Swimming Together Upstream: How to Align MLP Services with U.S. Healthcare Delivery.

Medical-legal partnership (MLP) embeds attorneys and paralegals into care delivery to help clinicians address root causes of health inequities. Notwithstanding decades of favorable outcomes, MLP is not as well-known as might be expected. In this essay, the authors explore ways in which strategic alignment of legal services with healthcare services in terms of professionalism, information collection and sharing, and financing might help the MLP movement become a more widespread, sustainable model for holistic care delivery.

BSHI/BTS guidance on crossmatching before deceased donor kidney transplantation.

All UK H&I laboratories and transplant units operate under a single national kidney offering policy, but there have been variations in approach regarding when to undertake the pre-transplant crossmatch test. In order to minimize cold ischaemia times for deceased donor kidney transplantation we sought to find ways to be able to report a crossmatch result as early as possible in the donation process. A panel of experts in transplant surgery, nephrology, specialist nursing in organ donation and H&I (all relevant UK laboratories represented) assessed evidence and opinion concerning five factors that relate to the effectiveness of the crossmatch process, as follows: when the result should be ready for reporting; what level of donor HLA typing is needed; crossmatch sample type and availability; fairness and equity; risks and patient safety. Guidelines aimed at improving practice based on these issues are presented, and we expect that following these will allow H&I laboratories to contribute to reducing CIT in deceased donor kidney transplantation.

Preliminary Thermoluminescent Dosimeter Glow Curve Analysis with Automated Glow Peak Identification for LiF:Mg,Ti.

ABSTRACT: When appropriately analyzed, thermoluminescent dosimeter glow curve analysis allows for improved quantification of thermoluminescent material behavior while flagging abnormalities. The mathematical separation of a glow curve into contributions from energetically unique trap states, or glow curve analysis, may be used to remove undesired effects of signal fading for complex materials. A generalized glow curve analysis software for the separation of glow curves is presented in this paper. Written in C++, the software uses the first-order kinetics model with automatic peak identification. The automatic identification of peaks is achieved through a unique peak-finding algorithm. The program was performance tested using experimental glow curve data from LiF:Mg,Ti, and comparative results are presented.

CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells.

Many metabolic phenotypes in cancer cells are also characteristic of proliferating nontransformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate and provide a model to distinguish the metabolic influences of oncogenic mutations and nononcogenic growth.

The Roles of Disliking, Deservingness, and Envy in Predicting Schadenfreude.

Schadenfreude (pleasure about another's misfortune) was studied using written scenarios that were manipulated to include elements that elicited disliking of the target, envy of the target, and/or deservingness of the misfortune. This was the first time all the three predictors were included in a single study, allowing for a test of their possible interactive effects. Study 1 created a large pool of scenarios based on a pilot study and had participants rate them regarding how much disliking, deservingness, or envy was felt. The eight scenarios that were most effective in eliciting the various combinations of predictors were then used in Study 2 to test for schadenfreude reactions. Results revealed strong main effects for disliking and deservingness. Interactions showed that disliking attenuated the effect of deservingness, especially for female participants. Finally, further evidence was found that malicious but not benign envy predicted schadenfreude.

Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

The Good, the Bad, and the Future of Drones in Tactical/Operational Medicine.

Unmanned aerial vehicles (UAVs) have seen expansion with their applications in many fields, including the opportunity these tools offer to improve medical care. Drones have significant potential for use in the tactical setting. New, unique possibilities for these drones are emerging constantly, but there is no standardized inclusion specifically with tactical medicine operations. This article is a review of the future possibilities of drones, the associated risks that drones present, and the current application of drone technology in the field of civilian operational/tactical medicine.

Subcutaneous rather than intravenous ustekinumab induction is associated with comparable circulating drug levels and early clinical response: a pilot study.

BACKGROUND: Ustekinumab (USK) is licenced for intravenous induction and subcutaneous (S/C) maintenance in Crohn's disease. AIM: To evaluate ustekinumab trough concentrations and clinical response with exclusive subcutaneous ustekinumab induction. METHODS: Patients with Crohn's disease who initiated treatment with subcutaneous ustekinumab at a single academic centre were included in this pilot study. A dosage of 360 mg ustekinumab was given subcutaneously in divided doses; 180 mg at Week 0, 90 mg at Week 1 and 90 mg at Week 2, with corresponding ustekinumab trough concentrations assessed to Week 8. The primary outcome measures were trough serum ustekinumab levels and clinical remission at Week 8. Secondary outcome measures were trough serum ustekinumab levels at Week 1 & 2 and changes in C-reactive protein, albumin and faecal calprotectin at Week 8. RESULTS: Nineteen patients were included. Median Week 8 ustekinumab trough concentrations were 6.1 µg/mL (Inter-quartile range 4-9.8 µg/mL). There was a significant improvement in Harvey Bradshaw index from Week 0 (median HBI 5; interquartile range 2-8) to Week 8 (median HBI 1; interquartile range 0-3) (P = 0.002). C-reactive protein levels did not change significantly but faecal calprotectin improved significantly; median faecal calprotectin at Week 0 was 533 µg/g; at Week 8, it was 278 µg/g (P = 0.038). CONCLUSIONS: Ustekinumab trough concentrations are comparable whether ustekinumab induction treatment was administered subcutaneously or intravenously. A significant improvement in symptoms and faecal calprotectin was noted. These results support the use of subcutaneous induction as an alternative if there are barriers to intravenous induction.

High-throughput identification of RNA nuclear enrichment sequences.

In the post-genomic era, thousands of putative noncoding regulatory regions have been identified, such as enhancers, promoters, long noncoding RNAs (lncRNAs), and a cadre of small peptides. These ever-growing catalogs require high-throughput assays to test their functionality at scale. Massively parallel reporter assays have greatly enhanced the understanding of noncoding DNA elements en masse Here, we present a massively parallel RNA assay (MPRNA) that can assay 10,000 or more RNA segments for RNA-based functionality. We applied MPRNA to identify RNA-based nuclear localization domains harbored in lncRNAs. We examined a pool of 11,969 oligos densely tiling 38 human lncRNAs that were fused to a cytosolic transcript. After cell fractionation and barcode sequencing, we identified 109 unique RNA regions that significantly enriched this cytosolic transcript in the nucleus including a cytosine-rich motif. These nuclear enrichment sequences are highly conserved and over-represented in global nuclear fractionation sequencing. Importantly, many of these regions were independently validated by single-molecule RNA fluorescence in situ hybridization. Overall, we demonstrate the utility of MPRNA for future investigation of RNA-based functionalities.

The Relationship Between Personality and Schadenfreude in Hypothetical Versus Live Situations.

This study sought to investigate how individual differences are related to schadenfreude (pleasure derived from another's misfortune) by replicating past findings and extending them to additional personality traits. Because most past research on schadenfreude has relied heavily on the use of reactions to hypothetical scenarios, an attempt was made to demonstrate external validity by also including a reaction to a live event (confederate misfortune). For the scenarios, schadenfreude was positively correlated with the Dark Triad and just world beliefs; negatively correlated with empathy and agreeableness; and uncorrelated with dispositional envy, self-esteem, or the remaining Big Five traits. For the live event, no personality traits were correlated with schadenfreude, suggesting responses to hypothetical situations may not be representative of real-life schadenfreude events.

Increased non-melanoma skin cancer risk in young patients with inflammatory bowel disease on immunomodulatory therapy: a retrospective single-centre cohort study.

BACKGROUND: Recent studies report an increased risk of non-melanoma skin cancer (NMSC) in immunosuppressed patients with inflammatory bowel disease (IBD). Concurrently, paediatric IBD incidence is rising, with more patients now exposed to immunomodulators from a younger age. OBJECTIVES: To investigate NMSC incidence and to examine the risk associated with immunomodulators in the development of NMSC in patients with IBD. METHODS: This was a retrospective single-centre cohort study. Patients with IBD attending a tertiary adult hospital from 1994 to 2013 were included. Skin cancer incidence was compared with population data from the National Cancer Registry of Ireland (NCRI) to calculate standardized incidence ratio (SIR). Logistic regression was utilized for risk factor analysis. RESULTS: Two thousand and fifty-three patients with IBD were studied. The SIR for NMSC in patients with IBD taking immunomodulators overall was 1.8 (95% CI: 1.0-2.7) with age-specific rates significantly elevated across certain age categories. Exposure to thiopurines (OR: 5.26, 95% CI: 2.15-12.93, P < 0.001) and in particular thiopurines and/or tumour necrosis factor alpha (TNF-α) inhibitors (OR: 6.45, 95% CI: 2.69-15.95, P < 0.001) was significantly associated with NMSC. The majority (82%) of those exposed to a TNF-α inhibitor also had thiopurine exposure. CONCLUSIONS: Compliance with skin cancer preventative measures should be highlighted to all patients with IBD. There should be a low threshold for dermatology referral for immunosuppressed patients, particularly those with a history of exposure to dual immunomodulators from a young age.

A statistical approach for identifying differential distributions in single-cell RNA-seq experiments.

The ability to quantify cellular heterogeneity is a major advantage of single-cell technologies. However, statistical methods often treat cellular heterogeneity as a nuisance. We present a novel method to characterize differences in expression in the presence of distinct expression states within and among biological conditions. We demonstrate that this framework can detect differential expression patterns under a wide range of settings. Compared to existing approaches, this method has higher power to detect subtle differences in gene expression distributions that are more complex than a mean shift, and can characterize those differences. The freely available R package scDD implements the approach.

The Cost of Blindness in the Republic of Ireland 2010-2020.

Aims. To estimate the prevalence of blindness in the Republic of Ireland and the associated financial and total economic cost between 2010 and 2020. Methods. Estimates for the prevalence of blindness in the Republic of Ireland were based on blindness registration data from the National Council for the Blind of Ireland. Estimates for the financial and total economic cost of blindness were based on the sum of direct and indirect healthcare and nonhealthcare costs. Results. We estimate that there were 12,995 blind individuals in Ireland in 2010 and in 2020 there will be 17,997. We estimate that the financial and total economic costs of blindness in the Republic of Ireland in 2010 were €276.6 million and €809 million, respectively, and will increase in 2020 to €367 million and €1.1 billion, respectively. Conclusions. Here, ninety-eight percent of the cost of blindness is borne by the Departments of Social Protection and Finance and not by the Department of Health as might initially be expected. Cost of illness studies should play a role in public policy making as they help to quantify the indirect or "hidden" costs of disability and so help to reveal the true cost of illness.

SEEING YOU FALL VS TAKING YOU DOWN: THE ROLES OF AGENCY AND LIKING IN SCHADENFREUDE.

People are more likely to experience schadenfreude, i.e., take pleasure in the misfortunes of another, if they do not like the person experiencing the downfall. In the current study, the roles of liking and agency (being the cause of the downfall vs a passive observer) were investigated using a live (rather than hypothetical) situation for participants to react to. Participants were exposed to a rude, neutral, or nice confederate who won a coveted prize. Participants were then put into a position to either cause the confederate to lose her prize, or to only passively observe it happen. Feelings of schadenfreude were strongest when participants were the agent of a rude other's downfall. Implications for incorporating aspects of this study into future research were discussed.

MADGiC: a model-based approach for identifying driver genes in cancer.

MOTIVATION: Identifying and prioritizing somatic mutations is an important and challenging area of cancer research that can provide new insights into gene function as well as new targets for drug development. Most methods for prioritizing mutations rely primarily on frequency-based criteria, where a gene is identified as having a driver mutation if it is altered in significantly more samples than expected according to a background model. Although useful, frequency-based methods are limited in that all mutations are treated equally. It is well known, however, that some mutations have no functional consequence, while others may have a major deleterious impact. The spatial pattern of mutations within a gene provides further insight into their functional consequence. Properly accounting for these factors improves both the power and accuracy of inference. Also important is an accurate background model. RESULTS: Here, we develop a Model-based Approach for identifying Driver Genes in Cancer (termed MADGiC) that incorporates both frequency and functional impact criteria and accommodates a number of factors to improve the background model. Simulation studies demonstrate advantages of the approach, including a substantial increase in power over competing methods. Further advantages are illustrated in an analysis of ovarian and lung cancer data from The Cancer Genome Atlas (TCGA) project.

Methods for collapsing multiple rare variants in whole-genome sequence data.

Genetic Analysis Workshop 18 provided whole-genome sequence data in a pedigree-based sample and longitudinal phenotype data for hypertension and related traits, presenting an excellent opportunity for evaluating analysis choices. We summarize the nine contributions to the working group on collapsing methods, which evaluated various approaches for the analysis of multiple rare variants. One contributor defined a variant prioritization scheme, whereas the remaining eight contributors evaluated statistical methods for association analysis. Six contributors chose the gene as the genomic region for collapsing variants, whereas three contributors chose nonoverlapping sliding windows across the entire genome. Statistical methods spanned most of the published methods, including well-established burden tests, variance-components-type tests, and recently developed hybrid approaches. Lesser known methods, such as functional principal components analysis, higher criticism, and homozygosity association, and some newly introduced methods were also used. We found that performance of these methods depended on the characteristics of the genomic region, such as effect size and direction of variants under consideration. Except for MAP4 and FLT3, the performance of all statistical methods to identify rare casual variants was disappointingly poor, providing overall power almost identical to the type I error. This poor performance may have arisen from a combination of (1) small sample size, (2) small effects of most of the causal variants, explaining a small fraction of variance, (3) use of incomplete annotation information, and (4) linkage disequilibrium between causal variants in a gene and noncausal variants in nearby genes. Our findings demonstrate challenges in analyzing rare variants identified from sequence data.