UK research priority setting for childhood neurological conditions.

AIM: To identify research priorities regarding the effectiveness of interventions for children and young people (CYP) with childhood neurological conditions (CNCs). These include common conditions such as epilepsies and cerebral palsy, as well as many rare conditions. METHOD: The National Institute for Health and Care Research (NIHR) and the James Lind Alliance (JLA) champion and facilitate priority setting partnerships (PSPs) between patients, caregivers, and clinicians (stakeholders) to identify the most important unanswered questions for research (uncertainties). A NIHR-JLA and British Paediatric Neurology Association collaboration used the JLA PSP methodology. This consisted of two surveys to stakeholders: survey 1 (to identify uncertainties) and survey 2 (a prioritization survey). The final top 10 priorities were agreed by consensus in a stakeholder workshop. RESULTS: One hundred and thirty-two charities and partner organizations were invited to participate. In survey 1, 701 participants (70% non-clinicians, including CYP and parent and caregivers) submitted 1800 uncertainties from which 44 uncertainties were identified for prioritization in survey 2; from these, 1451 participants (83% non-clinicians) selected their top 10 priorities. An unweighted amalgamated score across participant roles was used to select 26. In the final workshop, 14 health care professionals, 11 parent and caregivers, and two CYP ranked the 26 questions to finalize the top 10 priorities. Ten top priority questions were identified regarding interventions to treat CYP with CNCs and their associated comorbidities, for example, sleep, emotional well-being, and distressing symptoms. INTERPRETATION: The results of this study will inform research into the effectiveness of interventions for children with neurological conditions.

Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials.

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

Colorectal cancer screening in African Americans: are we following the guidelines?

PURPOSE: The age at onset, incidence, and mortality rate of colorectal cancer varies among racial groups being highest in African Americans. This increased risk led to the recommendation to begin screening at the age of 45 years. Whether the recommendation for screening of African Americans at an earlier age was implemented is unknown. METHODS: We used data from the Cancer Control Supplement of National Health Interview Survey (NHIS) conducted in the years 2005, 2010, and 2015 to analyze demographic data and use of colorectal screening (colonoscopy, stool heme testing, sigmoidoscopy, computed tomographic colonography) among the US population between the ages of 45-49 years. RESULTS: Data on colorectal screening was available from 6740 individuals; 16.5% were African Americans. Screening test use among African Americans in 2005, 2010, and 2015 was similar to use in Whites (i.e., 15.4% (95% CI 11.4-19.4), 28.4% (95% CI 19.3-30.4) and 20.2% (95% CI 14.8-25.5) vs. 16.9% (95% CI 15.1-18.6), 19.3% (95% CI 16.9-21.7), and 21.4% (95% CI 18.6-24.2) in 2005, 2010 and 2015, respectively. Observed screening test use rates may largely be accounted for by diagnostic exams. CONCLUSION: The recommendation for earlier colorectal screening of African Americans has not yet resulted in increased test utilization. These results emphasize the need for multidisciplinary actions to inform and implement public health policy.

How economic inequality shapes mobility expectations and behaviour in disadvantaged youth.

Economic inequality can have a range of negative consequences for those in younger generations, particularly for those from lower-socioeconomic status (SES) backgrounds. Economists and psychologists, among other social scientists, have addressed this issue, but have proceeded largely in parallel. This Perspective outlines how these disciplines have proposed and provided empirical support for complementary theoretical models. Specifically, both disciplines emphasize that inequality weakens people's belief in socioeconomic opportunity, thereby reducing the likelihood that low-SES young people will engage in behaviours that would improve their chances of upward mobility (for example, persisting in school or averting teenage pregnancy). In integrating the methods and techniques of economics and psychology, we offer a cohesive framework for considering this issue. When viewed as a whole, the interdisciplinary body of evidence presents a more complete and compelling framework than does either discipline alone. We use this unification to offer policy recommendations that would advance prospects for mobility among low-SES young people.

Firearms and accidental deaths: Evidence from the aftermath of the Sandy Hook school shooting.

Exposure to firearms increased substantially after the December 2012 shooting at Sandy Hook Elementary School in Newtown, Connecticut, where 20 children and 6 adults were killed. Gun sales spiked by 3 million, on the basis of the increase in the number of background checks for firearm purchases. Google searches for buying and cleaning guns increased. We used Vital Statistics mortality data to examine whether a spike in accidental firearm deaths occurred at the same time as the greater exposure to firearms. We also assessed whether the increase in these deaths was larger in those states where the spike in gun sales per capita was larger. We find that an additional 60 deaths overall, including 20 children, resulted from unintentional shootings in the immediate aftermath of Sandy Hook.

Investigating recent trends in the U.S. teen birth rate.

We investigate trends in the U.S. rate of teen childbearing between 1981 and 2010, focusing specifically on the sizable decline since 1991. We focus on establishing the role of state-level demographic changes, economic conditions, and targeted policies in driving recent aggregate trends. We offer three main observations. First, the recent decline cannot be explained by the changing racial and ethnic composition of teens. Second, the only targeted policies that have had a statistically discernible impact on aggregate teen birth rates are declining welfare benefits and expanded access to family planning services through Medicaid, but these policies can account for only 12.6 percent of the observed decline since 1991. Third, higher unemployment rates lead to lower teen birth rates and can account for 16 percent of the decline in teen birth rates since the Great Recession began.

Functional role of cellular senescence in biliary injury.

Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the senescence-associated phenotype, induction of senescence in nearby cells, and the depletion of stem cell subpopulations. Current evidence for the molecular mechanisms of senescence in the previously mentioned diseases is discussed in detail, with attention to recent advances on the role of pathways associated with senescence-associated phenotype, stress-induced senescence, telomere dysfunction, and autophagy.

Media Influences on Social Outcomes: The Impact of MTV's 16 and Pregnant on Teen Childbearing.

This paper explores the impact of the introduction of the widely viewed MTV reality show 16 and Pregnant on teen childbearing. Our main analysis relates geographic variation in changes in teen childbearing rates to viewership of the show. We implement an instrumental variables (IV ) strategy using local area MTV ratings data from a pre-period to predict local area 16 and Pregnant ratings. The results imply that this show led to a 4.3 percent reduction in teen births. An examination of Google Trends and Twitter data suggest that the show led to increased interest in contraceptive use and abortion.

Regulation of the extrinsic apoptotic pathway by microRNA-21 in alcoholic liver injury.

IL-6/Stat3 is associated with the regulation of transcription of key cellular regulatory genes (microRNAs) during different types of liver injury. This study evaluated the role of IL-6/Stat3 in regulating miRNA and miR-21 in alcoholic liver disease. By microarray, we identified that ethanol feeding significantly up-regulated 0.8% of known microRNAs in mouse liver compared with controls, including miR-21. Similarly, the treatment of normal human hepatocytes (N-Heps) and hepatic stellate cells (HSCs) with ethanol and IL-6 significantly increased miR-21 expression. Overexpression of miR-21 decreased ethanol-induced apoptosis in both N-Heps and HSCs. The expression level of miR-21 was significantly increased after Stat3 activation in N-Heps and HSCs, in support of the concept that the 5'-promoter region of miR-21 is regulated by Stat3. Using real time PCR, we confirmed that miR-21 activation is associated with ethanol-linked Stat3 binding of the miR-21 promoter. A combination of bioinformatics, PCR array, dual-luciferase reporter assay, and Western blot analysis revealed that Fas ligand (TNF superfamily, member 6) (FASLG) and death receptor 5 (DR5) are the direct targets of miR-21. Furthermore, inhibition of miR-21 by specific Vivo-Morpholino and knock-out of IL-6 in ethanol-treated mice also increased the expression of DR5 and FASLG in vivo during alcoholic liver injury. The identification of miR-21 as an important regulator of hepatic cell survival, transformation, and remodeling in vitro, as well as its upstream modulators and downstream targets, will provide insight into the involvement of altered miRNA expression in contributing to alcoholic liver disease progression and testing novel therapeutic approaches for human alcoholic liver diseases.

Molecular mechanisms of stem cell therapy in alcoholic liver disease.

Alcoholic liver disease affects a great number of people worldwide. With limited therapeutic options, stem cell therapy offers significant potential for these patients. To date, a limited number of clinical trials have produced transient clinical responses to cell therapy in patients with alcoholic liver disease. Stem cell therapy to reorganize the postnatal liver is an important theme and mission for patients with chronic liver disorders including alcoholic liver injury. We therefore should redevelop the evidence of cell-based liver regeneration therapy, focusing on targets (disease, patient's status and hepatic function), materials (cells, cytokines and genes), and methodology (stem cell types and their derived microparticles, transplantation route, implantation technology and tissue engineering). In this review, we summarize the recent findings regarding the experimental and clinical use of mesenchymal and liver stem cells, focusing mainly on the treatment of alcoholic liver disorders and their relevance in the field of regenerative medicine, and advances on the role of microvesicles and exosomes in this process. We discuss new advances in stem cell therapy from liver regeneration to liver re-organization, which is involved in the recent progress of on-going clinical trials, basic research in stem cell therapy and liver regeneration, and updated exosomes/microvesicles recovery/repairing technology.

The functional role of microRNAs in alcoholic liver injury.

The function of microRNAs (miRNAs) during alcoholic liver disease (ALD) has recently become of great interest in biological research. Studies have shown that ALD associated miRNAs play a crucial role in the regulation of liver-inflammatory agents such as tumour necrosis factor-alpha (TNF-α), one of the key inflammatory agents responsible for liver fibrosis (liver scarring) and the critical contributor of alcoholic liver disease. Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for TNF-α release by Kupffer cells. miRNAs are the critical mediators of LPS signalling in Kupffer cells, hepatocytes and hepatic stellate cells. Certain miRNAs, in particular miR-155 and miR-21, show a positive correlation in up-regulation of LPS signalling when they are exposed to ethanol. ALD is related to enhanced gut permeability that allows the levels of LPS to increase, leads to increased secretion of TNF-α by the Kupffer cells and subsequently promotes alcoholic liver injury through specific miRNAs. Meanwhile, two of the most frequently dysregulated miRNAs in steatohepatitis, miR-122 and miR-34a are the critical mediators in ethanol/LPS activated survival signalling during ALD. In this review, we summarize recent findings regarding the experimental and clinical aspects of functions of specific microRNAs, focusing mainly on inflammation and cell survival after ethanol/LPS treatment, and advances on the role of circulating miRNAs in human alcoholic disorders.

Why is the teen birth rate in the United States so high and why does it matter?

Teens in the United States are far more likely to give birth than in any other industrialized country in the world. U.S. teens are two and a half times as likely to give birth as compared to teens in Canada, around four times as likely as teens in Germany or Norway, and almost 10 times as likely as teens in Switzerland. Among more developed countries, Russia has the next highest teen birth rate after the United States, but an American teenage girl is still around 25 percent more likely to give birth than her counterpart in Russia. Moreover, these statistics incorporate the almost 40 percent fall in the teen birth rate that the United States has experienced over the past two decades. Differences across U.S. states are quite dramatic as well. A teenage girl in Mississippi is four times more likely to give birth than a teenage girl in New Hampshire--and 15 times more likely to give birth as a teen compared to a teenage girl in Switzerland. This paper has two overarching goals: understanding why the teen birth rate is so high in the United States and understanding why it matters. Thus, we begin by examining multiple sources of data to put current rates of teen childbearing into the perspective of cross-country comparisons and recent historical context. We examine teen birth rates alongside pregnancy, abortion, and "shotgun" marriage rates as well as the antecedent behaviors of sexual activity and contraceptive use. We seek insights as to why the rate of teen childbearing is so unusually high in the United States as a whole, and in some U.S. states in particular. We argue that explanations that economists have tended to study are unable to account for any sizable share of the variation in teen childbearing rates across place. We describe some recent empirical work demonstrating that variation in income inequality across U.S. states and developed countries can explain a sizable share of the geographic variation in teen childbearing. To the extent that income inequality is associated with a lack of economic opportunity and heightened social marginalization for those at the bottom of the distribution, this empirical finding is potentially consistent with the ideas that other social scientists have been promoting for decades but which have been largely untested with large data sets and standard econometric methods. Our reading of the totality of evidence leads us to conclude that being on a low economic trajectory in life leads many teenage girls to have children while they are young and unmarried and that poor outcomes seen later in life (relative to teens who do not have children) are simply the continuation of the original low economic trajectory. That is, teen childbearing is explained by the low economic trajectory but is not an additional cause of later difficulties in life. Surprisingly, teen birth itself does not appear to have much direct economic consequence. Moreover, no silver bullet such as expanding access to contraception or abstinence education will solve this particular social problem. Our view is that teen childbearing is so high in the United States because of underlying social and economic problems. It reflects a decision among a set of girls to "drop-out" of the economic mainstream; they choose non-marital motherhood at a young age instead of investing in their own economic progress because they feel they have little chance of advancement. This thesis suggests that to address teen childbearing in America will require addressing some difficult social problems: in particular, the perceived and actual lack of economic opportunity among those at the bottom of the economic ladder.

Reflux events detected by pH-MII do not determine fundoplication outcome.

BACKGROUND: Because of complications and its invasive nature, fundoplication is often a treatment of last resort for children with gastroesophageal reflux. Gastroesophageal reflux testing does not always predict who will benefit from antireflux surgery. Furthermore, there are no studies to determine whether a higher preoperative reflux burden, including acid and nonacid reflux, is associated with an improved postfundoplication outcome. The aim of the study was to determine predictors of fundoplication outcome including acid and nonacid reflux burden. PATIENTS AND METHODS: We retrospectively reviewed preoperative pH-multichannel intraluminal impedance tracings and medical records of 34 patients who underwent fundoplication. Patients were categorized as improved or not improved, and the demographic and reflux characteristics were compared between groups. Multivariate analysis was performed to determine predictors of outcome. RESULTS: No single reflux marker, including the number of acid, nonacid, total events, or the percentage of time that reflux was in the esophagus, predicted fundoplication outcome (P > 0.1). Neither a positive symptom index nor a positive symptom sensitivity index predicted postoperative improvement (P > 0.4). Receiver operating characteristic curve analysis failed to reveal an ideal value to maximize sensitivity for either the symptom index or the symptom sensitivity index. CONCLUSIONS: pH-multichannel intraluminal impedance testing may not be a useful tool in predicting fundoplication outcome.

Subsidized Contraception, Fertility, and Sexual Behavior.

We examine the impact of recent state-level Medicaid policy changes that expanded eligibility for family planning services to higher-income women and to Medicaid clients whose benefits would expire otherwise. We show that the income-based policy change reduced overall births to non-teens by about 2% and to teens by over 4%; estimates suggest a decline of 9% among newly eligible women. The reduction in fertility appears to have been accomplished via greater use of contraception. Our calculations indicate that allowing higher-income women to receive federally funded family planning cost on the order of $6,800 for each averted birth.

Parental involvement laws and fertility behavior.

This paper considers the impact of the introduction of laws requiring parental involvement in a minor's decision to abort a pregnancy. State-level data over the 1985-1996 period are used to examine abortion, birth, and pregnancy outcomes, while microdata from the 1988 and 1995 National Surveys of Family Growth (NSFG) are utilized to examine sexual activity and contraception. Quasi-experimental methods are employed that examine whether minors' fertility outcomes were affected in those locations that introduced these laws following their introduction and occurred for minors but not other women. I find that parental involvement laws resulted in fewer abortions for minors resulting from fewer pregnancies; there is no statistically significant impact on births. The reduction in pregnancy seems to be attributable to increased use of contraception rather than a reduction in sexual activity.

Maternal employment and overweight children.

This paper seeks to determine whether a causal relationship exists between maternal employment and childhood weight problems. We use matched mother-child data from the National Longitudinal Survey of Youth (NLSY) and employ econometric techniques to control for observable and unobservable differences across individuals and families that may influence both children's weight and their mothers' work patterns. Our results indicate that a child is more likely to be overweight if his/her mother worked more hours per week over the child's life. Analyses by subgroups show that it is higher socioeconomic status mothers whose work intensity is particularly deleterious for their children's overweight status.