Mapping the geographical distribution of the mucosa-associated gut microbiome in GI-symptomatic children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by cognitive, behavioral, and communication impairments. In the past few years, it has been proposed that alterations in the gut microbiota may contribute to an aberrant communication between the gut and brain in children with ASD. Consistent with this notion, several studies have demonstrated that children with ASD have an altered fecal microbiota compared with typically developing (TD) children. However, it is unclear where along the length of the gastrointestinal (GI) tract these alterations in microbial communities occur. In addition, the variation between specific mucosa-associated communities remains unknown. To address this gap in knowledge of the microbiome associated with ASD, biopsies from the antrum, duodenum, ileum, right colon, and rectum of children with ASD and age- and sex-matched TD children were examined by 16S rRNA sequencing. We observed an overall elevated abundance of Bacillota and Bacteroidota and a decreased abundance of Pseudomonadota in all GI tract regions of both male and female children with ASD compared with TD children. Further analysis at the genera level revealed unique differences in the microbiome in the different regions of the GI tract in children with ASD compared with TD children. We also observed sex-specific differences in the gut microbiota composition in children with ASD. These data indicate that the microbiota of children with ASD is altered in multiple regions of the GI tract and that different anatomic locations have unique alterations in mucosa-associated bacterial genera.NEW & NOTEWORTHY Analysis in stool samples has shown gut microbiota alterations in children with autism spectrum disorder (ASD) compared with typically developing (TD) children. However, it is unclear which segment(s) of the gut exhibit alterations in microbiome composition. In this study, we examined microbiota composition along the gastrointestinal (GI) tract in the stomach, duodenum, ileum, right colon, and rectum. We found site-specific and sex-specific differences in the gut microbiota of children with ASD, compared with controls.

Selexipag Dosing Strategies for Pediatric Patients with Pulmonary Arterial Hypertension.

This retrospective chart review of patients less than 18 years old with pulmonary arterial hypertension (PAH) receiving selexipag was conducted to describe selexipag dosing practices, impact on concomitant PAH therapies, and the safety and efficacy of selexipag. Twenty-seven patients aged 1-17 years started a median dose of oral selexipag 100 µg twice daily. Therapy was increased by a median of 100 µg twice daily every 6 days to a maximally tolerated median dose of 800 µg twice daily. All 24 patients on another prostacyclin derivative were able to discontinue therapy at their maximum tolerated selexipag dose; other concomitant PAH therapies did not change. Changes in echocardiogram data and 6-MWT results were variable. No patients discontinued selexipag; four patients received decreased doses due to flushing (n = 1), drug interactions (n = 2), or increased frequency of nose bleeds (n = 1).

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results.

Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and menstrual suppression or surgery prior to the next transfer has been reported to be beneficial. In this study, we performed endometrial biopsy in a subset of women with UEETF, testing for the oncogene BCL6 and the histone deacetylase SIRT1. We compared 205 PGT-A cycles outcomes and provide those results following treatment with GnRH agonist versus controls (no treatment). Based on these and previous promising results, we next performed a pilot randomized controlled trial comparing the orally active GnRH antagonist, elagolix, to oral contraceptive pill (OCP) suppression for 2 months before the next euploid embryo transfer, and monitored inflammation and miRNA expression in blood, before and after treatment. These studies support a role for endometriosis in UEETF and suggest that medical suppression of suspected disease with GnRH antagonist prior to the next transfer could improve success rates and address underlying inflammatory and epigenetic changes associated with UEETF.

Acceptability of a virtual prostate cancer survivorship care model in rural Australia: A multi-methods, single-centre feasibility pilot.

DESIGN: A multi-methods, single-centre pilot comprising a quasi-experimental pre-/post-test design and an exploratory qualitative study. SETTING: A rural Australian hospital and health service. PARTICIPANTS: Men newly diagnosed with localised prostate cancer who were scheduled to undergo, or had undergone, radical or robotic prostatectomy surgery within the previous 3 months. INTERVENTION: The intervention comprised a 12-week virtual care program delivered via teleconference by a specialist nurse, using a pre-existing connected care platform. The program was tailored to the post-operative recovery journey targeting post-operative care, psychoeducation, problem-solving and goal setting. MAIN OUTCOME MEASURES: Primary outcome: program acceptability. SECONDARY OUTCOMES: quality of life; prostate cancer-related distress; insomnia severity; fatigue severity; measured at baseline (T1); immediately post-intervention (T2); and 12 weeks post-intervention (T3). RESULTS: Seventeen participants completed the program. The program intervention showed very high levels (≥4/5) of acceptability, appropriateness and feasibility. At T1, 47% (n = 8) of men reported clinically significant psychological distress, which had significantly decreased by T3 (p = 0.020). There was a significant improvement in urinary irritative/obstructive symptoms (p = 0.030) and a corresponding decrease in urinary function burden (p = 0.005) from T1 to T3. CONCLUSIONS: This pilot has shown that a tailored nurse-led virtual care program, incorporating post-surgical follow-up and integrated low-intensity psychosocial care, is both acceptable to rural participants and feasible in terms of implementation and impact on patient outcomes.

Detection of Bacteria in Bladder Mucosa of Adult Females.

PURPOSE: Interstitial cystitis/bladder pain syndrome is a chronic urological condition diagnosed in nearly 8 million females in the United States. Whether urinary microbiota play an etiological role remains controversial. Most studies assessed the microbiota of interstitial cystitis/bladder pain syndrome patients with voided or catheterized urine as a proxy for bladder urothelium; however, urine may not be a true reflection of the bladder microbiota. Bladder biopsy tissue may provide a more accurate, and thus more clinically relevant, picture of bladder microbiota. MATERIALS AND METHODS: Bladder biopsy tissues were obtained from: (1) 30 females with interstitial cystitis/bladder pain syndrome (18-80 years old) via cystoscopically guided cold-cup biopsy following therapeutic bladder hydrodistention, and (2) 10 non-interstitial cystitis/bladder pain syndrome females undergoing pelvic organ prolapse repair. To detect bacteria, technical duplicates of each RNAlater-preserved biopsy were subjected to 16S rRNA gene sequencing. To visualize bacteria, paraformaldehyde-fixed, paraffin-embedded biopsies were subjected to a combined multiplexed fluorescence in situ hybridization and fluorescence immunohistochemistry assay and confocal microscopy. RESULTS: Bacteria were detected by 16S rRNA gene sequencing in at least 1 technical duplicate of most biopsies. The most abundant genus was Staphylococcus, followed by Lactobacillus; Escherichia was common but not abundant. There was no significant difference between interstitial cystitis/bladder pain syndrome patients and controls (P > .05). Combined fluorescence in situ hybridization and immunohistochemistry reproducibly detected 16S rRNA in epithelial cells and shed cells in the urothelium and lesioned areas and capillary walls in the lamina propria of human bladder biopsy tissue. CONCLUSIONS: We conclude that urothelial and urinary microbiota are similar but not identical in adult females.

Statistical inference with exchangeability and martingales.

In this paper, we start by reviewing exchangeability and its relevance to the Bayesian approach. We highlight the predictive nature of Bayesian models and the symmetry assumptions implied by beliefs of an underlying exchangeable sequence of observations. By taking a closer look at the Bayesian bootstrap, the parametric bootstrap of Efron and a version of Bayesian thinking about inference uncovered by Doob based on martingales, we introduce a parametric Bayesian bootstrap. Martingales play a fundamental role. Illustrations are presented as is the relevant theory. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

MEK1/2 activity modulates TREM2 cell surface recruitment.

Rare sequence variants in the microglial cell surface receptor TREM2 have been shown to increase the risk for Alzheimer's disease (AD). Disease-linked TREM2 mutations seem to confer a partial loss of function, and increasing TREM2 cell surface expression and thereby its function(s) might have therapeutic benefit in AD. However, druggable targets that could modulate microglial TREM2 surface expression are not known. To identify such targets, we conducted a screen of small molecule compounds with known pharmacology using human myeloid cells, searching for those that enhance TREM2 protein at the cell surface. Inhibitors of the kinases MEK1/2 displayed the strongest and most consistent increases in cell surface TREM2 protein, identifying a previously unreported pathway for TREM2 regulation. Unexpectedly, inhibitors of the downstream effector ERK kinases did not have the same effect, suggesting that noncanonical MEK signaling regulates TREM2 trafficking. In addition, siRNA knockdown experiments confirmed that decreased MEK1 and MEK2 were required for this recruitment. In iPSC-derived microglia, MEK inhibition increased cell surface TREM2 only modestly, so various cytokines were used to alter iPSC microglia phenotype, making cells more sensitive to MEK inhibitor-induced TREM2 recruitment. Of those tested, only IFN-gamma priming prior to MEK inhibitor treatment resulted in greater TREM2 recruitment. These data identify the first known mechanisms for increasing surface TREM2 protein and TREM2-regulated function in human myeloid cells and are the first to show a role for MEK1/MEK2 signaling in TREM2 activity.

Quantifying Population Burden and Effectiveness of Decentralized Surveillance Strategies for Skin-Presenting Neglected Tropical Diseases, Liberia.

We evaluated programmatic approaches for skin neglected tropical disease (NTD) surveillance and completed a robust estimation of the burden of skin NTDs endemic to West Africa (Buruli ulcer, leprosy, lymphatic filariasis morbidity, and yaws). In Maryland, Liberia, exhaustive case finding by community health workers of 56,285 persons across 92 clusters identified 3,241 suspected cases. A total of 236 skin NTDs (34.0 [95% CI 29.1-38.9]/10,000 persons) were confirmed by midlevel healthcare workers trained using a tailored program. Cases showed a focal and spatially heterogeneous distribution. This community health worker‒led approach showed a higher skin NTD burden than prevailing surveillance mechanisms, but also showed high (95.1%) and equitable population coverage. Specialized training and task-shifting of diagnoses to midlevel health workers led to reliable identification of skin NTDs, but reliability of individual diagnoses varied. This multifaceted evaluation of skin NTD surveillance strategies quantifies benefits and limitations of key approaches promoted by the 2030 NTD roadmap of the World Health Organization.

The tryptophan connection: cyclic peptide natural products linked via the tryptophan side chain.

Covering: from 1938 up to March 2021The electron-rich indole side chain of tryptophan is a versatile substrate for peptide modification. Upon the action of various cyclases, the tryptophan side chain may be linked to a nearby amino acid residue, opening the door to a diverse range of cyclic peptide natural products. These compounds exhibit a wide array of biological activity and possess fascinating molecular architectures, which have made them popular targets for total synthesis studies. This review examines the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with a discussion of their first total synthesis, and biosynthesis where this has been studied.

Time to complete hepatitis C cascade of care among patients identified during mass screening campaigns in rural Rwanda: a retrospective cohort study.

BACKGROUND: Since the discovery of direct-acting antivirals, treatment for hepatitis C virus (HCV) is increasingly accessible in low-resource settings, but quality of care in these settings is not known. We described progression through the cascade of care among individuals who screened positive for HCV antibodies during a mass screening campaign in Kirehe and Kayonza, two rural Rwandan districts, in September 2019. METHODS: This retrospective cohort study used routine clinical data to assess proportions of participants completing each stage of the cascade of care, including: (a) screening positive on rapid diagnostic test; (b) return of initial viral load results; (c) detectable viral load; (d) treatment assessment; (e) treatment initiation; (f) return of sustained virological response (SVR12) results; and (g) achieving SVR12. We proposed three indicators to assess timely care provision and used medians and interquartile ranges (IQR) to describe the time to complete the cascade of care. RESULTS: Overall, 666 participants screened HCV positive, among them, 452 (68.1%) were female and median age was 61 years (IQR: 47, 70). Viral load results were returned for 537 (80.6%) participants of whom 448 (83.4%) had detectable viral loads. Of these, 398 (88.8%) were assessed for treatment, 394 (99%) were initiated, but only 222 (56.3%) had results returned for SVR12. Among those with SVR12 results, 208 (93.7%) achieved SVR12. When assessing timely care provision, we found 65.9% (95% CI: 62.0, 69.7) of initial viral load results were returned ≤ 30 days of screening; 45% (95% CI: 40.1, 49.8) of people with detectable viral load completed treatment assessment ≤ 90 days of initial viral load results; and 12.5% (95% CI: 9.2, 16.3) of SVR12 results were returned ≤ 210 days of treatment initiation among those who initiated treatment. The overall median time from screening to SVR12 assessment was 437 days. CONCLUSION: Despite high rates of SVR12 among those who completed all stages of the cascade of care, we identified gaps and delays in the treatment cascade. Improving communication between viral load testing hubs and health facilities could reduce the turn-around time for viral load testing, and actively monitor timeliness of care provision could improve quality of HCV care.

Electroencephalogram background and head ultrasound together stratify seizure risk in neonates undergoing hypothermia.

The benefits of continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU) are increasingly appreciated, though expanding indications for cEEG may strain resources. The current standard of care in babies with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) includes cEEG monitoring throughout the entire TH and rewarming process (at least 72 h). Recent cEEG data demonstrate that most seizures occur within the first 24 h of monitoring. We hypothesized that abnormal head imaging and EEG background could stratify seizure risk in babies with HIE undergoing TH to identify candidates for early cEEG discontinuation. In this retrospective review of 126 neonates undergoing TH and cEEG, we identified seizures in 38 (30%) neonates, 33 (87%) of whom seized within the first 24 h of cEEG monitoring. EEG background was graded and demonstrated that 90% of neonates with seizures had a moderately/markedly abnormal background versus 33% of neonates who did not seize (p < 0.0001). Additionally, while head ultrasound (HUS) obtained before EEG did not stratify seizure risk alone, no neonates with both a normal/mildly abnormal EEG background and a normal HUS (0/25) experienced seizures in contrast to 60% (24/40) neonates with both an abnormal EEG background and an abnormal HUS (p < 0.0001). Our data suggest that neonates with abnormal EEG backgrounds and abnormal HUS should be monitored for seizures throughout TH and rewarming, while neonates with normal/mildly abnormal EEG backgrounds and normal HUS are at low risk of seizures after 24 h of monitoring, and thus would be candidates for early cEEG discontinuation.

Pulsed electromagnetic field (PEMF) as an adjunct therapy for pain management in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often experience chronic pelvic and even systemic pain that can be difficult to clinically manage. Pulsed electromagnetic field (PEMF) therapy, a non-invasive strategy that has shown significant efficacy for pain reduction in other chronic pain conditions, may provide benefit for pain management in patients with IC/BPS. METHODS: PEMF delivery to patients occurs via a bio-electromagnetic-energy device which consists of a flexible mat (180 × 50 cm) that the patient lies on for systemic, full-body delivery and/or a flexible pad (50 × 15 cm) for targeted delivery to a specific body region (e.g., pelvic area). The duration of individual sessions, number of sessions per day, total number of sessions, and follow-up observation period vary between previously published studies. Positive outcomes are typically reported as a significant reduction in visual analog scale (VAS) pain score and functional improvement assessed using validated questionnaires specific to the condition under study. RESULTS AND CONCLUSIONS: The use of PEMF has been evaluated as a therapeutic strategy for pain management in several clinical scenarios. Randomized, double-blinded, placebo-controlled trials have reported positive efficacy and safety profiles when PEMF was used to treat non-specific low back pain, patellofemoral pain syndrome, chronic post-operative pain, osteoarthritis-related pain, rheumatoid arthritis-related pain, and fibromyalgia-related pain. Based on these positive outcomes in a variety of pain conditions, clinical trials to evaluate whether PEMF can provide a safe, non-invasive therapeutic approach to improve symptoms of chronic pain and fatigue in patients with IC/BPS are warranted.

Long-term management options for sea urchin injury: a case series.

In the UK, sea urchin-related injuries (SUIs) most commonly present in returning travellers. Delayed complications mainly affect the skin but nerves, tendons, joints and bones may also be involved. The management of chronic reactions may be challenging and a variety of approaches have been described. Surgical measures are often undertaken, particularly when retained spines are suspected. We demonstrate, through three cases presenting in the UK with chronic SUIs, that conservative management, surgery and intralesional corticosteroids may all be associated with satisfactory outcomes. Management options should consider the presence of retained spines, injury site, symptoms and importantly, patient preference.

Functional genomic analyses of IC/BPS patient subgroups: a pilot study.

INTRODUCTION: To further facilitate understanding of disease pathophysiology and patient stratification in interstitial cystitis/bladder pain syndrome (IC/BPS), we utilized molecular phenotyping to compare three clinically distinct IC/BPS patient subgroups. MATERIALS AND METHODS: Total RNA (miRNA and mRNA) was isolated via standard protocols from IC/BPS patient bladder biopsies and assayed on whole genome and microRNA expression arrays. Data from three patient subgroups (n = 4 per group): (1) low bladder capacity (BC; ≤ 400 cc) without Hunner's lesion, (2) low BC with Hunner's lesion, and (3) non-low BC (> 400 cc) were used in comparative analyses to evaluate the influence of BC and HL on gene expression profiles in IC/BPS. RESULTS: The BC comparison (Group 1 v 3) identified 54 miRNAs and 744 mRNAs. Eleven miRNAs mapped to 40 genes. Hierarchical clustering of miRNA revealed two primary clusters: (1) 3/4 low BC patients; (2) 4/4 non-low and 1/4 low BC patients. Clustering of mRNA provided clear separation based on BC. The HL comparison (Group 1 v 2) identified 16 miRNAs and 917 mRNAs. 4 miRNAs mapped to 13 genes. Clustering of miRNA and mRNA revealed clear separation based on HL status. CONCLUSIONS: Significant molecular differences in IC/BPS were found to be associated with the low BC phenotype (e.g., an upregulation of cell proliferation and inflammation marker genes), as well as additional molecular findings that further define the HL+ phenotype (e.g., upregulation of genes involved in bioenergetics reactions) and suggest oxidative stress may play a role.

Epidemiologic and Genomic Reidentification of Yaws, Liberia.

We confirmed endemicity and autochthonous transmission of yaws in Liberia after a population-based, community-led burden estimation (56,825 participants). Serologically confirmed yaws was rare and focal at population level (24 cases; 2.6 [95% CI 1.4-3.9] cases/10,000 population) with similar clinical epidemiology to other endemic countries in West Africa. Unsupervised classification of spatially referenced case finding data indicated that yaws was more likely to occur in hard-to-reach communities; healthcare-seeking was low among communities, and clinical awareness of yaws was low among healthcare workers. We recovered whole bacterial genomes from 12 cases and describe a monophyletic clade of Treponema pallidum subspecies pertenue, phylogenetically distinct from known TPE lineages, including those affecting neighboring nonhuman primate populations (Taï Forest, Côte d'Ivoire). Yaws is endemic in Liberia but exhibits low focal population prevalence with evidence of a historical genetic bottleneck and subsequent local expansion. Reporting gaps appear attributable to challenging epidemiology and low disease awareness.

Initiation of hepatitis C treatment in two rural Rwandan districts: a mobile clinic approach.

BACKGROUND: To eliminate hepatitis C, Rwanda is conducting national mass screenings and providing to people with chronic hepatitis C free access to Direct Acting Antivirals (DAAs). Until 2020, prescribers trained and authorized to initiate DAA treatment were based at district hospitals, and access to DAAs remains expensive and geographically difficult for rural patients. We implemented a mobile clinic to provide DAA treatment initiation at primary-level health facilities among people with chronic hepatitis C identified through mass screening campaigns in rural Kirehe and Kayonza districts. METHODS: The mobile clinic team was composed of one clinician authorized to manage hepatitis, one lab technician, and one driver. Eligible patients received same-day clinical consultations, counselling, laboratory tests and DAA initiation. Using clinical databases, registers, and program records, we compared the number of patients who initiated DAA treatment before and during the mobile clinic campaign. We assessed linkage to care during the mobile clinical campaign and assessed predictors of linkage to care. We also estimated the cost per patient of providing mobile services and the reduction in out-of-pocket costs associated with accessing DAA treatment through the mobile clinic rather than the standard of care. RESULTS: Prior to the mobile clinic, only 408 patients in Kirehe and Kayonza had been initiated on DAAs over a 25-month period. Between November 2019 and January 2020, out of 661 eligible patients with hepatitis C, 429 (64.9%) were linked to care through the mobile clinic. Having a telephone number and complete address recorded at screening were strongly associated with linkage to care. The cost per patient of the mobile clinic program was 29.36 USD, excluding government-provided DAAs. Providing patients with same-day laboratory tests and clinical consultation at primary-level health facilities reduced out-of-pocket expenses by 9.88 USD. CONCLUSION: The mobile clinic was a feasible strategy for providing rapid treatment initiation among people chronically infected by hepatitis C, identified through a mass screening campaign. Compared to the standard of care, mobile clinics reached more patients in a much shorter time. This low-cost strategy also reduced out-of-pocket expenditures among patients. However, long-term, sustainable care would require decentralization to the primary health-centre level.

Hydrodistention does not alter bladder gene expression profiles in patients with non-Hunner lesion interstitial cystitis/bladder pain syndrome.

AIMS: Gene expression profiling of bladder biopsies in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), typically obtained following therapeutic bladder hydrodistention (HOD), is used to improve our understanding of molecular phenotypes. The objective of this study was to determine if the HOD procedure itself impacts the biopsy gene expression profile and, by extension, whether biopsies from non-HOD bladders are appropriate controls. METHODS: Bladder biopsies were obtained just before HOD and immediately following HOD from 10 consecutively recruited IC/BPS patients undergoing therapeutic HOD. Biopsies were also obtained from four non-IC/BPS patients who did not undergo HOD (controls). Total RNA was isolated from each of the 24 samples and used to query whole-genome microarrays. Differential gene expression analysis was performed to compare expression profiles of IC/BPS biopsies before and after HOD, and between IC/BPS and control biopsies. RESULTS: Principal component analysis revealed complete separation between gene expression profiles from IC/BPS and control samples (q ≤ 0.05) and while IC/BPS samples before and after HOD showed no significant differences in expressed genes, 68 transcripts were found to be significantly different between IC/BPS and control samples (q ≤ 0.05). CONCLUSIONS: The bladder HOD procedure itself does not significantly change gene expression within the IC/BPS patient bladder, a finding that provides evidence to support the use of biopsies from non-IC/BPS patients that have not undergone HOD as controls for gene expression studies.

Evaluation of different materials used for sealing of implant abutment access channel and the peri-implant sulcus microbiota: A 6-month, randomized controlled trial.

OBJECTIVE: Peri-implantitis has been attributed to a myriad of factors, including microleakage at the abutment-implant interface. Implant abutment access channel sealing materials (IACSM) are readily used in implant dentistry, with little evidence on their effect on microleakage. This study aims to evaluate the effect of IACSM on the microbial composition in the implant access channel and the peri-implant sulcus. METHODS: A total of n = 8 patients (64 implants) were included in this single-blinded, randomized controlled trial, whereas four different materials (cotton, polytetrafluoroethylene [PTFE], synthetic foam, or polyvinyl siloxane [PVS]) were randomly placed as an IACSM. Following 6 months, microbial analysis was completed on the IACSM and samples from the peri-implant sulci via PCR and high-throughput sequencing. Bacterial samples on the IACSM and in the peri-implant sulci were classified according to Socransky's microbial complexes. RESULTS: There was a preponderance of early colonizing bacteria within the IACSM, while the peri-implant sulci were dominated by Orange complex bacteria. The proportion of Red and Orange complex members on the IACSM was significantly less than in the peri-implant sulci. The proportion of Green, Yellow, and Blue complex members found on the IACSM was significantly greater than in the peri-implant sulci. Atopobium, a diverse species not included in the microbial complexes, was frequently detected in the peri-implant sulcus samples. CONCLUSIONS: No detectable effects of IACSM on the microbial community in the peri-implant sulcus or on the IACSM were identified. Variation of bacterial species was most dependent on the individual patient. No significant differences were found in the periodontal parameters between the different treatment groups.

An Objective Prior from a Scoring Rule.

In this paper, we introduce a novel objective prior distribution levering on the connections between information, divergence and scoring rules. In particular, we do so from the starting point of convex functions representing information in density functions. This provides a natural route to proper local scoring rules using Bregman divergence. Specifically, we determine the prior which solves setting the score function to be a constant. Although in itself this provides motivation for an objective prior, the prior also minimizes a corresponding information criterion.

Molecular Pathways Underlying Adaptive Repair of the Injured Kidney: Novel Donation After Cardiac Death and Acute Kidney Injury Platforms.

OBJECTIVE: To test the hypothesis that gene expression profiling in peripheral blood from patients who have undergone kidney transplantation (KT) will provide mechanistic insights regarding graft repair and regeneration. BACKGROUND: Renal grafts obtained from living donors (LD) typically function immediately, whereas organs from donation after cardiac death (DCD) or acute kidney injury (AKI) donors may experience delayed function with eventual recovery. Thus, recipients of LD, DCD, and AKI kidneys were studied to provide a more complete understanding of the molecular basis for renal recovery. METHODS: Peripheral blood was collected from LD and DCD/AKI recipients before transplant and throughout the first 30 days thereafter. Total RNA was isolated and assayed on whole genome microarrays. RESULTS: Comparison of longitudinal gene expression between LD and AKI/DCD revealed 2 clusters, representing 141 differentially expressed transcripts. A subset of 11 transcripts was found to be differentially expressed in AKI/DCD versus LD. In all recipients, the most robust gene expression changes were observed in the first day after transplantation. After day 1, gene expression profiles differed depending upon the source of the graft. In patients receiving LD grafts, the expression of most genes did not remain markedly elevated beyond the first day post-KT. In the AKI/DCD groups, elevations in gene expression were maintained for at least 5 days post-KT. In all recipients, the pattern of coordinate gene overexpression subsided by 28 to 30 days. CONCLUSIONS: Gene expression in peripheral blood of AKI/DCD recipients offers a novel platform to understand the potential mechanisms and timing of kidney repair and regeneration after transplantation.