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Probabilistic sensitivity analysis (PSA) demonstrates the parameter uncertainty in a decision problem. The technique involves sampling parameters from their respective distributions (rather than simply using mean/median parameter values). Guidance in the literature, and from health technology assessment bodies, on the number of simulations that should be performed suggests a ‘sufficient number’, or until ‘convergence’, which is seldom defined. The objective of this tutorial is to describe possible outcomes from PSA, discuss appropriate levels of accuracy, and present guidance by which an analyst can determine if a sufficient number of simulations have been conducted, such that results are considered to have converged. The proposed approach considers the variance of the outcomes of interest in cost-effectiveness analysis as a function of the number of simulations. A worked example of the technique is presented using results from a published model, with recommendations made on best practice. While the technique presented remains essentially arbitrary, it does give a mechanism for assessing the level of simulation error, and thus represents an advance over current practice of a round number of simulations with no assessment of model convergence.

To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment. Retrospective cohort study. Electronic health records within the UK's Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum. Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19. Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose. A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment.

The current study examined trajectories of maternal and paternal depression in the year following the birth of an infant sibling, and relations with family risk factors and firstborn children's internalizing and externalizing behavior problems. Latent class growth analysis was conducted on 231 families in a longitudinal investigation (prebirth and 1, 4, 8, and 12 months postbirth) and revealed four classes of families: both mother and father low in depressive symptoms (40.7%); mother high–father low (25.1%); father high–mother low (24.7%), and both mother and father high (9.5%). Families with both mothers and fathers high on depressive symptoms were higher on marital negativity, parenting stress, and children's internalizing and externalizing problems, and lower on marital positivity and parental efficacy than other classes. Children, parents, and marital relationships were more problematic in families with fathers higher on depressive symptoms than in families in which mothers were higher, indicating the significant role of paternal support for firstborn children undergoing the transition to siblinghood. Maternal and paternal depression covaried with an accumulation of family risks over time, no doubt increasing the likelihood of children's problematic adjustment after the birth of their infant sibling.

Fathers are a crucial source of support for children following the birth of an infant sibling. This study examined whether fathers were more vulnerable to the effects of interparental conflict than mothers, and whether there was a subsequent spillover cascade from interparental conflict to children's externalizing behavior problems. We followed 241 families after the birth of a second child. Mothers and fathers reported on interparental conflict and parental efficacy at 1 and 4 months postpartum and punitive discipline and firstborn children's externalizing behavior problems across a longitudinal investigation (prenatal and 4, 8, and 12 months postpartum). For both mothers and fathers, interparental conflict prenatally predicted decreased parental efficacy following the birth. Fathers’ lower parental efficacy was significantly associated with increased punitive discipline toward the older sibling at 4 months, whereas mothers’ lower parental efficacy was not. Coercive family processes were present between mothers’ and fathers’ punitive discipline and older siblings’ externalizing behavior problems. Results were inconsistent with the father vulnerability hypothesis in that both mothers and fathers were vulnerable to interparental conflict, which in turn spilled over to create coercive family processes that exacerbated children's externalizing behavior problems in the year following the birth of a second child.

Considerable effort has been made to categorise the bacterial composition of the human gut and correlate findings with gastrointestinal disease. The infant gut has long been considered sterile at birth followed by rapid colonisation; however, this view has recently been challenged. We examined first-pass meconium from healthy term infants to confirm or refute sterility. Healthy mothers were approached following vaginal delivery. First-pass meconium stools within 24 hours of delivery were obtained from healthy, breastfed infants with tight inclusion/exclusion criteria including rejecting any known antibiotic exposure - mother within 7 days preceding delivery or infant after birth. Stools were processed in triplicate for fluorescent in-situ hybridisation (FISH) with 16S rRNA-targeted probes including Bifidobacterium; Bacteroides-Prevotella; Lactobacillaceae/Enterococcaceae; Enterobacteriaceae; Streptococcaceae; Staphylococcaceae and Enterococcaceae. Absolute counts of all bacteria and proportional identification of each bacterial group were calculated. Confirmation of bacterial presence by PCR was undertaken on FISH-positive samples. The mothers of 31 newborn infants were recruited, 15 met inclusion/exclusion criteria and provided a sample within 24 hours of birth, processed in the lab within 4 hours. All babies were 37-40 weeks gestation. 8/15 were male, mean birth weight was 3.4 kg and mean maternal age was 32 years. Meconium samples from 10/15 (66%) infants had evidence of bacteria based on FISH analysis. Of these, PCR was positive in only 1. Positive FISH counts ranged from 2.2-41.8 x 10(4) cells/g with a mean of 15.4 x 10(4) cells/g. (The limit of detection for automated counting is 10(6) cells/g). Cell counts were too low to allow formal diversity analysis. Amplification by PCR was not possible despite positive spiked samples demonstrating the feasibility of reaction. One baby was dominated by Enterobacteriaceae. The others contained 2-5 genera, with Bifidobacterium, Enterobacteriaceae, Enterococcaceae and Bacteroides-Prevotella the most prevalent. There was no association between bacterial counts and rupture of membrane duration, time to passage of meconium or time to lab. This study provides evidence that low numbers of bacteria are present in first-pass meconium samples from healthy, vaginally-delivered, breastfed term infants. Only two-thirds of meconium samples had detectable bacteria, though at levels too low for automated counting or for reliable confirmation by PCR. This study suggests that gut bacterial colonisation is extremely limited at birth and occurs rapidly thereafter.

Fathers are more than social accidents. Research has demonstrated that fathers matter to children's development. Despite noted progress, challenges remain on how best to conceptualize and assess fathering and father-child relationships. The current monograph is the result of an SRCD-sponsored meeting of fatherhood scholars brought together to discuss these challenges and make recommendations for best practices for incorporating fathers in studies on parenting and children's development. The first aim of this monograph was to provide a brief update on the current state of research on fathering and to lay out a developmental ecological systems perspective as a conceptual framework for understanding the different spaces fathers inhabit in their children's lives. Because there is wide variability in fathers' roles, the ecological systems perspective situates fathers, mothers, children, and other caregivers within an evolving network of interrelated social relationships in which children and their parents change over time and space (e.g., residence). The second aim was to present examples of empirical studies conducted by members of the international working group that highlighted different methods, data collection, and statistical analyses used to capture the variability in father-child relationships. The monograph ends with a commentary that elaborates on the ecological systems framework with a discussion of the broader macrosystem and social-contextual influences that impinge on fathers and their children. The collection of articles contributes to research on father-child relationships by advancing theory and presenting varied methods and analysis strategies that assist in understanding the father-child relationship and its impact on child development.

Modern oral nicotine delivery (MOND) offers potentially reduced harm nicotine delivery for adult smokers who do not wish to quit. Most clinical studies to date have characterised MOND with lower nicotine content, therefore, this study aimed to assess products with higher nicotine strengths. This randomised, open-label, cross-over, confinement study, conducted in Sweden, compared the nicotine pharmacokinetic and subjective effects of three MOND products, zoneX #5 slim (14 mg nicotine/pouch), zoneX #5 (16 mg) and zoneX #6 (20 mg), and a tobacco snus product (Skruf Slim Fresh #5 (16.6 mg)) in 27 adult snus or MOND users. The zoneX #6 product delivered the highest levels of nicotine; however, all products exhibited similar reductions in urge to use nicotine during and following a controlled product use session. Furthermore, the zoneX products generally scored more favourably than the snus on a 7-point Likert product evaluation scale for satisfaction, psychological reward, aversion and relief, assessed 8 h after the start of product use. There was some indication that pouch size may influence nicotine uptake, however, further characterisation is required. All study products demonstrated good short-term tolerability, with no serious adverse events observed. Overall, the findings support that MOND has tobacco harm reduction potential, providing a satisfactory alternative for adult smokers. Clinical Trial identifier: NCT05452278 https://clinicaltrials.gov/ .

Deep vein thrombosis (DVT) is a blood clot most commonly found in the leg, which can lead to fatal pulmonary embolism (PE). Compression ultrasound of the legs is the diagnostic gold standard, leading to a definitive diagnosis. However, many patients with possible symptoms are not found to have a DVT, resulting in long referral waiting times for patients and a large clinical burden for specialists. Thus, diagnosis at the point of care by non-specialists is desired. We collect images in a pre-clinical study and investigate a deep learning approach for the automatic interpretation of compression ultrasound images. Our method provides guidance for free-hand ultrasound and aids non-specialists in detecting DVT. We train a deep learning algorithm on ultrasound videos from 255 volunteers and evaluate on a sample size of 53 prospectively enrolled patients from an NHS DVT diagnostic clinic and 30 prospectively enrolled patients from a German DVT clinic. Algorithmic DVT diagnosis performance results in a sensitivity within a 95% CI range of (0.82, 0.94), specificity of (0.70, 0.82), a positive predictive value of (0.65, 0.89), and a negative predictive value of (0.99, 1.00) when compared to the clinical gold standard. To assess the potential benefits of this technology in healthcare we evaluate the entire clinical DVT decision algorithm and provide cost analysis when integrating our approach into diagnostic pathways for DVT. Our approach is estimated to generate a positive net monetary benefit at costs up to £72 to £175 per software-supported examination, assuming a willingness to pay of £20,000/QALY.