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.

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.

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.

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.

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.

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.

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.

Genealogies of mouse inbred strains.

The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently.

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.

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.

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.

Transcriptional regulation of meiosis in yeast.

The genes required for meiosis and sporulation in yeast are expressed at specific points in a highly regulated temporal pathway. Recent experiments using DNA microarrays to examine gene expression during meiosis and the identification of many regulatory factors have provided important advances in our understanding of how genes are regulated at the different stages of meiosis.

Critical illness with AH1N1v influenza in pregnancy: a comparison of two population-based cohorts.

OBJECTIVE: To compare admissions to intensive care units (ICUs) with confirmed AH1N1v influenza in pregnancy in Australia, New Zealand and the UK. DESIGN: National cohort studies. SETTING: ICUs in Australia, New Zealand and the UK. POPULATION: Fifty-nine women admitted to ICUs in Australia and New Zealand in June-August 2009, and 57 women admitted to ICUs in the UK in September 2009-January 2010. METHODS: Comparison of cohort data. MAIN OUTCOME MEASURES: Incidence of ICU admission, comparison of characteristics and outcomes. RESULTS: There was a significantly higher ICU admission risk in Australia and New Zealand than in the UK (risk ratio 2.59, 95% CI 1.75-3.85). Indigenous women from Australia and women with Maori/Pacific Island backgrounds from New Zealand had the highest admission risk (29.7 admissions per 10 000 maternities, 95% CI 17.9-46.3). Women admitted in Australia and New Zealand were significantly more likely to have a pre-existing medical condition (51% versus 21%, P = 0.001), but were less likely to receive antiviral treatment (80% versus 93%, P = 0.038) than women admitted in the UK. Women admitted in the UK had a longer length of hospital stay (median 21 days, range 3-128 days) than women admitted in Australia and New Zealand (median 12 days, range 3-66 days), but there were no other differences in maternal or pregnancy outcomes. CONCLUSIONS: The difference in admission risk may reflect a second phase effect from successful clinical and public health interventions, as well as differences in population characteristics between the countries. The overall severity of the AH1N1v influenza infection in pregnancy is evident, and emphasises the importance of an ongoing immunisation programme in pregnant women in both northern and southern hemispheres.

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.

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.

Surface X-ray speckles: coherent surface diffraction from Au(001).

We present coherent speckled x-ray diffraction patterns obtained from a monolayer of surface atoms. We measured both the specular anti-Bragg reflection and the off-specular hexagonal reconstruction peak for the Au(001) surface reconstruction. We observed fluctuations of the speckle patterns even when the integrated intensity appears static. By autocorrelating the speckle patterns, we were able to identify two qualitatively different surface dynamic behaviors of the hex reconstruction depending on the sample temperature.

Undiagnosed diabetes-data from the English longitudinal study of ageing.

AIMS: Diabetes UK estimates a quarter of UK cases of diabetes are undiagnosed; 750,000 people have undiagnosed diabetes in addition to 2.25 million with known diabetes, but research studies examining this are contradictory. The aim was to determine the prevalence of, and risk factors for, undiagnosed diabetes in the population of England aged > 50 years and to calculate the percentage of cases of undiagnosed diabetes. METHODS: This was a cross-sectional study in a nationally representative sample of 6739 people aged 52-79 years from the English Longitudinal Study of Ageing (ELSA) 2004/2005. Diabetes cases were ascertained by self-reported doctor diagnosis of diabetes. A fasting plasma glucose measurement after a minimum of 8-h fast was available for 2387 (38% of the participants without diabetes). Undiagnosed diabetes cases were based on a fasting plasma glucose >or= 7.0 mmol/l. RESULTS: The overall weighted prevalence of diabetes was 9.1%; 502 people (7.5%) had self-reported diabetes (9.0% of men and 6.0% of women); 36 (1.7%) had undiagnosed diabetes (2.6% of men and 0.8% of women). Of cases of diabetes, 18.5% were undiagnosed (22% in men, 12% in women). Significant risk factors for undiagnosed diabetes were male sex, higher body mass index, waist circumference, systolic blood pressure and triglycerides. CONCLUSIONS: In 2004 the prevalence of undiagnosed diabetes, and the proportion of cases of diabetes that were undiagnosed, appear smaller than in previous studies. This is likely to be due to increased awareness of diabetes and improved clinical care resulting in many of those with previously undetected disease having been diagnosed.