Feasibility and ethics of using data from the Scottish newborn blood spot archive for research.

Background: Newborn heel prick blood spots are routinely used to screen for inborn errors of metabolism and life-limiting inherited disorders. The potential value of secondary data from newborn blood spot archives merits ethical consideration and assessment of feasibility for public benefit. Early life exposures and behaviours set health trajectories in childhood and later life. The newborn blood spot is potentially well placed to create an unbiased and cost-effective population-level retrospective birth cohort study. Scotland has retained newborn blood spots for all children born since 1965, around 3 million in total. However, a moratorium on research access is currently in place, pending public consultation. Methods: We conducted a Citizens' Jury as a first step to explore whether research use of newborn blood spots was in the public interest. We also assessed the feasibility and value of extracting research data from dried blood spots for predictive medicine. Results: Jurors delivered an agreed verdict that conditional research access to the newborn blood spots was in the public interest. The Chief Medical Officer for Scotland authorised restricted lifting of the current research moratorium to allow a feasibility study. Newborn blood spots from consented Generation Scotland volunteers were retrieved and their potential for both epidemiological and biological research demonstrated. Conclusions: Through the Citizens' Jury, we have begun to identify under what conditions, if any, should researchers in Scotland be granted access to the archive. Through the feasibility study, we have demonstrated the potential value of research access for health data science and predictive medicine.

Management and Outcomes of Adults Diagnosed with Acute Pulmonary Embolism in Primary Care: Community-Based Retrospective Cohort Study.

BACKGROUND: The management and outcomes of patients diagnosed with acute pulmonary embolism in primary care have not been characterized. OBJECTIVE: To describe 30-day outcomes stratified by initial site-of-care decisions DESIGN: Multicenter retrospective cohort study PARTICIPANTS: Adults diagnosed with acute pulmonary embolism in primary care in a large, diverse community-based US health system (2013-2019) MAIN MEASURES: The primary outcome was a composite of 30-day serious adverse events (recurrent venous thromboembolism, major bleeding, and all-cause mortality). The secondary outcome was 7-day pulmonary embolism-related hospitalization, either initial or delayed. KEY RESULTS: Among 652 patient encounters (from 646 patients), median age was 64 years; 51.5% were male and 70.7% identified as non-Hispanic white. Overall, 134 cases (20.6%) were sent home from primary care and 518 cases (79.4%) were initially referred to the emergency department (ED) or hospital. Among the referred, 196 (37.8%) were discharged home from the ED without events. Eight patients (1.2%; 95% CI 0.5-2.4%) experienced a 30-day serious adverse event: 4 venous thromboemboli (0.6%), 1 major bleed (0.2%), and 3 deaths (0.5%). Seven of these patients were initially hospitalized, and 1 had been sent home from primary care. All 3 deaths occurred in patients with known metastatic cancer initially referred to the ED, hospitalized, then enrolled in hospice following discharge. Overall, 328 patients (50.3%) were hospitalized within 7 days: 322 at the time of the index diagnosis and 6 following initial outpatient management (4 clinic-only and 2 clinic-plus-ED patients). CONCLUSIONS: Patients diagnosed with acute pulmonary embolism in this primary care setting uncommonly experienced 30-day adverse events, regardless of initial site-of-care decisions. Over 20% were managed comprehensively by primary care. Delayed 7-day pulmonary embolism-related hospitalization was rare among the 51% treated as outpatients. Primary care management of acute pulmonary embolism appears to be safe and could have implications for cost-effectiveness and patient care experience.

Central nervous system intravascular lymphoma leading to rapidly progressive dementia.

Intravascular lymphoma is an uncommon subtype of B-cell lymphoma with neoplastic cells limited to the lumen of small blood vessels. We report a case of a 52-year-old man who presented with constitutional symptoms and rapidly progressive dementia. He was found to have diffuse leptomeningeal and faint parenchymal enhancement on magnetic resonance imaging and was subsequently diagnosed with intravascular lymphoma following a brain biopsy. He responded remarkably well to systemic and intrathecal chemotherapy. The diagnosis and treatment of intravascular lymphoma have been guided by a few case reports and are largely based on expert opinion.

The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse.

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

Objectively Measured Daily Physical Activity and Postural Changes as Related to Positive and Negative Affect Using Ambulatory Monitoring Assessments.

OBJECTIVE: The aim of the study was to determine whether objectively measured daily physical activity and posture of sitting, standing, and sit-to-stand transitions are associated with daily assessments of affect. METHODS: Participants (N = 51, 49% female) wore ActivPal accelerometers for 24 h/d for seven consecutive days. Time spent sitting, standing, and being physically active and sit-to-stand transitions were derived for each day. Participants also completed a mood inventory each evening. Multilevel models examined within- and between-person associations of daily physical activity with positive and negative affect, adjusting for age, sex, body mass index, education, and sleep duration. RESULTS: Within-person associations showed that a 1-hour increase in daily physical activity was associated with a decrease in negative affect over the same day (B = -0.11, 95% confidence interval [CI], -0.21 to -0.01). Between-person associations indicated a borderline significant association between higher average daily physical activity levels and higher positive affect (B = 1.85, 95% CI = -0.25 to 3.94). There were no between- or within-person associations between sitting, standing, and sit-to-stand transitions with affect. CONCLUSIONS: Promoting physical activity may be a potential intervention strategy to acutely suppress negative affective states.

Instruments for assessing readiness to commence suck feeds in preterm infants: effects on time to establish full oral feeding and duration of hospitalisation.

BACKGROUND: One of the most challenging milestones for preterm infants is the acquisition of safe and efficient feeding skills. The majority of healthy full term infants are born with skills to coordinate their suck, swallow and respiration. However, this is not the case for preterm infants who develop these skills gradually as they transition from tube feeding to suck feeds. For preterm infants the ability to engage in oral feeding behaviour is dependent on many factors. The complexity of factors influencing feeding readiness has led some researchers to investigate the use of an individualised assessment of an infant's abilities. A limited number of instruments that aim to indicate an individual infant's readiness to commence either breast or bottle feeding have been developed. OBJECTIVES: To determine the effects of using a feeding readiness instrument when compared to no instrument or another instrument on the outcomes of time to establish full oral feeding and duration of hospitalisations. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE via PubMed (1966 to 22 February 2016), EMBASE (1980 to 22 February 2016), and CINAHL (1982 to 22 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing a formal instrument to assess a preterm infant's readiness to commence suck feeds with either no instrument (usual practice) or another feeding readiness instrument. DATA COLLECTION AND ANALYSIS: The standard methods of Cochrane Neonatal were used. Two authors independently screened potential studies for inclusion. No studies were found that met our inclusion criteria. MAIN RESULTS: No studies met the inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no evidence to inform clinical practice, with no studies meeting the inclusion criteria for this review. Research is needed in this area to establish an evidence base for the clinical utility of implementing the use of an instrument to assess feeding readiness in the preterm infant population.

Pancreatic B-13 Cell Trans-Differentiation to Hepatocytes Is Dependent on Epigenetic-Regulated Changes in Gene Expression.

The proliferative B-13 pancreatic cell line is unique in its ability to generate functional hepatocyte-like (B-13/H) cells in response to exposure to glucocorticoid. In these studies, quantitatively comparable hepatic levels of liver-specific and liver-enriched transcription factor and hepatocyte defining mRNA transcripts were expressed after 10-14 days continuous treatment with glucocorticoid. This conversion in phenotype was associated with increased Gr-α mRNA expression and translation of a functional N-terminally truncated variant protein that localized to the nucleus in B-13/H cells. A short (6 hours) pulse exposure to glucocorticoid was also sufficient to transiently activate the Gr and irreversibly drive near identical conversion to B-13/H cells. Examination of epigenetic-related mechanisms demonstrated that B-13 DNA was rapidly methylated and de-methylated over the initial 2 days in response to both continuous or pulse exposure with glucocorticoid. DNA methylation and glucocorticoid-dependent conversion to an hepatic B-13/H phenotype was blocked by the methylation inhibitor, 5-azacytidine. Conversion to an hepatic B-13/H phenotype was also blocked by histone deacetylase inhibitors. Previous experiments have identified N-terminal Sgk1 variant proteins as pivotal to the mechanism(s) associated with pancreatic-hepatic differentiation. Both continuous and pulse exposure to DEX was sufficient to result in a near-similar robust transcriptional increase in Sgk1c mRNA expression from undetectable levels in B-13 cells. Notably, expression of Sgk1c mRNA remained constitutive 14 days later; including after pulse exposure to glucocorticoid and this induction was inhibited by 5-azacytidine or by histone deacetylase inhibitors. These data therefore suggest that exposing B-13 cells to glucocorticoid results in a Gr-dependent pulse in DNA methylation and likely other epigenetic changes such as histone modifications that leads to constitutive expression of Sgk1c and irreversible reprogramming of B-13 cells into B-13/H cells. Understanding and application of these mechanism(s) may enhance the functionality of stem cell-derived hepatocytes generated in vitro.

Health resource utilization among US veterans with psychogenic nonepileptic seizures: A comparison before and after video-EEG monitoring.

OBJECTIVE: Prior to establishing the correct diagnosis, patients with psychogenic nonepileptic seizures (PNES) frequently endure significant costs and morbidities associated with utilization of health care resources. In this study of the US veterans population, we aimed to investigate for potential changes in health resource utilization before versus after video-EEG (VEEG) confirmation and disclosure of the PNES diagnosis. METHODS: We prospectively studied 65 veterans with VEEG confirmed diagnosis of PNES, and followed their health care utilization during the subsequent 3 years after the diagnosis. Primary outcomes entailed comparing the quantities of post-VEEG outpatient visits and diagnostic procedures versus those during the 3-year span prior to the diagnosis. Secondary outcome involved specifically the measures of seizure-related antiepileptic drug (AED) use from time points before and after VEEG. RESULTS: Within the category of non-psychiatric outpatient visits, we observed significant post-diagnostic decrease in the utilization of PNES-related outpatient visits (p < 0.001). Contrastingly, we found significant post-diagnostic increase in the utilization of non-PNES-related outpatient visits (p = 0.004). When examining exclusively for psychiatric outpatient visits, we further observed a trend toward increased attendance of outpatient visits (p = 0.056) after VEEG. Utilization of diagnostic procedures was not significantly different before versus after VEEG (p = 0.293). 52.3% of the patients were prescribed AEDs for seizure-related purpose during the one-year period leading up to VEEG. By comparison, only 7.7%, 12.3%, and 10.8% of the patients were still on AEDs for seizure-related purpose at the one-year, two-year, and three-year time points after VEEG, respectively. CONCLUSION: We demonstrate new evidence that VEEG confirmation of the PNES diagnosis among US veterans can significantly reduce key measures of non-psychiatric/PNES-related resource utilization, while also potentially associating with appropriate enhancement of psychiatric outpatient visits. However, our results suggest that within this patient population, further efforts are necessary to address heightened demands for non-PNES-related outpatient visits after VEEG.

Overactive bladder.

Overactive bladder syndrome is highly prevalent, and increasingly so with aging. It is characterized by the presence of urinary urgency, and can be associated with incontinence, increased voiding frequency, and nocturia. Assessment needs to exclude serious medical disorders that might present with similar symptoms, and a bladder diary is an invaluable part of understanding the presentation. Initial management is conservative, comprising education, bladder training, and advice on fluid intake. Drug therapy options include antimuscarinic medications and beta-3 adrenergic receptor agonists. Persistent overactive bladder syndrome, despite initial therapy, requires a review of the patient's understanding of conservative management and compliance, and adjustment of medications. For refractory cases, specialist review and urodynamic testing should be considered; this may identify detrusor overactivity or increased filling sensation, and needs to exclude additional factors, such as stress incontinence and voiding dysfunction. Botulinum neurotoxin-A bladder injections can be used in severe overactivity, provided the patient is able and willing to do intermittent self-catheterisation, which is necessary in about 5% of treated patients. Sacral nerve stimulation and tibial nerve stimulation are other approaches. Major reconstructive surgery, such as augmentation cystoplasty, is rarely undertaken in modern practice but remains a possibility in extreme cases.

A systematic review of the effectiveness of warming interventions for women undergoing cesarean section.

BACKGROUND: Women undergoing cesarean section are vulnerable to adverse effects associated with inadvertent perioperative hypothermia, but there has been a lack of synthesized evidence for temperature management in this population. This systematic review aimed to synthesize the best available evidence in relation to preventing hypothermia in mothers undergoing cesarean section surgery. METHODS: Randomized controlled trials meeting the inclusion criteria (adult patients of any ethnic background, with or without comorbidities, undergoing any mode of anesthesia for any type of cesarean section) were eligible for consideration. Active or passive warming interventions versus usual care or placebo, aiming to limit or manage core heat loss in women undergoing cesarean section were considered. The primary outcome was maternal core temperature. A comprehensive search with no language restrictions was undertaken of multiple databases from their inception until May 2012. Two independent reviewers using the standardized critical appraisal instrument for randomized controlled trials from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instruments (JBI-MASTARI) assessed retrieved papers for methodological quality and conducted data collection. Where possible, results were combined in a fixed effects meta-analysis using the Cochrane Collaboration Review Manager software. Due to heterogeneity for one outcome, random effects meta-analysis was also used. RESULTS: A combined total of 719 participants from 12 studies were included. Intravenous fluid warming was found to be effective at maintaining maternal temperature and preventing shivering. Warming devices, including forced air warming and under-body carbon polymer mattresses, were effective at preventing hypothermia. However, effectiveness increased if the devices were applied preoperatively. Preoperative warming devices reduced shivering and improved neonatal temperatures at birth. Intravenous fluid warming did not improve neonatal temperature, and the effectiveness of warming interventions on umbilical pH remains unclear. LINKING EVIDENCE TO ACTION: Intravenous fluid warming by any method improves maternal temperature and reduces shivering during and after cesarean section, as does preoperative body warming. Preoperative warming strategies should be utilized where possible. Preoperative or intraoperative warmed IV fluids should be standard practice. Warming strategies are less effective when intrathecal opioids are administered. Further research is needed to investigate interventions in emergency cesarean section surgery. Larger scale studies using standardized, clinically meaningful temperature measurement time points are required.

An exploration of the alcohol policy environment in post-conflict countries.

AIMS: Populations in countries emerging from armed conflict may have elevated levels of harmful alcohol use due to risk factors such as trauma exposure, increased daily stressors, elevated levels of mental health disorders, urbanization, and weak alcohol control policies and institutions. This study explores the challenges and opportunities for strengthening alcohol control policies in post-conflict countries. METHODS: Exploratory qualitative approach: experts (from United Nations agencies, non-governmental organizations, academic institutions and independent consultants) selected on the basis of their experience were interviewed. Thematic analysis identified key emergent themes. RESULTS: Perceived challenges to addressing harmful alcohol use in post-conflict countries included: lack of priority and recognition among key actors; limited resources and capacity, including in policy enforcement; and the role of the alcohol industry. Perceived opportunities included: increasing recognition of the harmful health and social effects of alcohol globally; sharing information, experience, and expertise to more effectively strengthen alcohol control policies; and collecting better data to advocate and inform stronger alcohol policies. CONCLUSION: This exploratory study provides a starting point to better understand the alcohol policy environment in post-conflict settings but considerably more research is required.

Promoting responsible conduct of research: a Canadian perspective.

This article compares the current Canadian and American approaches to governing the responsible conduct of research. The Canadian Secretariat on Responsible Conduct of Research acts on behalf of Canada's three federal research agencies to implement their Framework on Responsible Conduct of Research. It operates not on the basis of regulatory authority, like its U.S. counterpart, the Office of Research Integrity, but rather on the basis of making compliance a condition of eligibility for funding. Both offices are dedicated to promoting good research practices and to enforcing good standards of research practice.

Local cooling for relieving pain from perineal trauma sustained during childbirth.

BACKGROUND: Perineal trauma is common during childbirth and may be painful. Contemporary maternity practice includes offering women numerous forms of pain relief, including the local application of cooling treatments. OBJECTIVES: To evaluate the effectiveness and side effects of localised cooling treatments compared with no treatment, other forms of cooling treatments and non-cooling treatments. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 January 2012), CINAHL (1982 to 10 January 2012), the Australian New Zealand Clinical Trials Register (10 January 2012) and contacted experts in the field. SELECTION CRITERIA: Published and unpublished randomised and quasi-randomised trials (RCTs) that compared localised cooling treatment applied to the perineum with no treatment or other treatments applied to relieve pain related to perineal trauma sustained during childbirth. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trials for inclusion, assessed trial quality and extracted data. A sub-set of data were double checked for accuracy. Analyses were performed on an intention-to-treat basis where data allowed. We sought additional information from the authors of three trials. MAIN RESULTS: Ten published RCTs were included (involving 1825 women). Comparisons were local cooling treatments (ice packs, cold gel pads (with or without compression) or cold/iced baths) with no treatment, gel pads with compression, hamamelis water (witch hazel), pulsed electromagnetic energy (PET), hydrocortisone/pramoxine foam (Epifoam), oral paracetamol or warm baths. Ice packs provided improved pain relief 24 to 72 hours after birth compared with no treatment (risk ratio (RR) 0.61; 95% confidence interval (CI) 0.41 to 0.91; one study, n = 208). Women preferred the utility of the gel pads compared with ice packs or no treatment (RR 0.82; 95% CI 0.73, 0.92). Differences detected in a composite of perineal oedema and bruising and overall wound healing were noted in one small study, favouring cold gel pads (n = 37) over ice (n = 35, mean difference (MD) 0.63 on a scale of 0 to 15; 95% CI 0.20 to 1.06) or no treatment (n = 39, MD -2.10; 95% CI -3.80 to -0.40) three to 14 days after giving birth. Women reported more pain (RR 5.60; 95% CI 2.35 to 13.33; one study, 100 women) and used more additional analgesia (RR 4.00; 95% CI 1.44 to 11.13; one study, 100 women) following the application of ice packs compared with PET. AUTHORS' CONCLUSIONS: There is only limited evidence to support the effectiveness of local cooling treatments (ice packs, cold gel pads, cold/iced baths) applied to the perineum following childbirth to relieve pain.

Instruments for assessing readiness to commence suck feeds in preterm infants: effects on time to establish full oral feeding and duration of hospitalisation.

BACKGROUND: One of the most challenging milestones for preterm infants is the acquisition of safe and efficient feeding skills. The majority of healthy full term infants are born with skills to coordinate their suck, swallow and respiration. However, this is not the case for preterm infants who develop these skills gradually as they transition from tube feeding to suck feeds. For preterm infants the ability to engage in oral feeding behaviour is dependent on many factors. The complexity of factors influencing feeding readiness has led some researchers to investigate the use of an individualised assessment of an infant's abilities. A limited number of instruments that aim to indicate an individual infant's readiness to commence either breast or bottle feeding have been developed. OBJECTIVES: To determine the effects of using a feeding readiness instrument when compared to no instrument or another instrument on the outcomes of time to establish full oral feeding and duration of hospitalisation. SEARCH METHODS: We used the standard methods of the Cochrane Neonatal Review Group, including a search of the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE via EBSCO (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL via EBSCO (1982 to July 2010), Web of Science via EBSCO (1980 to July 2010) and Health Source (1980 to July 2010). Other sources such as cited references from retrieved articles and databases of clinical trials were also searched. We did not apply any language restriction. We updated this search in March 2012. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing a formal instrument to assess a preterm infant's readiness to commence suck feeds with either no instrument (usual practice) or another feeding readiness instrument. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used. Two authors independently screened potential studies for inclusion. No studies were found that met our inclusion criteria. MAIN RESULTS: No studies met the inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no evidence to inform clinical practice, with no studies meeting the inclusion criteria for this review. Research is needed in this area to establish an evidence base for the clinical utility of implementing the use of an instrument to assess feeding readiness in the preterm infant population.

Assessment of women with defecatory dysfunction and manual splinting using dynamic pelvic floor magnetic resonance imaging.

OBJECTIVE: This study aimed to describe magnetic resonance imaging (MRI) findings in women with defecatory dysfunction who perform manual splinting. METHODS: This is a retrospective study of 29 patients from a single urogynecology center who presented with complaints of defecatory dysfunction and who reported manual splinting to assist with bowel movements. Patients were scheduled for an MRI study with a novel "splinting" protocol to evaluate the effects of their manual splinting on the pelvic floor. The protocol involved asking patients to splint during the MRI, as they normally would when trying to defecate. The goal was to evaluate any change in pelvic anatomy and compensation for an anatomic defect that could potentially lead to their defecatory dysfunction. Magnetic resonance images of the pelvis were obtained at rest, with pelvic floor contraction, with Valsalva, and during manual splinting. These images were then reviewed by radiologists who evaluated various parameters, including anorectal angle, levator ani muscle integrity, and the presence of rectocele, cystocele, apical prolapse, and enterocele. The external and internal anal sphincters were also evaluated for continuity. RESULTS: From September 2008 to October 2010, 29 women reported defecatory dysfunction and the need for manual splinting. Their mean (SD) age was 55.2 (10.5) years. Magnetic resonance images showed a rectocele in 86.2% of the study group, cystocele in 75.9%, enterocele in 10.3%, and a defect of the levator ani muscles in 17.2%. Twenty-one (72.4%) women had more than 1 of these defects. In addition, 27.6% had an anorectal angle less than 90 degrees or greater than 105 degrees.Patients in the study group splinted in the vagina (58.6%), on the perineum (31.0%), or on the buttock (10.3%). In all but 1 woman (96.6%), splinting improved or completely corrected the identified defect(s) as evidenced with MRI. Among those who used vaginal splinting, 52.9% of defects were corrected and 47.1% were improved. Perineal splinting corrected 55.6% and improved 33.3% of cases and was ineffective in 11.1% of cases, whereas buttock splinting corrected 33.3% and improved 66.7% of cases. CONCLUSIONS: Most women in our study group who used manual splinting to assist in defecation are compensating for a pelvic floor defect that can be detected on MRI. Magnetic resonance imaging of the pelvis may help elucidate the etiology of the defecatory dysfunction in some women and may assist pelvic reconstructive surgeons in planning surgical correction of pelvic floor defects. Magnetic resonance imaging may also identify defects in the pelvic floor that are, at the present time, not amenable to surgical correction.