Preferred analysis methods for single genomic regions in RNA sequencing revealed by processing the shape of coverage

The informational content of RNA sequencing is currently far from being completely explored. Most of the analyses focus on processing tables of counts or finding isoform deconvolution via exon junctions. This article presents a comparison of several techniques that can be used to estimate differential expression of exons or small genomic regions of expression, based on their coverage function shapes. The problem is defined as finding the differentially expressed exons between two samples using local expression profile normalization and statistical measures to spot the differences between two profile shapes. Initial experiments have been done using synthetic data, and real data modified with synthetically created differential patterns. Then, 160 pipelines (5 types of generator × 4 normalizations × 8 difference measures) are compared. As a result, the best analysis pipelines are selected based on linearity of the differential expression estimation and the area under the ROC curve. These platform-independent techniques have been implemented in the Bioconductor package rnaSeqMap. They point out the exons with differential expression or internal splicing, even if the counts of reads may not show this. The areas of application include significant difference searches, splicing identification algorithms and finding suitable regions for QPCR primers

Effects of comorbid anxiety disorders on the longitudinal course of pediatric bipolar disorders

OBJECTIVE: To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP). METHOD: As part of the Course and Outcome of Bipolar Youth study, 413 youth, who were 7 through 17 years or age and who met criteria for DSM-IV BP-I (n = 244), BP-II (n = 28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n = 141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed. RESULTS: At intake and during the follow-up, 62% of youth with BP met criteria for at least 1 anxiety disorder. About 50% of the BP youth with anxiety had ≥2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety. CONCLUSIONS: Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, and more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted

Machine learning based prediction of COVID-19 mortality suggests repositioning of anticancer drug for treating severe cases

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19

Hospitalized patients dying with SARS-CoV-2 infection—an analysis of patient characteristics and management in ICU and general ward of the LEOSS registry

BACKGROUND: COVID-19 is a severe disease with a high need for intensive care treatment and a high mortality rate in hospitalized patients. The objective of this study was to describe and compare the clinical characteristics and the management of patients dying with SARS-CoV-2 infection in the acute medical and intensive care setting. METHODS: Descriptive analysis of dying patients enrolled in the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS), a non-interventional cohort study, between March 18 and November 18, 2020. Symptoms, comorbidities and management of patients, including palliative care involvement, were compared between general ward and intensive care unit (ICU) by univariate analysis. RESULTS: 580/4310 (13%) SARS-CoV-2 infected patients died. Among 580 patients 67% were treated on ICU and 33% on a general ward. The spectrum of comorbidities and symptoms was broad with more comorbidities (≥ four comorbidities: 52% versus 25%) and a higher age distribution (>65 years: 98% versus 70%) in patients on the general ward. 69% of patients were in an at least complicated phase at diagnosis of the SARS-CoV-2 infection with a higher proportion of patients in a critical phase or dying the day of diagnosis treated on ICU (36% versus 11%). While most patients admitted to ICU came from home (71%), patients treated on the general ward came likewise from home and nursing home (44% respectively) and were more frequently on palliative care before admission (29% versus 7%). A palliative care team was involved in dying patients in 15%. Personal contacts were limited but more often documented in patients treated on ICU (68% versus 47%). CONCLUSION: Patients dying with SARS-CoV-2 infection suffer from high symptom burden and often deteriorate early with a demand for ICU treatment. Therefor a demand for palliative care expertise with early involvement seems to exist

Cognitive flexibility and performance in children and adolescents with threshold and sub-threshold bipolar disorder

Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or “not otherwise specified” (NOS) participating in multi-site Course and Outcome of Bipolar Youth study compared to typically developing controls (TDC) without psycho-pathology. In particular, we sought to test the hypothesis that BD-I and BD-II youths with full threshold episodes of mania or hypomania would have cognitive deficits, including in reversal learning, vs. those BD-NOS participants with sub-threshold episodes and TDCs. N = 175 participants (BD-I = 81, BD-II = 11, BD-NOS = 28, TDC = 55) completed Cambridge Neuropsychological Automated Testing Battery (CANTAB) tasks. A priori analyses of the simple reversal stage of the CANTAB intra-/extra-dimensional shift task showed that aggregated BD-I/II participants required significantly more trials to complete the task than either BD-NOS participants with sub-syndromal manic/hypomanic symptoms or than TDCs. BD participants across sub-types had impairments in sustained attention and information processing for emotionally valenced words. Our results align with prior findings showing that BD-I/II youths with distinct episodes have specific alterations in reversal learning. More broadly, our study suggests that further work is necessary to see the interaction between neurocognitive performance and longitudinal illness course. Additional work is required to identify the neural underpinnings of these differences as targets for potential novel treatments, such as cognitive remediation

CT694 and pgp3 as Serological Tools for Monitoring Trachoma Programs.

Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n = 160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n = 11) and control sera from a non-endemic group of U.S. children (n = 122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI = 2 or most severe) had a higher median antibody response to pgp3 (p = 0.0041) and CT694 (p = 0.0282) than those with normal exams (TF/TI = 0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Objectives Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. Conclusions These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these association

Optimality regions and fluctuations for Bernoulli last passage models

We study the sequence alignment problem and its independent version,the discrete Hammersley process with an exploration penalty. We obtain rigorous upper bounds for the number of optimality regions in both models near the soft edge.At zero penalty the independent model becomes an exactly solvable model and we identify cases for which the law of the last passage time converges to a Tracy-Widom law

Longitudinal Associations Between Interpersonal Relationship Functioning and Mood Episode Severity in Youth With Bipolar Disorder

This study examined the longitudinal association between mood episode severity and relationships in BP youth. Participants were 413 Course and Outcome of Bipolar Youth study youth, aged 12.6 ± 3.3 years. Monthly ratings of relationships (parents, siblings, and friends) and mood episode severity were assessed by the Adolescent Longitudinal Interval Follow-Up Evaluation (ALIFE) Psychosocial Functioning Schedule (PFS) and Psychiatric Rating Scales (PSR) on average every 8.2 months over 5.1 years. Correlations examined whether participants with increased episode severity also reported poorer relationships, and also examined whether fluctuations in episode severity predicted fluctuations in relationships, and vice versa. Results indicated that participants with greater mood episode severity also had worse relationships. Longitudinally, participants had largely stable relationships. To the extent that there were associations, changes in parental relationships may precede changes in episode severity, although the magnitude of this finding was small. Findings have implications for relationship interventions in BP youth