Analysis of Beta Distribution for Subjective Uncertainty Analysis in Cost Models

Subjective uncertainty exists within the realm of cost estimation. Typical methodology for subjective uncertainty involves elicitation from a subject matter expert to provide a high, low, and most likely value -- defining a triangular distribution -- to model said uncertainty. This manuscript explores ways to leverage research on elicitation geared towards defining a triangular distribution and provide a simple conversion to a beta distribution usable by cost analysts with various degrees of mathematical knowledge. Furthermore, this manuscript attempts to demonstrate the benefits of using a beta distribution through its application as a conjugate prior for Bayesian updating in cost models

AMPA receptor translocation and phosphorylation are induced by transcranial direct current stimulation in rats.

Abstract Over the last decade, the interest in transcranial direct current stimulation (tDCS) has continued to increase, along with consideration of how it affects neuroplasticity mechanisms in the brain. Both human and animal studies have demonstrated numerous benefits and, although its application has increased, the neurophysiological mechanisms underlying tDCS' beneficial effects remain largely unknown. Recent studies have shown that long-term potentiation (LTP) increases following tDCS. In this work, we utilized a rodent model of tDCS to directly assess changes in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a critical protein for enhancing synaptic transmission. Animals were subjected to 250 μA of direct current (DC) stimulation for 30 min with immediate tissue collection. Translocation and phosphorylation of AMPA receptors were examined using protein immunoblot analysis following a subcellular fractionation method. Our findings show that a single application of in vivo tDCS can affect both the translocation and phosphorylation of AMPA receptors in the hippocampus while increasing AMPA receptor phosphorylation in the hypothalamus. In the hippocampus, tDCS increased AMPA translocation to the synapse and increased the phosphorylation of the S831 site on GluA1. In the hypothalamus, no statistically significant changes were observed in AMPA translocation while an increase in the phosphorylation of the S831 site was observed. No changes in the phosphorylation of GluA1 at the S845 site were detected in either brain region. In sum, our findings identify specific AMPA receptor changes induced by tDCS, thereby providing further details on the mechanisms by which tDCS could affect the establishment of LTP and modulate neuroplasticity

Minimization of a Protein−DNA Dimerizer

A protein−DNA dimerizer constructed from a DNA-binding polyamide and the peptide FYPWMKG facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. The Exd binding domain can be reduced to a dipeptide WM attached to the polyamide through an ε-aminohexanoic acid linker with retention of protein−DNA dimerizer activity. Screening a library of analogues indicated that the tryptophan indole moiety is more important than methionine's side chain or the N-terminal acetamide. Remarkably, switching the stereochemistry of the tryptophan residue (l to d) stabilizes the dimerizer•Exd•DNA ternary complex at 37 °C. These observations provide design principles for artificial transcription factors that may function in concert with the cellular regulatory circuitry

Humanistic counselling plus pastoral care as usual versus pastoral care as usual for the treatment of psychological distress in adolescents in UK state schools (ETHOS):a randomised controlled trial

Background About one in seven adolescents have a mental health disorder in England, UK. School counselling is one of the most common means of trying to address such a problem. We aimed to determine the effectiveness and cost-effectiveness of school-based humanistic counselling (SBHC) for the treatment of psychological distress in young people in England, UK. Methods We did a two-arm, individually randomised trial in 18 secondary state-funded schools across the Greater London area of the UK. Participants were randomly assigned (1:1) using a centrally secure randomisation procedure with random permuted blocks to either SBHC plus schools' pastoral care as usual (PCAU), or PCAU alone. Participants were pupils aged 13–16 years who had moderate-to-severe levels of emotional symptoms (measured by a score of ≥5 on the Strengths and Difficulties Questionnaire Emotional Symptoms scale) and were assessed as competent to consent to participate in the trial. Participants, providers, and assessors (who initially assessed and enrolled participants) were not masked but testers (who measured outcomes) were masked to treatment allocation. The primary outcome was psychological distress at 12 weeks (Young Person's Clinical Outcomes in Routine Evaluation measure [YP-CORE]; range 0–40), analysed on an intention-to-treat basis (with missing data imputed). Costs were assessed at 24 weeks (Client Service Receipt Inventory and service logs). The trial was registered with ISRCTN, number ISRCTN10460622. Findings 329 participants were recruited between Sept 29, 2016, and Feb 8, 2018, with 167 (51%) randomly assigned to SBHC plus PCAU and 162 (49%) to PCAU. 315 (96%) of 329 participants provided data at 12 weeks and scores were imputed for 14 participants (4%). At baseline, the mean YP-CORE scores were 20·86 (SD 6·38) for the SBHC plus PCAU group and 20·98 (6·41) for the PCAU group. Mean YP-CORE scores at 12 weeks were 16·41 (SD 7·59) for the SBHC plus PCAU group and 18·34 (7·84) for the PCAU group (difference 1·87, 95% CI 0·37–3·36; p=0·015), with a small effect size (0·25, 0·03–0·47). Overall costs at 24 weeks were £995·20 (SD 769·86) per pupil for the SBHC plus PCAU group and £612·89 (1224·56) for the PCAU group (unadjusted difference £382·31, 95% CI £148·18–616·44; p=0·0015). The probability of SBHC being more cost-effective reached 80% at a willingness to pay of £390 for a 1-point improvement on the YP-CORE. Five serious adverse events occurred for four participants in the SBHC plus PCAU group, all involving suicidal intent. Two serious adverse events occurred for two participants in the PCAU group, one involving suicidal intent. Interpretation The addition of SBHC to PCAU leads to small reductions in psychological distress, but at an additional economic cost. SBHC is a viable treatment option but there is a need for equally rigorous evaluation of alternative interventions. Funding This work was supported by the Economic and Social Research Council (grant reference ES/M011933/1)

Dynamics of male pelvic floor muscle contraction observed with transperineal ultrasound imaging differ between voluntary and evoked coughs

Coughing provokes stress urinary incontinence, and voluntary coughs are employed clinically to assess pelvic floor dysfunction. Understanding urethral dynamics during coughing in men is limited, and it is unclear whether voluntary coughs are an appropriate surrogate for spontaneous coughs. We aimed to investigate the dynamics of urethral motion in continent men during voluntary and evoked coughs. Thirteen men (28–42 years) with no history of urological disorders volunteered to participate. Transperineal ultrasound (US) images were recorded and synchronized with measures of intraabdominal pressure (IAP), airflow, and abdominal/chest wall electromyography during voluntary coughs and coughs evoked by inhalation of nebulized capsaicin. Temporal and spatial aspects of urethral movement induced by contraction of the striated urethral sphincter (SUS), levator ani (LA), and bulbocavernosus (BC) muscles and mechanical aspects of cough generation were investigated. Results showed coughing involved complex urethral dynamics. Urethral motion implied SUS and BC shortening and LA lengthening during preparatory and expulsion phases. Evoked coughs resulted in greater IAP, greater bladder base descent (LA lengthening), and greater midurethral displacement (SUS shortening). The preparatory inspiration cough phase was shorter during evoked coughs, as was the latency between onset of midurethral displacement and expulsion. Maximum midurethral displacement coincided with maximal bladder base descent during voluntary cough, but followed it during evoked cough. The data revealed complex interaction between muscles involved in continence in men. Spatial and temporal differences in urethral dynamics and cough mechanics between cough types suggest that voluntary coughing may not adequately assess capacity of the continence mechanism

Minimization of a Protein−DNA Dimerizer

A protein−DNA dimerizer constructed from a DNA-binding polyamide and the peptide FYPWMKG facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. The Exd binding domain can be reduced to a dipeptide WM attached to the polyamide through an ε-aminohexanoic acid linker with retention of protein−DNA dimerizer activity. Screening a library of analogues indicated that the tryptophan indole moiety is more important than methionine's side chain or the N-terminal acetamide. Remarkably, switching the stereochemistry of the tryptophan residue (l to d) stabilizes the dimerizer•Exd•DNA ternary complex at 37 °C. These observations provide design principles for artificial transcription factors that may function in concert with the cellular regulatory circuitry

Childhood socioeconomic position and adult mental wellbeing:Evidence from four British birth cohort studies

There is much evidence showing that childhood socioeconomic position is associated with physical health in adulthood; however existing evidence on how early life disadvantage is associated with adult mental wellbeing is inconsistent. This paper investigated whether childhood socioeconomic position (SEP) is associated with adult mental wellbeing and to what extent any association is explained by adult SEP using harmonised data from four British birth cohort studies.The sample comprised 20,717 participants with mental wellbeing data in the Hertfordshire Cohort Study (HCS), the MRC National Survey of Health and Development (NSHD), the National Child Development Study (NCDS), and the British Cohort Study (BCS70). Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) scores at age 73 (HCS), 60-64 (NSHD), 50 (NCDS), or 42 (BCS70) were used. Harmonised socioeconomic position (Registrar General's Social Classification) was ascertained in childhood (age 10/11) and adulthood (age 42/43). Associations between childhood SEP, adult SEP, and wellbeing were tested using linear regression and multi-group structural equation models.More advantaged father's social class was associated with better adult mental wellbeing in the BCS70 and the NCDS. This association was independent of adult SEP in the BCS70 but fully mediated by adult SEP in the NCDS. There was no evidence of an association between father's social class and adult mental wellbeing in the HCS or the NSHD.Socioeconomic conditions in childhood are directly and indirectly, through adult socioeconomic pathways, associated with adult mental wellbeing, but findings from these harmonised data suggest this association may depend on cohort or age

Evidence for Quantum Interference in SAMs of Arylethynylene Thiolates in Tunneling Junctions with Eutectic Ga-In (EGaIn) Top-Contacts

This paper compares the current density (J) versus applied bias (V) of self-assembled monolayers (SAMs) of three different ethynylthiophenol-functionalized anthracene derivatives of approximately the same thickness with linear-conjugation (AC), cross-conjugation (AQ), and broken-conjugation (AH) using liquid eutectic Ga-In (EGaIn) supporting a native skin (~1 nm thick) of Ga2O3 as a nondamaging, conformal top-contact. This skin imparts non-Newtonian rheological properties that distinguish EGaIn from other top-contacts; however, it may also have limited the maximum values of J observed for AC. The measured values of J for AH and AQ are not significantly different (J ≈ 10-1 A/cm2 at V = 0.4 V). For AC, however, J is 1 (using log averages) or 2 (using Gaussian fits) orders of magnitude higher than for AH and AQ. These values are in good qualitative agreement with gDFTB calculations on single AC, AQ, and AH molecules chemisorbed between Au contacts that predict currents, I, that are 2 orders of magnitude higher for AC than for AH at 0 < |V| < 0.4 V. The calculations predict a higher value of I for AQ than for AH; however, the magnitude is highly dependent on the position of the Fermi energy, which cannot be calculated precisely. In this sense, the theoretical predictions and experimental conclusions agree that linearly conjugated AC is significantly more conductive than either cross-conjugated AQ or broken conjugate AH and that AQ and AH cannot necessarily be easily differentiated from each other. These observations are ascribed to quantum interference effects. The agreement between the theoretical predictions on single molecules and the measurements on SAMs suggest that molecule-molecule interactions do not play a significant role in the transport properties of AC, AQ, and AH.

Microarray labeling extension values: laboratory signatures for Affymetrix GeneChips

Interlaboratory comparison of microarray data, even when using the same platform, imposes several challenges to scientists. RNA quality, RNA labeling efficiency, hybridization procedures and data-mining tools can all contribute variations in each laboratory. In Affymetrix GeneChips, about 11–20 different 25-mer oligonucleotides are used to measure the level of each transcript. Here, we report that ‘labeling extension values (LEVs)’, which are correlation coefficients between probe intensities and probe positions, are highly correlated with the gene expression levels (GEVs) on eukayotic Affymetrix microarray data. By analyzing LEVs and GEVs in the publicly available 2414 cel files of 20 Affymetrix microarray types covering 13 species, we found that correlations between LEVs and GEVs only exist in eukaryotic RNAs, but not in prokaryotic ones. Surprisingly, Affymetrix results of the same specimens that were analyzed in different laboratories could be clearly differentiated only by LEVs, leading to the identification of ‘laboratory signatures’. In the examined dataset, GSE10797, filtering out high-LEV genes did not compromise the discovery of biological processes that are constructed by differentially expressed genes. In conclusion, LEVs provide a new filtering parameter for microarray analysis of gene expression and it may improve the inter- and intralaboratory comparability of Affymetrix GeneChips data