Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts.

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

Free Energy Perturbation Approach for Accurate Crystalline Aqueous Solubility Predictions.

Early assessment of crystalline thermodynamic solubility continues to be elusive for drug discovery and development despite its critical importance, especially for the ever-increasing fraction of poorly soluble drug candidates. Here we present a detailed evaluation of a physics-based free energy perturbation (FEP+) approach for computing the thermodynamic aqueous solubility. The predictive power of this approach is assessed across diverse chemical spaces, spanning pharmaceutically relevant literature compounds and more complex AbbVie compounds. Our approach achieves predictive (RMSE = 0.86) and differentiating power (R2 = 0.69) and therefore provides notably improved correlations to experimental solubility compared to state-of-the-art machine learning approaches that utilize quantum mechanics-based descriptors. The importance of explicit considerations of crystalline packing in predicting solubility by the FEP+ approach is also highlighted in this study. Finally, we show how computed energetics, including hydration and sublimation free energies, can provide further insights into molecule design to feed the medicinal chemistry DMTA cycle.

Overturned abusive head trauma and shaken baby syndrome convictions in the United States: Prevalence, legal basis, and medical evidence.

BACKGROUND: Media reports and the Innocence Network assert that wrongful Abusive Head Trauma (AHT)/Shaken Baby Syndrome (SBS) convictions pervade the United States (U.S.) criminal justice system. Yet, no empirical evaluation of overturned AHT/SBS convictions has been conducted. OBJECTIVE: To evaluate the prevalence, legal basis, and characteristics of appellate rulings of AHT/SBS convictions. PARTICIPANTS AND SETTING: U.S. appellate cases in a legal database, Westlaw. METHODS: Retrospective review of AHT/SBS convictions that had appellate rulings from January 2008 through December 2018. Multiple search terms ensured all potential AHT/SBS cases were included. A mixed-methods analysis was conducted on overturned AHT/SBS convictions. RESULTS: We identified a total of 1431 unique AHT/SBS criminal convictions that had appellate rulings since 2008. Of those, 49 convictions (3%) were overturned, and 1382 (97%) were affirmed/upheld. Of those overturned, 20 cases (1% overall) were overturned on medical evidence-related grounds. The most common themes from the medical evidence-related reversals were controversy over the AHT/SBS diagnosis (n = 12) and accidental injury mechanism (n = 11). After being overturned on appeal, upon retrial, 42% of defendants either re-plead guilty to or were convicted again of the same offense. CONCLUSION(S): AHT/SBS convictions are rarely overturned on medical evidence-related grounds. When overturned, medical evidence-related themes seldom reflect new scientific or clinical discoveries, but rather are alternative or differing medical opinions from those offered at the original trial. Our data tends to support the concerns of other authors regarding irresponsible communication of medical information in AHT/SBS cases.

Inferior vena cava filter fracture with strut migration on CT with volume rendering.

We present the computed tomography findings in a patient with a fractured IVC filter and migration of a broken strut to the right lower quadrant. The filter morphology and strut fragment are well demonstrated on volume rendered images confirming the value of volumetric 3D computed tomography imaging to evaluate IVC filter integrity and identify migrated filter fragments.

Novel Physics-Based Ensemble Modeling Approach That Utilizes 3D Molecular Conformation and Packing to Access Aqueous Thermodynamic Solubility: A Case Study of Orally Available Bromodomain and Extraterminal Domain Inhibitor Lead Optimization Series.

Drug design with patient centricity for ease of administration and pill burden requires robust understanding of the impact of chemical modifications on relevant physicochemical properties early in lead optimization. To this end, we have developed a physics-based ensemble approach to predict aqueous thermodynamic crystalline solubility, with a 2D chemical structure as the input. Predictions for the bromodomain and extraterminal domain (BET) inhibitor series show very close match (0.5 log unit) with measured thermodynamic solubility for cases with low crystal anisotropy and good match (1 log unit) for high anisotropy structures. The importance of thermodynamic solubility is clearly demonstrated by up to a 4 log unit drop in solubility compared to kinetic (amorphous) solubility in some cases and implications thereof, for instance on human dose. We have also demonstrated that incorporating predicted crystal structures in thermodynamic solubility prediction is necessary to differentiate (up to 4 log unit) between solubility of molecules within the series. Finally, our physics-based ensemble approach provides valuable structural insights into the origins of 3-D conformational landscapes, crystal polymorphism, and anisotropy that can be leveraged for both drug design and development.

Admission to long-stay residential care and mortality among people with and without dementia living at home but on the boundary of residential care: a competing risks survival analysis.

BACKGROUND: Health policy in many countries is underpinned by a commitment to support dependent older people to remain in their own home for as long as possible and practicable. This study explores factors affecting both admission to long-stay residential care (LSRC) and mortality among people with and without dementia who are currently living at home with intensive formal care support. METHODS: This is a cross-sectional study based on administrative data collected on 429 dependent older people in Ireland, 269 of whom were people with dementia. A cause-specific hazard model was used to investigate the hazard of admission to LSRC, while accounting for mortality as a competing risk and vice versa. RESULTS: Admission to LSRC was higher for people with dementia relative to people without and for those receiving lower amounts of informal care. The hazard of mortality was significantly higher for older people aged 85+, whereas it was lower for individuals with a medium level of dependency relative to those with high levels of dependency. The hazard of mortality was also influenced by the amount of informal care provision. CONCLUSION: People with dementia are more likely to be admitted to LSRC than people without. Care for people with dementia needs to be more specialised and personal, and intensity of provision should not be equated to the number of care hours on offer. Informal care provision may help to prevent admission to LSRC. Advanced age, physical dependency and informal care provision affect mortality, raising interesting issues in relation to resource allocation.

Few Versus Many-Body Physics of an Impurity Immersed in a Superfluid of Spin 1/2 Attractive Fermions.

In this Letter we investigate the properties of an impurity immersed in a superfluid of strongly correlated spin 1/2 fermions and we calculate the beyond-mean-field corrections to the energy of a weakly interacting impurity. We show that these corrections are divergent and have to be regularized by properly accounting for three-body physics in the problem and that our approach naturally provides a unifying framework for Bose and Fermi polaron physics.

Akkermansia muciniphila is permissive to arthritis in the K/BxN mouse model of arthritis.

Studies have identified abnormalities in the microbiota of patients with arthritis. To evaluate the pathogenicity of human microbiota, we performed fecal microbial transplantation from children with spondyloarthritis and controls to germ-free KRN/B6xNOD mice. Ankle swelling was equivalent in those that received patient vs. control microbiota. Principal coordinates analysis revealed incomplete uptake of the human microbiota with over-representation of two genera (Bacteroides and Akkermansia) among the transplanted mice. The microbiota predicted the extent of ankle swelling (R2 = 0.185, p = 0.018). The abundances of Bacteroides (r = -0.510, p = 0.010) inversely and Akkermansia (r = 0.367, p = 0.078) directly correlated with ankle swelling. Addition of Akkermansia muciniphila to Altered Schaedler's Flora (ASF) resulted in small but statistically significant increased ankle swelling as compared to mice that received ASF alone (4.0 mm, 3.9-4.1 vs. 3.9 mm, IQR 3.6-4.0, p = 0.041), as did addition of A. muciniphila cultures to transplanted human microbiota as compared to mice that received transplanted human microbiota alone (4.5 mm, IQR 4.3-5.5 vs. 4.1 mm, IQR 3.9-4.3, p = 0.019). This study supports previous findings of an association between A. muciniphila and arthritis.

Morphomechanics of dermis-A method for non-destructive testing of collagenous tissues.

BACKGROUND: Collagenous tissues store, transmit and dissipate elastic energy during mechanical deformation. In skin, mechanical energy is stored during loading and then is dissipated, which protects skin from mechanical failure. Thus, energy storage (elastic properties) and dissipation (viscous properties) are important characteristics of extracellular matrices (ECMs) that support the cyclic loading of ECMs without tissue failure. METHODS: Uniaxial stress-strain measurements on decellularized human dermis have been made and compared to results of a non-destructive technique involving optical coherence tomography (OCT) combined with vibrational analysis. In addition, Poisson's ratio has been determined for tensile deformation of decellularized dermis. RESULTS: The modulus of decellularized dermis measured using standard tensile stress-strain tests and that determined from calculations derived from natural frequency measurements give similar results. It is also observed that Poisson's ratio for dermis is between 0.38 and 0.63 after correction for changes in volume that occur during tensile deformation. These results suggest that the assumption that dermis and other ECMs deform at constant volume is incorrect and will lead to differences in the calculated modulus by conventional tensile stress-strain measurements. CONCLUSIONS: It is proposed that OCT in conjunction with vibrational analysis is a convenient way to non-destructively measure the modulus of decellularized dermis, ECMs and other materials that have a positive curvature to their stress-strain curves. Tensile deformation of dermis and possibly other ECMs is associated with an increase in Poisson's ratio consistent with a model of fluid expulsion from collagen fibrils during stretching. The value of Poisson's ratio should be considered in analyzing the mechanical properties of ECMs since at least dermis appears to be compressible during tensile deformation. Fluid expression during tensile deformation may play a role in mechanotransduction in skin in a similar manner to cartilage and bone tissue.

Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer.

E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with ß1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.

Introduced and Native Parasitoid Wasps Associated With Larch Casebearer (Lepidoptera: Coleophoridae) in Western Larch.

The larch casebearer [Coleophora laricella (Hubner)], a non-native insect, continues to impact western larch (Larix occidentalis Nutt.) through defoliation events in the Pacific Northwest. Biological control programs starting in the 1960s released seven species of parasitoid wasps to control C. laricella outbreaks. However, information about current population dynamics of C. laricella and associated parasitoids remains lacking. Therefore, the goal of this study was to document the presence, current distributions, densities, and parasitism rates of introduced and native parasitoid wasps occurring on C. laricella throughout the Northwestern U.S. range of L. occidentalis. We sampled L. occidentalis trees at multiple sites in Oregon, Washington, Idaho, and Montana. C. laricella was present at all sites with average state densities ranging from 6.2 to 13.1 moths/100 buds. We recovered two introduced hymenopteran biological control agents; Agathis pumila (Ratzeburg: Braconidae) at 79% of the sites, and Chrysocharis laricinellae (Ratzeburg: Eulophidae) at 63% of the sites. Fourteen species of native parasitic wasps were also recovered. The most common species were: Bracon sp., Spilochalcis albifrons, and Mesopolobus sp. The average native species parasitism rate across the four states was 9.0%, which was higher than the introduced species Ch. laricinellae (2.9%), but not as high as A. pumila (19.3%). While survey results suggest that native species may be more important for the control of C. laricella than previously thought, A. pumila remains the major source of regional control. However, further research is needed to better understand how introduced and native parasitoids interact to control invasive pest populations.

A mixture of Bose and Fermi superfluids.

Superconductivity and superfluidity of fermionic and bosonic systems are remarkable many-body quantum phenomena. In liquid helium and dilute gases, Bose and Fermi superfluidity has been observed separately, but producing a mixture in which both the fermionic and the bosonic components are superfluid is challenging. Here we report on the observation of such a mixture with dilute gases of two lithium isotopes, lithium-6 and lithium-7. We probe the collective dynamics of this system by exciting center-of-mass oscillations that exhibit extremely low damping below a certain critical velocity. Using high-precision spectroscopy of these modes, we observe coherent energy exchange and measure the coupling between the two superfluids. Our observations can be captured theoretically using a sum-rule approach that we interpret in terms of two coupled oscillators.

Accuracy and interrater reliability for the diagnosis of Barrett's neoplasia among users of a novel, portable high-resolution microendoscope.

The high-resolution microendoscope (HRME) is a novel imaging modality that may be useful in the surveillance of Barrett's esophagus in low-resource or community-based settings. In order to assess accuracy and interrater reliability of microendoscopists in identifying Barrett's-associated neoplasia using HRME images, we recruited 20 gastroenterologists with no microendoscopic experience and three expert microendoscopists in a large academic hospital in New York City to interpret HRME images. They prospectively reviewed 40 HRME images from 28 consecutive patients undergoing surveillance for metaplasia and low-grade dysplasia and/or evaluation for high-grade dysplasia or cancer. Images were reviewed in a blinded fashion, after a 4-minute training with 11 representative images. All imaged sites were biopsied and interpreted by an expert pathologist. Sensitivity of all endoscopists for identification of high-grade dysplasia or cancer was 0.90 (95% confidence interval [CI]: 0.88-0.92) and specificity was 0.82 (95% CI: 0.79-0.85). Positive and negative predictive values were 0.72 (95% CI: 0.68-0.77) and 0.94 (95% CI: 0.92-0.96), respectively. No significant differences in accuracy were observed between experts and novices (0.90 vs. 0.84). The kappa statistic for all raters was 0.56 (95% CI: 0.54-0.58), and the difference between groups was not significant (0.64 vs. 0.55). These data suggest that gastroenterologists can diagnose Barrett's-related neoplasia on HRME images with high sensitivity and specificity, without the aid of prior microendoscopy experience.

Genetic determinants of neuroglobin transcription.

Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3' end of NGB within the same LD block, 52 Kb apart and modestly correlated (r (2) = 0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3' and 5' flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.

Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development.

Britain's oldest birth cohort study, the MRC National Survey of Health and Development (NSHD) provides data to explore life time influences on ageing. The latest data collection was undertaken between 2006 and 2011 when study members were aged 60-64 and consisted of postal and pre-assessment questionnaires to eligible study members, followed by invitation to attend one of six clinical research facilities (CRFs) across the UK for clinical assessments, and dietary diaries and activity monitors in the days following the CRF visit. The option of a home visit for clinical assessments was provided if the study member refused or was unable to attend the CRF. We examined response and attrition, here describing rates overall and for postal and clinical assessment modes of data collection, identifying socioeconomic and health-related predictors of response, and assessing the continued representativeness of the sample. In total, 2,661 (84 % of the target sample) responded. Lower educational attainment, lower childhood cognition and lifelong smoking independently predicted lower likelihood of both overall response and CRF cooperation. At 53 years, not owning one's home and not being married predicted lower likelihood of overall response whereas manual social class and obesity predicted lower likelihood of CRF cooperation. Providing for collection of biomedical data in the home and use of assessment instruments and modes to retain study members with lower education attainment, lower cognition and poorer health behaviours should be priorities for helping reduce attrition amongst vulnerable ageing study members.

Contemporary management and outcomes for infants born with oesophageal atresia.

BACKGROUND: Reports on the management and outcome of rare conditions, such as oesophageal atresia, are frequently limited to case series reporting single-centre experience over many years. The aim of this study was to identify all infants born with oesophageal atresia in the UK and Ireland to describe current clinical practice and outcomes. METHODS: This was a prospective multicentre cohort study of all infants born with oesophageal atresia and/or tracheo-oesophageal fistula in 2008-2009 in the UK and Ireland to record current clinical management and early outcomes. RESULTS: A total of 151 infants admitted to 28 paediatric surgical units were identified. Some aspects of perioperative management were universal, including oesophageal decompression, operative technique and the use of transanastomotic tubes. However, there were a number of areas where clinical practice varied considerably, including the routine use of perioperative chest drains, postoperative contrast studies and antireflux medication, with each of these being employed in 30-50 per cent of patients. There was a trend towards routine postoperative ventilation. CONCLUSION: The prospective methodology used in this study can help identify practices that all surgeons employ and also those that few surgeons use. Areas of clinical equipoise can be recognized and avenues for further research identified.

Planning dementia services: new estimates of current and future prevalence rates of dementia for Ireland.

OBJECTIVES: The paper provides new estimates of dementia prevalence at a national and local level in Ireland and new projections of future numbers of people with dementia. METHODS: The prevalence of dementia at a national and local level has been calculated by applying European Collaboration on Dementia (EuroCoDe) prevalence rates to data from the Census of Population 2006. The National Disability Survey has been used to estimate the number of people with Down syndrome and dementia. Projections of future numbers of people with dementia have been calculated by applying EuroCoDe prevalence rates to the most recently available population projections from the Central Statistics Office (CSO). RESULTS: It is estimated that there were 41 740 people with dementia in Ireland in 2006. Estimates show that there are clear regional differences in prevalence of dementia across Ireland, with the largest proportion of people with dementia in the West of Ireland, and the Dublin North Eastern region having the lowest share of dementia. Our best estimate is that there are 700 people with Down syndrome and dementia in Ireland. Applying EuroCoDe prevalence rates to the most recent CSO population projections shows that the prevalence of dementia in Ireland will increase to between 67 493 and 70 000 in 2021 and to between 140 580 and 147 000 in 2041. CONCLUSIONS: Although there are several limitations to these estimates, the data provide timely and useful information for planning effective health and social care services, as well as raising public and professional awareness about dementia at a national level.

Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor-guanine nucleotide-binding protein, (GNAS) fusion bioassay.

Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2-3% prevalence in the population. The most common form of hyperthyroidism is Graves' disease. A diagnostic biomarker for Graves' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide-binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7·8, 8·7 and 7·6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves' disease.

The role of BMI across the life course in the relationship between age at menarche and diabetes, in a British Birth Cohort.

AIMS: Previous research showing an inverse association between age of menarche and adult diabetes relied on recalled age at menarche and did not adjust for BMI across the life course. We investigated the relationship between age at menarche and diabetes, and whether childhood, adolescent or adult BMI attenuates this relationship. METHODS: We used data from the Medical Research Council National Survey of Health and Development, a British birth cohort study of men and women born in 1946, with contemporaneous recording of the age of menarche, BMI at 2, 7, 15 and 20-53 years and diabetes status to 53 years. RESULTS: A significant inverse relationship between age at menarche and diabetes [hazard ratio = 0.73 per year older age at menarche (95% CI 0.56-0.96), P = 0.02] was attenuated by adjustment for adult BMI [hazard ratio 0.85 (95% CI 0.65-1.10), P = 0.2]. The effect of age at menarche on Type 2 diabetes was very similar to that for all types of diabetes. Attenuation of the association between age at menarche and diabetes was also observed with BMI at 15 years, but less so with BMI measured earlier in childhood. CONCLUSIONS: Earlier age at menarche is associated with a higher risk of diabetes, and specifically Type 2 diabetes, in later life, which is most strongly attenuated by adolescent and adult adiposity. Early menarche may be clinically useful in identifying women who are at risk of later adiposity and so of developing Type 2 diabetes.