fontan failure (HR 1.36; CI 1.07-1.73; p = 0.011). Weight gain in adulthood is associated with the development of Fontan failure.

Sizing heart transplant donors in adults with congenital heart disease.

OBJECTIVE: Optimal donor sizing for heart transplantation (HT) in adults with congenital heart disease (CHD) remains unclear, given the propensity for pulmonary hypertension related to shunting, staged repairs, and periods of pulmonary overcirculation. We studied HT outcomes related to donor size matching in the adult CHD population. METHODS: We conducted a retrospective cohort analysis of patients with CHD undergoing HT in the United States from January 1, 2000, to December 31, 2015. Patients were selected from the United Network for Organ Sharing database; 827 patients met inclusion criteria and were analyzed. RESULTS: At a median follow-up of 1462 days, 548 (66.3%) subjects were alive and 279 (33.7%) were deceased. All-cause mortality did not differ based on donor sizing (by predicted heart mass ratio: hazard ratio, 1.03; confidence interval, 0.86-1.23; P = .74). Pulmonary hypertension was not significantly associated with survival (by predicted heart mass ratio, χ2 = 2.01, P = .73). CONCLUSIONS: Our data demonstrate that donor oversizing, to the extent used in current practice, does not affect survival after HT in adults with CHD. Our findings from the United Network for Organ Sharing database demonstrate that donor oversizing in these patients is not associated with improved mortality.

HeartMate 3 in a ccTGA patient.

A 49-year-old female with congenitally corrected (or levo-) transposition of the great arteries complicated by nonischemic cardiomyopathy presented for worsening heart failure despite guideline-directed medical therapy and was found to be in cardiogenic shock. She successfully underwent ventricular assist device placement with a HeartMate III to her systemic right ventricle as a bridge to transplantation.

Shape Similarity by Fractal Dimensionality: An Application in the de novo Design of (-)-Englerin A Mimetics.

Molecular shape and pharmacological function are interconnected. To capture shape, the fractal dimensionality concept was employed, providing a natural similarity measure for the virtual screening of de novo generated small molecules mimicking the structurally complex natural product (-)-englerin A. Two of the top-ranking designs were synthesized and tested for their ability to modulate transient receptor potential (TRP) cation channels which are cellular targets of (-)-englerin A. Intracellular calcium assays and electrophysiological whole-cell measurements of TRPC4 and TRPM8 channels revealed potent inhibitory effects of one of the computer-generated compounds. Four derivatives of this identified hit compound had comparable effects on TRPC4 and TRPM8. The results of this study corroborate the use of fractal dimensionality as an innovative shape-based molecular representation for molecular scaffold-hopping.

Sensitivity of musculoskeletal model-based lumbar spinal loading estimates to type of kinematic input and passive stiffness properties.

The study investigated the potential for obtaining more accurate spine joint reaction force (JRF) estimates from musculoskeletal models by incorporating dynamic stereo X-ray imaging (DSX)-based in vivo lumbar vertebral rotational and translational kinematics compared to generic, rhythm (RHY)-based kinematics, while also observing the influence of accompanying inputs: intervertebral segment stiffness and neutral state. A full-body OpenSim® musculoskeletal model, constructed by combining existing lower- and upper-body models, was driven based on one volunteer's (female; age 25; 60.8 kg; 176 cm) anthropometrics and kinematics from a series of upright standing and straight-legged dynamic lifting tasks. The lumbar spine portion was modified in a step-wise manner to observe effects of: (1) RHY vs. DSX lumbar kinematics; (2) No disc (bushing) stiffness (NBS); generic, linear bushing stiffness (LBS); subject-specific nonlinear bushing stiffness (NLBS); (3) Upright standing (UP) vs. Supine (SUP) neutral state; (4) Weight lifted: 4.5 kg vs. 13.6 kg. L4L5 JRF from 24 model variations based on combinations of aforementioned parameters were compared. Rhythm-based kinematics without translational components tends to over-predict JRF (31% and 39% for compression and shear, respectively) compared to DSX-based kinematics. Additionally, differences due to accompanying passive stiffness and neutral state choice combinations were even larger (>50%), indicating heightened demand on the quality of these accompanying inputs. The study not only highlights model sensitivity to choices made regarding the three primary inputs-kinematics, passive stiffness and neutral state- separately, but also how interactions between these choices can result in significant variability in joint loading estimates.

Heart transplantation and in-hospital outcomes in adult congenital heart disease patients with Fontan: A decade nationwide analysis from 2004 to 2014.

INTRODUCTION: Treatment of adult congenital heart disease patients who require advanced therapies remains challenging due to high perioperative and wait-list mortality and limited donors. Patients palliated with Fontan are at the highest risk of early mortality due to multiorgan involvement and few centers able to safely transplant them. We sought to evaluate the early outcomes of heart transplants in these adult Fontan patients. METHODS: Using the Nationwide Inpatient Sample database, we identified all adults aged at least 18 years old who underwent heart transplantation across U.S. hospitals from 2004 to 2014. We then identified those with specific ICD-9 codes to include tricuspid atresia, hypoplastic left heart syndrome and common ventricle. Multivariate regression models were created to adjust for potential confounders. RESULTS: A total of 93 Fontan patients underwent heart transplant during the study time (0.5% of all heart transplants). Compared to non-Fontan heart transplantations, Fontan patients were younger, with a higher incidence of liver disease and coagulopathy. Fontan patients receiving heart transplant had higher mortality during transplant hospitalization compared to non-Fontan patients (26.3% vs 5.3% OR, 18.10, CI, 5.06-65.0 P < .001). Extracorporeal membrane oxygenator (ECMO) usage and bleeding were also higher in the Fontan cohort with an OR of 5.30 (P = .016) and 5.32 (P = .015) for ECMO and bleeding, respectively. The remaining outcomes were similar for both cohorts. CONCLUSION: Adults with Fontan palliation undergoing heart transplantation have exceptionally high inpatient mortality, which is nearly five times that of non-Fontan heart transplant recipients, perhaps related to a delayed referral, surgical complexity, and coexistent, underrecognized liver failure.

A Dynamic Radiographic Imaging Study of Lumbar Intervertebral Disc Morphometry and Deformation In Vivo.

Intervertebral discs are important structural components of the spine but also are significant sources of morbidity, especially for the "low back" lumbar region. Mechanical damage to, or degeneration of, the lumbar discs can diminish their structural integrity and elicit debilitating low back pain. Advancement of reparative or regenerative means to treat damaged or degenerated discs is hindered by a lack of basic understanding of the disc load-deformation characteristics in vivo. The current study presents an in vivo analysis of the morphometry and deformation of lumbar (L2-S1) intervertebral discs in 10 healthy participants while performing a common lifting act, using novel dynamic radiographic imaging of the lumbar vertebral body motion. Data analyses show uniquely different (p < 0.05) characteristics in morphometry, normal and shear strain patterns of the L5S1 discs, while the rest of lumbar discs exhibit great similarity. In particular shear strains in L2-L5 discs exhibited stronger linear correlations (R2 ≥ 0.80) between strain changes and amount of lumbar flexion-extension motion compared to L5S1 (R2 ≤ 0.5). The study therefore advances the state of knowledge on in vivo mechanical responses of the lumbar intervertebral discs during functional tasks.