Netrin 1 directs vascular patterning and maturity in the developing kidney.

The intricate vascular system of the kidneys supports body fluid and organ homeostasis. However, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin 1 (Ntn1) is a secreted ligand that is crucial for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing mouse kidney and conditional deletion (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys with extended nephrogenesis. Wholemount 3D analyses additionally revealed the loss of a predictable vascular pattern in Foxd1GC/+;Ntn1fl/fl kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of our observed phenotypes, whole kidney RNA-seq revealed disruptions to genes and programs associated with stromal cells, vasculature and differentiating nephrons. Together, our findings highlight the significance of Ntn1 to proper vascularization and kidney development.

Discontinuation of anti-tumour necrosis factor alpha treatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

BACKGROUND: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. OBJECTIVES: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. METHODS: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. RESULTS: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. CONCLUSIONS: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

Characterisation of a smoke/ aerosol exposure in vitro system (SAEIVS) for delivery of complex mixtures directly to cells at the air-liquid interface.

In vitro testing is important to characterise biological effects of consumer products, including nicotine delivery products such as cigarettes, e-cigarettes and heated tobacco products. Users' cells are exposed to these products' aerosols, of variant chemical compositions, as they move along the respiratory tract. In vitro exposure systems are available to model such exposures, including delivery of whole aerosols to cells, and at the air-liquid interface. Whilst there are clear advantages of such systems, factors including time to aerosol delivery, aerosol losses and number of cell cultures that can be exposed at one time could be improved. This study aimed to characterise a custom-built smoke/ aerosol exposure in vitro system (SAEIVS) using 1R6F reference cigarette smoke. This system contains five parallel smoking chambers and delivers different dilutions of smoke/ aerosol to two separate cell culture exposure chambers in <10 s. Using two dosimetry measures (optical density 400 nm [OD400 ]; mass spectrometric nicotine quantification), the SAEIVS demonstrated excellent linearity of smoke dilution prior to exposure (R2  = 0.9951 for mass spectrometric quantification; R2  = 0.9965 for OD400 ) and consistent puff-wise exposures across 24 and 96 well plates in cell culture relevant formats (e.g., within inserts). Smoke loss was lower than previously reported for other systems (OD400 : 16%; nicotine measurement: 20%). There was good correlation of OD400 and nicotine measurements, indicating that OD was a useful surrogate for exposure dosimetry for the product tested. The findings demonstrated that the SAEIVS is a fit-for-purpose exposure system for the reproducible dose-wise exposure assessment of nicotine delivery product aerosols.

Subjective machines: Probabilistic risk assessment based on deep learning of soft information.

For several years machine learning methods have been proposed for risk classification. While machine learning methods have also been used for failure diagnosis and condition monitoring, to the best of our knowledge, these methods have not been used for probabilistic risk assessment. Probabilistic risk assessment is a subjective process. The problem of how well machine learning methods can emulate expert judgments is challenging. Expert judgments are based on mental shortcuts, heuristics, which are susceptible to biases. This paper presents a process for developing natural language-based probabilistic risk assessment models, applying deep learning algorithms to emulate experts' quantified risk estimates. This allows the risk analyst to obtain an a priori risk assessment when there is limited information in the form of text and numeric data. Universal sentence embedding (USE) with gradient boosting regression (GBR) trees trained over limited structured data presented the most promising results. When we apply these models' outputs to generate survival distributions for autonomous systems' likelihood of loss with distance, we observe that for open water and ice shelf operating environments, the differences between the survival distributions generated by the machine learning algorithm and those generated by the experts are not statistically significant.

The in vitro ToxTracker and Aneugen Clastogen Evaluation extension assay as a tool in the assessment of relative genotoxic potential of e-liquids and their aerosols.

In vitro (geno)toxicity assessment of electronic vapour products (EVPs), relative to conventional cigarette, currently uses assays, including the micronucleus and Ames tests. Whilst informative on induction of a finite endpoint and relative risk posed by test articles, such assays could benefit from mechanistic supplementation. The ToxTracker and Aneugen Clastogen Evaluation analysis can indicate the activation of reporters associated with (geno)toxicity, including DNA damage, oxidative stress, the p53-related stress response and protein damage. Here, we tested for the different effects of a selection of neat e-liquids, EVP aerosols and Kentucky reference 1R6F cigarette smoke samples in the ToxTracker assay. The assay was initially validated to assess whether a mixture of e-liquid base components, propylene glycol (PG) and vegetable glycerine (VG) had interfering effects within the system. This was achieved by spiking three positive controls into the system with neat PG/VG or phosphate-buffered saline bubbled (bPBS) PG/VG aerosol (nicotine and flavour free). PG/VG did not greatly affect responses induced by the compounds. Next, when compared to cigarette smoke samples, neat e-liquids and bPBS aerosols (tobacco flavour; 1.6% freebase nicotine, 1.6% nicotine salt or 0% nicotine) exhibited reduced and less complex responses. Tested up to a 10% concentration, EVP aerosol bPBS did not induce any ToxTracker reporters. Neat e-liquids, tested up to 1%, induced oxidative stress reporters, thought to be due to their effects on osmolarity in vitro. E-liquid nicotine content did not affect responses induced. Additionally, spiking nicotine alone only induced an oxidative stress response at a supraphysiological level. In conclusion, the ToxTracker assay is a quick, informative screen for genotoxic potential and mechanisms of a variety of (compositionally complex) samples, derived from cigarettes and EVPs. This assay has the potential for future application in the assessment battery for next-generation (smoking alternative) products, including EVPs.

Lipocalin-type Prostaglandin D2 Synthase appears to function as a Novel Adipokine Preventing Adipose Dysfunction in response to a High Fat Diet.

Adipose dysfunction is the primary defect in obesity that contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and some cancers. Previously, we demonstrated the development of NAFLD in lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice regardless of diet. In the present study, we examined the role of L-PGDS in adipose in response to a high fat diet. We observed decreased expression of L-PGDS in adipose tissue and concomitant lower plasma levels in a dietary model of obesity as well as in insulin resistant 3T3-L1 adipocytes. We show reduced adiponectin expression and phosphorylation of AMPK in white adipose tissue of L-PGDS KO mice after 14 weeks on a high fat diet as compared to control C57BL/6 mice. We also observe an increased fat content in L-PGDS KO mice as demonstrated by adipocyte hypertrophy and increased expression of lipogenenic genes. We confirmed our in vivo findings in in vitro 3T3-L1 adipocytes, using an enzymatic inhibitor of L-PGDS (AT56). Rosiglitazone treatment drastically increased L-PGDS expression in insulin resistant 3T3-L1 adipocytes and increased adiponectin expression and AMPK phosphorylation in AT56 treated 3T3-L1 adipocytes. We conclude that the absence of L-PGDS has a deleterious effect on adipose tissue functioning, which further reduces insulin sensitivity in adipose tissue. Consequently, we propose L-PGDS appears to function as a potential member of the adipokine secretome involved in the regulation of the obesity-associated metabolic syndrome.

When it's needed most: a blueprint for resident creative writing workshops during inpatient rotations.

BACKGROUND: Narrative Medicine may mitigate physician burnout by increasing empathy and self-compassion, and by encouraging physicians to deeply connect with patient stories/experiences. However, Narrative Medicine has been difficult to implement on hectic inpatient teaching services that are often the most emotionally taxing for residents. OBJECTIVE: To evaluate programmatic and learner outcomes of a novel narrative medicine curriculum implementation during inpatient medicine rotations for medical residents. Programmatic outcomes included implementation lessons. Learner outcomes included preliminary understanding of impact on feelings of burnout. Additionally, we developed a generalizable narrative medicine framework for program implementation across institutions. METHODS: We developed and implemented a monthly 45-min Narrative Medicine workshop on Stanford's busiest and emotionally-demanding inpatient rotation (medical oncology). Using the Physician Wellbeing Inventory (PWBI, range 1-7; 3-4 = high burnout risk; ≥4, high burnout), we anonymously assessed resident burnout during pre-implementation control year (2017-2018, weeks 1 and 4), and implementation year (2018-2019, weeks 1 and 4). We interviewed program directors and facilitators regarding curriculum implementation challenges/facilitators. RESULTS: Residents highly rated the narrative medicine curriculum, and the residency program renewed the course for 3 additional years. We identified success factors for programmatic success including time neutrality, control of session, learning climate, building trust, staff partnership, and facilitators training. During control year, resident burnout was initially high (n = 16; mean PBWI = 3.0, SD: 1.1) and increased by the final week (n = 15; PBWI = 3.4, SD: 1.6). During implementation year, resident burnout was initially similar (n = 13; PBWI = 3.1, SD: 1.9) but did not rise as much by rotation end (n = 24; PBWI = 3.3, SD: 1.6). Implementation was underpowered to detect small effect sizes. Based on our our experience and literature review, we propose an educational competency framework potentially helpful to facilitate inpatient narrative medicine workshops, as a blueprint for other institutions. CONCLUSIONS: Inpatient Narrative Medicine is feasible to implement during a challenging inpatient rotation and may have important short-term effects in mitigating burnout rise, with more study needed. We share teaching tools and propose a competency framework which may be useful to support development of inpatient narrative medicine curricula across institutions.

Lipocalin-type prostaglandin D2 synthase deletion induces dyslipidemia and non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D2 receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment.

BMAL1 controls glucose uptake through paired-homeodomain transcription factor 4 in differentiated Caco-2 cells.

The transcription factor aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) is an essential regulator of the circadian clock, which controls the 24-h cycle of physiological processes such as nutrient absorption. To examine the role of BMAL1 in small intestinal glucose absorption, we used differentiated human colon adenocarcinoma cells (Caco-2 cells). Here, we show that BMAL1 regulates glucose uptake in differentiated Caco-2 cells and that this process is dependent on the glucose transporter sodium-glucose cotransporter 1 (SGLT1). Mechanistic studies show that BMAL1 regulates glucose uptake by controlling the transcription of SGLT1 involving paired-homeodomain transcription factor 4 (PAX4), a transcriptional repressor. This is supported by the observation that clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated endonuclease Cas9 (Cas9) knockdown of PAX4 increases SGLT1 and glucose uptake. Chromatin immunoprecipitation (ChIP) and ChIP-quantitative PCR assays show that the knockdown or overexpression of BMAL1 decreases or increases the binding of PAX4 to the hepatocyte nuclear factor 1-α binding site of the SGLT1 promoter, respectively. These findings identify BMAL1 as a critical mediator of small intestine carbohydrate absorption and SGLT1.

Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial.

BACKGROUND: In the UK, gout management is suboptimum, with only 40% of patients receiving urate-lowering therapy, usually without titration to achieve a target serum urate concentration. Nurses successfully manage many diseases in primary care. We compared nurse-led gout care to usual care led by general practitioners (GPs) for people in the community. METHODS: Research nurses were trained in best practice management of gout, including providing individualised information and engaging patients in shared decision making. Adults who had experienced a gout flare in the previous 12 months were randomly assigned 1:1 to receive nurse-led care or continue with GP-led usual care. We assessed patients at baseline and after 1 and 2 years. The primary outcome was the percentage of participants who achieved serum urate concentrations less than 360 µmol/L (6 mg/dL) at 2 years. Secondary outcomes were flare frequency in year 2, presence of tophi, quality of life, and cost per quality-adjusted life-year (QALY) gained. Risk ratios (RRs) and 95% CIs were calculated based on intention to treat with multiple imputation. This study is registered with www.ClinicalTrials.gov, number NCT01477346. FINDINGS: 517 patients were enrolled, of whom 255 were assigned nurse-led care and 262 usual care. Nurse-led care was associated with high uptake of and adherence to urate-lowering therapy. More patients receiving nurse-led care had serum urate concentrations less than 360 µmol/L at 2 years than those receiving usual care (95% vs 30%, RR 3·18, 95% CI 2·42-4·18, p<0·0001). At 2 years all secondary outcomes favoured the nurse-led group. The cost per QALY gained for the nurse-led intervention was £5066 at 2 years. INTERPRETATION: Nurse-led gout care is efficacious and cost-effective compared with usual care. Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes. FUNDING: Arthritis Research UK.

Seizure and epilepsy publication in nonneurology journals.

PURPOSE: The prevalence and characteristics of seizure and epilepsy research published in nonneurology journals are unknown. Characterizing this published research allows for insight into the relevance of seizures and epilepsy in other specialties and may increase opportunity for cross-specialty collaboration. METHODS: In this observational study, we reviewed the top five highly cited clinical journals within eleven specialties in the InCites Journal Citation Reports (JCR) database (2016). For each specialty, we collected 2013-2017 PubMed data on publications with MeSH Major Topic of "seizures," "epilepsy," or "status epilepticus." Medical subject headings (MeSH) in PubMed are standardized terms assigned by subject analysts. MeSH Major Topic identifies articles in which a specified topic is the major focus of the article. We also retrieved author country and medical specialty affiliations. We analyzed whether author specialty affiliation was 1) concordant with journal medical specialty, 2) neurology-related, or 3) other. RESULTS: Articles on "seizures," "epilepsy," or "status epilepticus" had the following prevalence in specialty clinical journals: cardiac and cardiovascular systems (0.01%); clinical neurology (5.34%); critical care medicine (0.20%); emergency medicine (0.47%); general and internal medicine (0.44%); neuroimaging (2.05%); neurosurgery (2.23%); obstetrics and gynecology (0.16%); oncology (0.01%); pediatrics (0.69%); and psychiatry (0.23%). Within general and internal medicine, neuroimaging, and pediatrics, seizure-related articles are more likely to be first-authored by someone with a neurology-related affiliation. Within critical care medicine, emergency medicine, neurosurgery, and obstetrics and gynecology, seizure-related articles were more likely to be first-authored by someone whose affiliation is within the field. CONCLUSIONS: Our study characterizes seizure and epilepsy research published in nonneurology journals. We found that there is a paucity of such research published in nonneurology journals, whether authored by neurologists or other specialists. This is not ideal since nonneurologists are often first-line providers for recognizing, diagnosing, or managing seizures prior to assessment by a neurologist. Cross-specialty collaboration should be strongly encouraged in clinical research.

An examination of father vulnerability and coercive family process after the birth of a sibling: A spillover cascade model.

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.

Maternal and paternal trajectories of depressive symptoms predict family risk and children's emotional and behavioral problems after the birth of a sibling.

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.

Toxicological comparison of cigarette smoke and e-cigarette aerosol using a 3D in vitro human respiratory model.

With the growing prevalence of e-cigarettes as an alternative to conventional cigarettes amongst smokers worldwide, there is a need for new methods to evaluate their relative toxicological profile as part of a safety assessment. Initiatives to replace, reduce and refine animal testing have led to developments of new methodologies utilizing organotypic, in vitro tissue models. Here we use a respiratory epithelial model, EpiAirway, to examine the biological effects of nicotine-containing blu PLUS + e-cigarettes, with or without blueberry flavoring, in comparison to conventional cigarette smoke. Tissues were exposed at the air-liquid interface to cigarette smoke or e-cigarette aerosol generated using a VITROCELL VC1 smoking/vaping robot. Following exposure to cigarette smoke, there was a significant decrease in tissue viability and barrier function. Additionally, secretion of inflammatory cytokines, interleukin 6 and 8 (IL-6, IL-8) altered and a marker of DNA damage, γ-H2AX, was significantly increased. Conversely, tissues exposed to up to 400 puffs of e-cigarette aerosol with or without blueberry flavor did not differ compared to air-exposed tissues in any of the measured endpoints. Overall, the tested e-cigarette products induced significantly less cytotoxicity than conventional cigarette smoke under the conditions of test and suggest such products have the potential for reduced health risks. Our results also demonstrate that organotypic tissue models are useful for assessing the biological impact of e-cigarettes and their flavorings.

The use of Genomic Allergen Rapid Detection (GARD) assays to predict the respiratory and skin sensitising potential of e-liquids.

Electronic cigarettes (e-cigarettes) are an increasingly popular alternative to combustible tobacco cigarettes among smokers worldwide. A growing body of research indicates that flavours play a critical role in attracting and retaining smokers into the e-cigarette category, directly contributing to declining smoking rates and tobacco harm reduction. The responsible selection and inclusion levels of flavourings in e-liquids must be guided by toxicological principles. Some flavour ingredients, whether natural extracts or synthetic, are known allergens. In this study, we used the Genomic Allergen Rapid Detection (GARD) testing strategy to predict and compare the respiratory and skin sensitising potential of three experimental and two commercial e-liquids. These novel, myeloid cell-based assays use changes in the transcriptional profiles of genomic biomarkers that are collectively relevant for respiratory and skin sensitisation. Our initial results indicate that the GARD assays were able to differentiate and broadly classify e-liquids based on their sensitisation potential, which are defined mixtures. Further studies need to be conducted to assess whether and how these assays could be used for the screening and toxicological assessment of e-liquids to support product development and commercialisation.

Chapter IV: In Search of the Father-Infant Activation Relationship: A Person-Centered Approach.

The current study explored whether fathers and mothers from 195 two-parent U.S. families engaged in a form of activation parenting (i.e., sensitivity, cognitive stimulation, and moderate intrusiveness) with their secondborn, 12-month-old infants during a 15-min challenging teaching task, and to determine if this type of interaction was more common among fathers. Mean comparisons showed that fathers were lower on sensitivity, positive regard, and stimulation of development, and were more detached than mothers. Latent Profile Analyses revealed similar supportive, disengaged, and activation parenting profiles for fathers and mothers, with more fathers in the activation class. Chi-square analyses found significant associations across mothers and fathers; most infants (30%) had activation fathers and mothers, with 26% having supportive mothers and activation fathers, and 11.4% having two supportive parents. Parenting profiles were unrelated to attachment security. Results need to be replicated with children of different ages, with families from different backgrounds, and beyond the challenging teaching paradigm.

Advancing Research and Measurement on Fathering and Child Development.

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.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

Ibutilide Effectiveness and Safety in the Cardioversion of Atrial Fibrillation and Flutter in the Community Emergency Department.

STUDY OBJECTIVE: Little is known about the use of ibutilide for cardioversion in atrial fibrillation and flutter outside of clinical trials. We seek to describe patient characteristics, ibutilide administration patterns, cardioversion rates, and adverse outcomes in the community emergency department (ED) setting. We also evaluate potential predictors of cardioversion success. METHODS: Using a retrospective cohort of adults who received ibutilide in 21 community EDs between January 2009 and June 2015, we gathered demographic and clinical variables from electronic health records and structured manual chart review. We calculated rates of cardioversion and frequency of ventricular tachycardia within 4 hours and estimated adjusted odds ratios (aOR) in a multivariate regression model for potential predictors of cardioversion. RESULTS: Among 361 patients, the median age was 61 years (interquartile range 53 to 71 years) and most had recent-onset atrial fibrillation and flutter (98.1%). Five percent of the cohort had a history of heart failure. The initial QTc interval was prolonged (>480 ms) in 29.4% of patients, and 3.1% were hypokalemic (<3.5 mEq/L). The mean ibutilide dose was 1.5 mg (SD 0.5 mg) and the rate of ibutilide-related cardioversion within 4 hours was 54.8% (95% confidence interval [CI] 49.6% to 60.1%), 50.5% for atrial fibrillation and 75.0% for atrial flutter. Two patients experienced ventricular tachycardia (0.6%), both during their second ibutilide infusion. Age (in decades) (aOR 1.3; 95% CI 1.1 to 1.5), atrial flutter (versus atrial fibrillation) (aOR 2.7; 95% CI 1.4 to 5.1), and no history of atrial fibrillation and flutter (aOR 2.0; 95% CI 1.2 to 3.1) were associated with cardioversion. CONCLUSION: The effectiveness and safety of ibutilide in this community ED setting were consistent with clinical trial results despite less stringent patient selection criteria.

Associations between Parental Relocation Following Separation in Childhood and Maladjustment in Adolescence and Young Adulthood.

Petitions by custodial parents to relocate children away from non-custodial parents present difficult choices for family courts. In the current study, the sample (N = 81) was randomly recruited through the children's schools according to the following criteria: Children were 12 years old and at the time resided primarily with their mothers; mothers had been living with a male partner "acting in a father role" for at least the previous year. Thirty-eight children had been separated by more than an hour's drive from their biological fathers due to either their mothers or fathers relocating. The data were collected from two reporters (children and mothers) at five time points (child ages 12.5, 14, 15.5, 19.5, and 22) by trained interviewers using standardized measures with adequate reliability and validity. Long-distance separation from biological fathers prior to age 12 was linked in adolescence and young adulthood to serious behavior problems, anxiety and depression symptoms, and disturbed relationships with all three parental figures (i.e., biological fathers, mothers, and step-fathers). These associations held after controlling for mother-stepfather conflict and domestic violence, mothers' family income, and mother-biological father relationship quality. These longitudinal findings over time replicated the cross-sectional findings of Braver, Ellman, and Fabricius (2003) and Fabricius and Braver (2006). Policy implications for parental long-distance relocation following separation are discussed.