Vitamin B5 is a context-dependent dietary regulator of nociception.

Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies. Here we identify new conserved and druggable analgesic targets using tissue-specific functional genomic screening of candidate "pain" genes in the fly. From these efforts we describe 23 new pain genes for further consideration. This included Acsl, a fatty acid-metabolizing enzyme and mammalian orthologs are involved in arachidonic acid metabolism. Acsl knockdown and mutant larvae showed delayed nocifensive responses to localized and global noxious heat. Mechanistically, knockdown of Acsl reduced dendritic branching of nociceptive neurons. Surprisingly, the pain phenotype in these animals could be rescued through dietary intervention with vitamin B5, highlighting the interplay between genetics, metabolism and nutrient environment to establish sensory perception thresholds. Together, our functional genomic screening within the sensory nociceptor has identified new nociception genes that provide a better understanding of pain biology and can help guide the development of new painkillers.

Cardiac power output ratio: Novel survival predictor after percutaneous ventricular assist device in cardiogenic shock.

AIMS: Currently, there is limited data on prognostic indicators after insertion of percutaneous ventricular assist device (PVAD) in the treatment of cardiogenic shock (CS). This study evaluated the prognostic role of cardiac power output (CPO) ratio, defined as CPO at 24 h divided by early CPO (30 min to 2 h), in CS patients after PVAD. METHODS AND RESULTS: Consecutive CS patients from the QEH-PVAD Registry were followed up for survival at 90 days after PVAD. Among 121 consecutive patients, 98 underwent right heart catheterization after PVAD, with CPO ratio available in 68 patients. The CPO ratio and 24-h CPO, but not the early CPO post PVAD, were significantly associated with 90-day survival, with corresponding area under curve in ROC analysis of 0.816, 0.740, and 0.469, respectively. In multivariate analysis, only the CPO ratio and lactate level at 24 h remained as independent survival predictors. The CPO ratio was not associated with age, sex, and body size. Patients with lower CPO ratio had significantly lower coronary perfusion pressure, worse right heart indices, and higher pulmonary vascular resistance. A lower CPO ratio was also significantly associated with mechanical ventilation and higher creatine kinase levels in myocardial infarction patients. CONCLUSION: In post-PVAD patients, the CPO ratio outperformed the absolute CPO values and other haemodynamic metrics in predicting survival at 90 days. Such a proportional change of CPO over time, likely reflecting native heart function recovery, may help to guide management of CS patients post-PVAD.

Use of intravascular ultrasound in inferior STEMI due to Type A aortic dissection.

A 57-year-old woman with good past health was admitted to the accident and emergency department at an outside hospital for sudden onset chest pain. Electrocardiogram revealed ST-segment elevation at inferior leads.

A Phase I Trial of a Methionine Restricted Diet with Concurrent Radiation Therapy.

Methionine is an essential amino acid critical for cell growth and survival. Preclinical evidence suggests a methionine restricted diet (MRD) sensitizes cancer to radiation therapy (RT), without significant adverse effects. However, this has never been evaluated in humans. The purpose of this pilot study was to evaluate the safety and feasibility of concurrent MRD with standard-of-care definitive RT in adults with any non-skin cancer malignancy. The MRD extended from 2 wk before RT initiation, through 2 wk beyond RT completion. The primary endpoint of safety was assessed as rate of grade 3 or higher acute and late toxicities. Feasibility was assessed with quantitative plasma amino acid panel every 2 wk during the MRD (target plasma methionine 13 µM). Nine patients were accrued over a two-year period, with five able to complete the treatment course. The trial was closed due to slow accrual and subjects' difficulty maintaining the diet. No grade 3 or higher adverse events were observed. Subjects' average methionine level was 18.8 µM during treatment, with average nadir 16.8 µM. These findings suggest the safety of concurrent MRD with RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients.

Morphological and functional types of tricuspid regurgitation: prognostic value in patients undergoing tricuspid annuloplasty during left-sided valvular surgery.

BACKGROUND: The nonuniform benefit of tricuspid annuloplasty may be explained by the proportionality of tricuspid regurgitation (TR) severity to right ventricular (RV) area. The purpose of this study was to delineate distinct morphological phenotypes of functional TR and investigate their prognostic implications in patients undergoing tricuspid annuloplasty during left-sided valvular surgery. METHODS: The ratios of pre-procedural effective regurgitant orifice area (EROA) with right ventricular end-diastolic area (RVDA) were retrospectively assessed in 290 patients undergoing tricuspid annuloplasty. Based on optimal thresholds derived from penalized splines and maximally selected rank statistics, patients were stratified into proportionate (EROA/RVDA ratio ≤ 1.74) and disproportionate TR (EROA/RVDA ratio > 1.74). RESULTS: Overall, 59 (20%) and 231 (80%) patients had proportionate and disproportionate TR, respectively. Compared to those with proportionate TR, patients with disproportionate TR were older, had a higher prevalence of atrial fibrillation, lower pulmonary pressures, more impaired RV function, and larger tricuspid leaflet tenting area. Over a median follow-up of 4.1 years, 79 adverse events (47 heart failure hospitalizations and 32 deaths) occurred. Patients with disproportionate TR had higher rates of adverse events than those with proportionate TR (32% vs 10%; P = 0.001) and were independently associated with poor outcomes on multivariate analysis. TR proportionality outperformed guideline-based classification of TR severity in outcome prediction and provided incremental prognostic value to both the EuroSCORE II and STS score (incremental χ2 = 6.757 and 9.094 respectively; both P < 0.05). CONCLUSIONS: Disproportionate TR is strongly associated with adverse prognosis and may aid patient selection and risk stratification for tricuspid annuloplasty with left-sided valvular surgery.

Clinical Value of Computational Angiography-derived Fractional Flow Reserve in Stable Coronary Artery Disease.

The utilization of FFR remains low. Our study evaluated the per-vessel prognostic value of computational pressure-flow dynamics-derived FFR (caFFR) among patients with stable coronary artery disease. A total of 3329 vessels from 1308 patients were included and analysed. They were stratified into ischaemic (caFFR ≤ 0.8) and non-ischaemic (caFFR > 0.8) cohorts, and the associations between PCI and outcomes were evaluated. The third cohort comprised all included vessels, and the associations between treatment adherent-to-caFFR (PCI in vessels with caFFR ≤ 0.8 and no PCI in vessels with caFFR > 0.8) and outcomes were evaluated. The primary outcome was VOCE, defined as a composite of vessel-related cardiovascular mortality, non-fatal myocardial infarction, and repeat revascularization. PCI was associated with a lower 3-year risk of VOCE in the ischaemic cohort (HR, 0.44; 95% CI, 0.26-0.74; P = 0.002) but not in the non-ischaemic cohort. The risk of VOCE was lower in the adherent-to-caFFR group (n = 2649) (HR, 0.69; 95% CI, 0.48-0.98; P = 0.039). A novel index that uses coronary angiography images to estimate FFR may have substantial clinical value in guiding management among patients with stable coronary artery disease.

Team-Based Coaching Intervention to Improve Contrast-Associated Acute Kidney Injury: A Cluster-Randomized Trial.

BACKGROUND: Up to 14% of patients in the United States undergoing cardiac catheterization each year experience AKI. Consistent use of risk minimization preventive strategies may improve outcomes. We hypothesized that team-based coaching in a Virtual Learning Collaborative (Collaborative) would reduce postprocedural AKI compared with Technical Assistance (Assistance), both with and without Automated Surveillance Reporting (Surveillance). METHODS: The IMPROVE AKI trial was a 2×2 factorial cluster-randomized trial across 20 Veterans Affairs medical centers (VAMCs). Participating VAMCs received Assistance, Assistance with Surveillance, Collaborative, or Collaborative with Surveillance for 18 months to implement AKI prevention strategies. The Assistance and Collaborative approaches promoted hydration and limited NPO and contrast dye dosing. We fit logistic regression models for AKI with site-level random effects accounting for the clustering of patients within medical centers with a prespecified interest in exploring differences across the four intervention arms. RESULTS: Among VAMCs' 4517 patients, 510 experienced AKI (235 AKI events among 1314 patients with preexisting CKD). AKI events in each intervention cluster were 110 (13%) in Assistance, 122 (11%) in Assistance with Surveillance, 190 (13%) in Collaborative, and 88 (8%) in Collaborative with Surveillance. Compared with sites receiving Assistance alone, case-mix-adjusted differences in AKI event proportions were -3% (95% confidence interval [CI], -4 to -3) for Assistance with Surveillance, -3% (95% CI, -3 to -2) for Collaborative, and -5% (95% CI, -6 to -5) for Collaborative with Surveillance. The Collaborative with Surveillance intervention cluster had a substantial 46% reduction in AKI compared with Assistance alone (adjusted odds ratio=0.54; 0.40-0.74). CONCLUSIONS: This implementation trial estimates that the combination of Collaborative with Surveillance reduced the odds of AKI by 46% at VAMCs and is suggestive of a reduction among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: IMPROVE AKI Cluster-Randomized Trial (IMPROVE-AKI), NCT03556293.

Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

Chronic stress-driven glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts.

Chronic environmental stress can profoundly impact cell and body function. Although the underlying mechanisms are poorly understood, epigenetics has emerged as a key link between environment and health. The genomic effects of stress are thought to be mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans, which act via the glucocorticoid receptor (GR). To dissect how chronic stress-driven GR activation influences epigenetic and cell states, human fibroblasts underwent prolonged exposure to physiological stress levels of cortisol and/or a selective GR antagonist. Cortisol was found to drive robust changes in cell proliferation, migration, and morphology, which were abrogated by concomitant GR blockade. The GR-driven cell phenotypes were accompanied by widespread, yet genomic context-dependent, changes in DNA methylation and mRNA expression, including gene loci with known roles in cell proliferation and migration. These findings provide insights into how chronic stress-driven functional epigenomic patterns become established to shape key cell phenotypes.

Sub-second periodicity in a fast radio burst.

Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light years1. The nature of their progenitors and their emission mechanism remain open astrophysical questions2. Here we report the detection of the multicomponent FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components, with a significance of 6.5σ. The long (roughly 3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere3,4, as opposed to emission regions located further away from the star, as predicted by some models5.

Evidence of Two-Source King Plot Nonlinearity in Spectroscopic Search for New Boson.

Optical precision spectroscopy of isotope shifts can be used to test for new forces beyond the standard model, and to determine basic properties of atomic nuclei. We measure isotope shifts on the highly forbidden ^{2}S_{1/2}→^{2}F_{7/2} octupole transition of trapped ^{168,170,172,174,176}Yb ions. When combined with previous measurements in Yb^{+} and very recent measurements in Yb, the data reveal a King plot nonlinearity of up to 240σ. The trends exhibited by experimental data are explained by nuclear density functional theory calculations with the Fayans functional. We also find, with 4.3σ confidence, that there is a second distinct source of nonlinearity, and discuss its possible origin.

Occupational performance issues in older adults with subjective cognitive decline.

PURPOSE: To describe and categorize difficulties in daily activities of older adults with subjective cognitive decline (SCD) compared to individuals with mild cognitive impairment (MCI). METHODS: Deductive quantitative content analysis was used to classify reported issues in the performance of meaningful daily activities, in older adults with SCD (n = 67; age= 70 ± 6.3) or MCI (n = 42; age= 72 ± 6.6). The occupational performance issues were identified using the Canadian Occupational Performance Measure, a semi-structured interview, and categorised using the International Classification of Functioning, Disability and Health (ICF). RESULTS: Both groups identified issues in all nine ICF "Activities and Participation" domains, with no significant group effects on seven of them. The most frequently affected "Activities and Participation" domains in both groups were "Self-care" (e.g. exercise and diet); "Community, social and civic life" (e.g. social-leisure activities); and "General tasks and demands" (e.g. time management). Over 90% of the issues in both groups were described in the context of difficulties in "Mental functions" (e.g. memory and higher-level cognitive functions). CONCLUSIONS: Older adults with SCD, although independent, identified a variety of daily activities that they are not performing satisfactorily, remarkably similar in nature to the occupational performance issues described by older adults with MCI.Implications for RehabilitationOlder adults with SCD identified difficulties in performing social and leisure activities, maintaining healthy lifestyle behaviours, and managing multiple daily tasks.The daily challenges described by older adults with SCD are similar in nature to those identified by those with MCI.Older adults with SCD and MCI describe their daily challenges are related not only to memory problems, but also to executive dysfunction.Interventions for older adults with SCD should aim to improve self-identified problems in everyday functioning.

Radium-223 dichloride causes transient changes in natural killer cell population and cytotoxic function.

RATIONALE: Natural killer (NK) cells play an important role in both the innate and adaptive arms of the immune system. While previous studies have demonstrated the effects of ionizing radiation on cytotoxic function of NK cells, little is known about how a chronic exposure to high LET alpha particles emitted by radionuclides will affect both NK population size and function. This study was conducted to determine the effects of 223RaCl2 on splenic NK cell population size and function in Swiss Webster mice. METHODS: Swiss Webster mice were administered intravenously with 0, 50, or 600 kBq/kg 223RaCl2. Spleens were harvested at 5, 12, and 19 days post-administration. The numbers of splenocytes per spleen were enumerated and flow cytometry was used to assess changes in the distribution of splenocyte subpopulations of B, CD4 and CD8 T lymphocytes, and NK cells. NK functional activity was quantified using YAC-1 target cells and the 51Cr-release assay. RESULTS: The total number of splenocytes was unaffected by 223RaCl2. However, significant changes in the distribution of splenocyte subpopulations were observed for NK cells and CD8 T lymphocytes. NK functional activity was enhanced substantially relative to controls at 12 days post-administration, but decreased markedly by day 19. CONCLUSION: NK functional activity is both diminished and enhanced by 223RaCl2 depending on both administered activity and time post-administration. These results suggest that there may be an optimum window of time to combine the 223RaCl2-induced antitumor NK cell response with other cancer therapies that elicit immune activation.

Modeling bystander effects that cause growth delay of breast cancer xenografts in bone marrow of mice treated with radium-223.

RATIONALE: The role of radiation-induced bystander effects in cancer therapy with alpha-particle emitting radiopharmaceuticals remains unclear. With renewed interest in using alpha-particle emitters to sterilize disseminated tumor cells, micrometastases, and tumors, a better understanding of the direct effects of alpha particles and the contribution of the bystander responses they induce is needed to refine dosimetric models that help predict clinical benefit. Accordingly, this work models and quantifies the relative importance of direct effects (DE) and bystander effects (BE) in the growth delay of human breast cancer xenografts observed previously in the tibiae of mice treated with 223RaCl2. METHODS: A computational model of MDA-MB-231 and MCF-7 human breast cancer xenografts in the tibial bone marrow of mice administered 223RaCl2 was created. A Monte Carlo radiation transport simulation was performed to assess individual cell absorbed doses. The responses of the breast cancer cells to direct alpha particle irradiation and gamma irradiation were needed as input data for the model and were determined experimentally using a colony-forming assay and compared to the responses of preosteoblast MC3T3-E1 and osteocyte-like MLO-Y4 bone cells. Using these data, a scheme was devised to simulate the dynamic proliferation of the tumors in vivo, including DE and BE propagated from the irradiated cells. The parameters of the scheme were estimated semi-empirically to fit experimental tumor growth. RESULTS: A robust BE component, in addition to a much smaller DE component, was required to simulate the in vivo tumor proliferation. We also found that the relative biological effectiveness (RBE) for cell killing by alpha particle radiation was greater for the bone cells than the tumor cells. CONCLUSION: This modeling study demonstrates that DE of radiation alone cannot explain experimental observations of 223RaCl2-induced growth delay of human breast cancer xenografts. Furthermore, while the mechanisms underlying BE remain unclear, the addition of a BE component to the model is necessary to provide an accurate prediction of the growth delay. More complex models are needed to further comprehend the extent and complexity of 223RaCl2-induced BE.

Radium-223-Induced Bystander Effects Cause DNA Damage and Apoptosis in Disseminated Tumor Cells in Bone Marrow.

Radiation-induced bystander effects have been implicated in contributing to the growth delay of disseminated tumor cells (DTC) caused by 223RaCl2, an alpha particle-emitting radiopharmaceutical. To understand how 223RaCl2 affects the growth, we have quantified biological changes caused by direct effects of radiation and bystander effects caused by the emitted radiations on DTC and osteocytes. Characterizing these effects contribute to understanding the efficacy of alpha particle-emitting radiopharmaceuticals and guide expansion of their use clinically. MDA-MB-231 or MCF-7 human breast cancer cells were inoculated intratibially into nude mice that were previously injected intravenously with 50 or 600 kBq/kg 223RaCl2. At 1-day and 3-days postinoculation, tibiae were harvested and examined for DNA damage (γ-H2AX foci) and apoptosis in osteocytes and cancer cells located within and beyond the range (70 µm) of alpha particles emitted from the bone surface. Irradiated and bystander MDA-MB-231 and MCF-7 cells harbored DNA damage. Bystander MDA-MB-231 cells expressed DNA damage at both treatment levels while bystander MCF-7 cells required the higher administered activity. Osteocytes also had DNA damage regardless of inoculated cancer cell line. The extent of DNA damage was quantified by increases in low (1-2 foci), medium (3-5 foci), and high (5+ foci) damage. MDA-MB-231 but not MCF-7 bystander cells showed increases in apoptosis in 223RaCl2-treated animals, as did irradiated osteocytes. In summary, radiation-induced bystander effects contribute to DTC cytotoxicity caused by 223RaCl2. IMPLICATIONS: This observation supports clinical investigation of the efficacy of 223RaCl2 to prevent breast cancer DTC from progressing to oligometastases.

Analysis of Survival Benefits of Living Versus Deceased Donor Liver Transplant in High Model for End-Stage Liver Disease and Hepatorenal Syndrome.

BACKGROUND AND AIMS: Previous recommendations suggested living donor liver transplantation (LDLT) should not be considered for patients with Model for End-Stage Liver Disease (MELD) > 25 and hepatorenal syndrome (HRS). APPROACH AND RESULTS: Patients who were listed with MELD > 25 from 2008 to 2017 were analyzed with intention-to-treat (ITT) basis retrospectively. Patients who had a potential live donor were analyzed as ITT-LDLT, whereas those who had none belonged to ITT-deceased donor liver transplantation (DDLT) group. ITT-overall survival (OS) was analyzed from the time of listing. Three hundred twenty-five patients were listed (ITT-LDLT n = 212, ITT-DDLT n = 113). The risk of delist/death was lower in the ITT-LDLT group (43.4% vs. 19.8%, P < 0.001), whereas the transplant rate was higher in the ITT-LDLT group (78.3% vs. 52.2%, P < 0.001). The 5-year ITT-OS was superior in the ITT-LDLT group (72.6% vs. 49.5%, P < 0.001) for patients with MELD > 25 and patients with both MELD > 25 and HRS (56% vs. 33.8%, P < 0.001). Waitlist mortality was the highest early after listing, and the distinct alteration of slope at survival curve showed that the benefits of ITT-LDLT occurred within the first month after listing. Perioperative outcomes and 5-year patient survival were comparable for patients with MELD > 25 (88% vs. 85.4%, P = 0.279) and patients with both MELD > 25 and HRS (77% vs. 76.4%, P = 0.701) after LDLT and DDLT, respectively. The LDLT group has a higher rate of renal recovery by 1 month (77.4% vs. 59.1%, P = 0.003) and 3 months (86.1% vs, 74.5%, P = 0.029), whereas the long-term estimated glomerular filtration rate (eGFR) was similar between the 2 groups. ITT-LDLT reduced the hazard of mortality (hazard ratio = 0.387-0.552) across all MELD strata. CONCLUSIONS: The ITT-LDLT reduced waitlist mortality and allowed an earlier access to transplant. LDLT in patients with high MELD/HRS was feasible, and they had similar perioperative outcomes and better renal recovery, whereas the long-term survival and eGFR were comparable with DDLT. LDLT should be considered for patients with high MELD/HRS, and the application of LDLT should not be restricted with a MELD cutoff.

Mutations in domain IV of elongation factor EF-G confer -1 frameshifting.

A recent crystal structure of a ribosome complex undergoing partial translocation in the absence of elongation factor EF-G showed disruption of codon-anticodon pairing and slippage of the reading frame by -1, directly implicating EF-G in preservation of the translational reading frame. Among mutations identified in a random screen for dominant-lethal mutations of EF-G were a cluster of six that map to the tip of domain IV, which has been shown to contact the codon-anticodon duplex in trapped translocation intermediates. In vitro synthesis of a full-length protein using these mutant EF-Gs revealed dramatically increased -1 frameshifting, providing new evidence for a role for domain IV of EF-G in maintaining the reading frame. These mutations also caused decreased rates of mRNA translocation and rotational movement of the head and body domains of the 30S ribosomal subunit during translocation. Our results are in general agreement with recent findings from Rodnina and coworkers based on in vitro translation of an oligopeptide using EF-Gs containing mutations at two positions in domain IV, who found an inverse correlation between the degree of frameshifting and rates of translocation. Four of our six mutations are substitutions at positions that interact with the translocating tRNA, in each case contacting the RNA backbone of the anticodon loop. We suggest that EF-G helps to preserve the translational reading frame by preventing uncoupled movement of the tRNA through these contacts; a further possibility is that these interactions may stabilize a conformation of the anticodon that favors base-pairing with its codon.

Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts.

Psychosocial stress, especially when chronic or excessive, can increase disease risk and accelerate biological aging. Although the underlying mechanisms are unclear, in vivo studies have associated exposure to stress and glucocorticoid stress hormones with shorter telomere length. However, the extent to which prolonged glucocorticoid exposure can shorten telomeres in controlled experimental settings remains unknown. Using a well-characterized cell line of human fibroblasts that undergo gradual telomere shortening during serial passaging in culture, we show that prolonged exposure (up to 51 days) to either naturalistic levels of the human endogenous glucocorticoid cortisol or the more potent synthetic glucocorticoid dexamethasone is not sufficient to accelerate telomere shortening. While our findings await extension in other cell types and biological contexts, they indicate that the in vivo association of psychosocial stress with telomere shortening is unlikely to be mediated by a direct and universal glucocorticoid effect on telomere length.