"It just depends": Parent, teacher, and expert conceptualization of social communication in young autistic children.

LAY ABSTRACT: Improving social communication is often one goal during early autism services. However, researchers do not yet know whether their ideas about which social communication skills should be targeted during services for young autistic children are the same as the goals of autism community members, such as parents, teachers, and expert clinicians. This study used focus groups (meetings of small groups of community members) to ask people from these groups about what aspects of social communication are most important to support in young autistic children. A total of 43 people participated in these focus groups. These groups included parents (three groups; 21 people), teachers (two groups; 8 people), and experts in early social communication and autism (two groups; 14 people). Focus group participants talked about several aspects of social communication that were already familiar to the research team, such as problems with expressive communication, language understanding, and social interaction. However, participants also talked about several parts of social communication that were less familiar to the research team and had usually not been mentioned in previous research. These included (1) considering the value of unusual forms of communication, (2) taking context and setting into account when considering social communication, and (3) how communication and emotion regulation impact one another. The information from these focus groups will be helpful to making sure that researchers and clinicians focus their social communication supports on areas that are most important to parents and teachers.

TGFB1 induces fetal reprogramming and enhances intestinal regeneration.

The gut epithelium has a remarkable ability to recover from damage. We employed a combination of high-throughput sequencing approaches, mouse genetics, and murine and human organoids and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. The depletion of macrophages or genetic disruption of TGFB signaling significantly impaired the regenerative response. Intestinal regeneration is characterized by the induction of a fetal-like transcriptional signature during repair. In organoid culture, TGFB1 treatment was necessary and sufficient to induce the fetal-like/regenerative state. Mesenchymal cells were also responsive to TGFB1 and enhanced the regenerative response. Mechanistically, pro-regenerative factors, YAP/TEAD and SOX9, are activated in the epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for cellular therapy.

Enhancing stakeholder roles in autism early interventions in the United States: A stakeholder-driven research agenda.

LAY ABSTRACT: In this article, we outline a stakeholder-driven research agenda to guide future early intervention research for children with autism. Our research team collaborated with autism service providers, parents of individuals with autism, and autistic people to create this research agenda by (1) conducting workshops with community members and (2) distributing a survey to a larger number of community members around the country. The finalized research agenda includes (1) Guiding Principles for current and future research, (2) Research Priorities focused on early intervention for individuals with autism, and (3) Systems Implications to consider in future clinical, research, and policy efforts for early intervention. The full version of the research agenda is available in Supplemental Material. This article lists the main points of the research agenda and discusses unique themes highlighted by the community members. One main conclusion is that researchers need to include community members in decision-making and consultant positions throughout the research process to best meet the needs of the broader autism community. We have created a researcher workbook which we hope may facilitate these community consultation efforts. This workbook is available in Supplemental Material.

Effect of third-party components on emissions from a pod style electronic cigarette.

Electronic nicotine delivery systems (ENDS) have been associated with a dramatic increase in youth becoming addicted to nicotine following decades-long decline in cigarette smoking uptake. The United States Food and Drug Administration, Center for Tobacco Products (FDA/CTP) is responsible for regulating devices and consumable materials associated with ENDS. State and federal regulations regarding flavoring compounds in ENDS liquids (e-liquids) may be circumvented when vendors market refillable reservoirs side-by-side with noncompliant e-liquids. This study investigated the effect of third-party refillable versus manufacturer-supplied single-use reservoirs on total particulate matter (TPM) and nicotine emissions. The maximum TPM yield per puff was 5.6 times higher for the third-party (Blankz) reservoir (12.4 mg/puff) in comparison with the manufacturer's (JUUL) reservoir (2.2 mg/puff), whereas the maximum TPM concentration was over 7 times higher for third party (0.200 mg/ml) versus manufacturer (0.028 mg/ml) pod. The third-party pod was tested with nicotine concentrations ranging from 0% to 4%. The mass ratio of nicotine present in the aerosol (mg Nic/mg TPM) was found to be approximately the same as the mass ratio of the e-liquid (mg Nic/mg e-liquid) for both pods and all 3 nicotine laden e-liquids tested. Toxicant exposure may increase when consumers use third-party pods with ENDS devices. Refillable reservoirs are a significant barrier to regulatory restrictions on potentially toxic additives to e-liquids. It is recommended FDA/CTP require emissions characterization of third-party reservoirs used with each ENDS they are compatible with and should be required to demonstrate no increased potential toxicant exposure in comparison with manufacturer-provided reservoirs.

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration.

The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for the application of the TGFB-induced regenerative circuit in cellular therapy.

Putting "ME" into measurement: Adapting self-report health measures for use with individuals with intellectual disability.

BACKGROUND: Self-report is important for measuring health outcomes; however, most research in intellectual disability (ID) relies on proxy report. The lack of cognitively accessible measures is one barrier to accurate self-reporting by individuals with ID. AIMS: This paper describes the process of adapting self-report measures of health status, health-related quality of life, and environment for use by individuals with ID and presents evidence on their usability (accessibility), usefulness (independent self-report), and reliability (internal consistency and test-retest). METHODS AND PROCEDURES: We used an inclusive research approach, in which we collaborated with adults with ID to revise, cognitively test, and pilot test cognitively accessible self-report measures. Technology supported the independent completion of measures. We assessed usability, usefulness, and reliability of these measures in 41 adults with ID. OUTCOMES AND RESULTS: The resulting measures are useful (independently completed) and usable (elicit a range of responses), with modest reliability (internal consistency and test-retest). CONCLUSIONS AND IMPLICATIONS: Self- report by adults with ID is feasible. A key element of this measure adaptation process was engaging adults with ID. More research is needed to understand the reliability and validity of the adapted measures and the characteristics of the population for whom they are most usable.

Methenamine hippurate compared with antibiotic prophylaxis to prevent recurrent urinary tract infections in women: the ALTAR non-inferiority RCT.

BACKGROUND: Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women. DESIGN: Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months' treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year. SETTING: Eight UK NHS secondary care sites. PARTICIPANTS: A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial. INTERVENTIONS: A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted. MAIN OUTCOME MEASURES: The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient's expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction. RESULTS: Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months' data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in Escherichia coli cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew E. coli resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in E. coli isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms. LIMITATIONS: This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation. CONCLUSIONS: This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics. RECOMMENDATIONS FOR RESEARCH: Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics. TRIAL REGISTRATION: This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.

Women with recurrent urine infections often require preventative treatment to reduce the frequency of infection episodes. Daily low-dose antibiotic medication is a guideline-recommended treatment option for these women. There is increasing concern globally regarding antibiotic-resistant infections, which has led researchers to look at alternative treatments. This trial was conducted to find out whether or not taking an alternative treatment that is not an antibiotic [i.e. methenamine hippurate (Hiprex^®; Mylan NV, Canonsburg, PA, USA)] was as effective as the standard daily low-dose antibiotics. A total of 240 women from across the UK took part in the trial. They were divided equally into two groups; half of the women were given methenamine hippurate and the other half were given standard low-dose antibiotics. Both treatments were prescribed to be taken every day for 1 year. To make a fair comparison, people were put into the two groups at random using a computer program. Aspects of the trial that could be improved were identified through telephone interviews with patients and recruiting staff. Feedback from these telephone interviews helped to ensure the successful conduct of the trial. Patients were followed up for 18 months, comprising the 12 months when they were taking treatment and a 6-month follow-up phase after they had finished treatment. We found that the non-antibiotic option of methenamine hippurate was no worse than the current standard treatment of daily antibiotics in preventing urinary tract infection episodes in adult women. For both treatments, patients expressed high levels of satisfaction. One advantage of the methenamine hippurate treatment was that infecting bacteria were slightly less likely to develop resistance to antibiotics. We also evaluated health-care costs of both treatments and found that methenamine hippurate seemed worthwhile to the NHS in the short term, but there was uncertainty over longer-term costs and benefits. These results will help patients with repeated urinary tract infections to decide on treatment options, particularly if they want to avoid prolonged courses of preventative antibiotics.

Multidrug-resistant Uro-associated Escherichia coli Populations and Recurrent Urinary Tract Infections in Patients Performing Clean Intermittent Self-catheterisation.

BACKGROUND: The AnTIC trial linked continuous low-dose antibiotic prophylaxis treatments to a lower incidence of symptomatic urinary tract infections (UTIs) among individuals performing clean intermittent self-catheterisation (CISC). OBJECTIVE: To explore potential mechanisms underlying the protective effects of low-dose antibiotic prophylaxis treatments, blood and urine samples and uro-associated Escherichia coli isolates from AnTIC participants were analysed. DESIGN SETTING AND PARTICIPANTS: Blood samples (n = 204) were analysed for TLR gene polymorphisms associated with UTI susceptibility and multiple urine samples (n = 558) were analysed for host urogenital responses. E.coli sequence data for 45 temporal isolates recovered from the urine samples of 16 trial participants in the prophylaxis (n = 9) and no-prophylaxis (n = 7) study arms, and characterised by multidrug resistance (MDR), were used to classify individual strains. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: TLR polymorphism data were analysed using Poisson regression. Concentrations of urine host defence markers were analysed using linear mixed-effects models, which accounted for repeated urine samples. RESULTS AND LIMITATIONS: Urine samples from CISC users, irrespective of antibiotic treatment regimens, were associated with robust urothelial innate responses. No links were identified between TLR genotype and CISC user susceptibility to recurrent UTIs. Microbiological study data were limited to the predominant MDR E. coli population; participants prescribed low-dose prophylactic antibiotics were predominantly colonised by a single uro-associated E. coli strain, while participants given acute antibiotic treatments were each colonised by more than one E. coli strain. CONCLUSIONS: Antibiotic treatments did not impact urogenital responses to infection in CISC users. Host genetics in terms of TLR polymorphisms played no role in determining CISC user susceptibility to or protection from recurrent UTIs. Prophylactic antibiotic treatments associated with MDR E. coli were associated with colonisation by stable uro-associated E. coli genotypes. PATIENT SUMMARY: Our findings show that the natural urogenital defences of clean intermittent self-catheterisation (CISC) users were not impacted by antibiotic treatments. For some CISC users, prophylaxis with low-dose antibiotics selected for a stable, predominantly, Esherichia coli rich uromicrobiota.

Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial.

OBJECTIVE: To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics. DESIGN: Multicentre, open label, randomised, non-inferiority trial. SETTING: Eight centres in the UK, recruiting from June 2016 to June 2018. PARTICIPANTS: Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment. INTERVENTIONS: Random assignment (1:1, using permuted blocks of variable length via a web based system) to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed. MAIN OUTCOME MEASURE: Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months. RESULTS: Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants (antibiotics, n=102 (85%); methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year (95% confidence interval 0.65 to 1.12) in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49 (90% confidence interval 0.15 to 0.84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild. CONCLUSION: Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. TRIAL REGISTRATION: ISRCTN70219762.

Symptoms of Autism Spectrum Disorder in Children With Down Syndrome and Williams Syndrome.

Research suggests that people with a Williams syndrome (WS) or Down syndrome (DS) diagnosis display an increased prevalence of autism spectrum disorder (ASD) when compared to the general population. This study aimed to examine characteristics of ASD in a group of children with DS or WS. Results suggest that children with DS and WS exhibit higher levels of autism symptoms than the general population, particularly in the area of unusual behaviors, and that these elevations are not solely due to deficits in adaptive behavior. There are many possible explanations for these elevations, such as issues with measurement, etiological overlap, or similar behavioral phenotypes. More research is needed to further our understanding of the overlap of ASD symptoms in these populations.

Mapping Development of the Human Intestinal Niche at Single-Cell Resolution.

The human intestinal stem cell niche supports self-renewal and epithelial function, but little is known about its development. We used single-cell mRNA sequencing with in situ validation approaches to interrogate human intestinal development from 7-21 weeks post conception, assigning molecular identities and spatial locations to cells and factors that comprise the niche. Smooth muscle cells of the muscularis mucosa, in close proximity to proliferative crypts, are a source of WNT and RSPONDIN ligands, whereas EGF is expressed far from crypts in the villus epithelium. Instead, an PDGFRAHI/F3HI/DLL1HI mesenchymal population lines the crypt-villus axis and is the source of the epidermal growth factor (EGF) family member NEUREGULIN1 (NRG1). In developing intestine enteroid cultures, NRG1, but not EGF, permitted increased cellular diversity via differentiation of secretory lineages. This work highlights the complexities of intestinal EGF/ERBB signaling and delineates key niche cells and signals of the developing intestine.

Hedgehog Signaling in Intestinal Development and Homeostasis.

The hedgehog (Hh) signaling pathway plays several diverse regulatory and patterning roles during organogenesis of the intestine and in the regulation of adult intestinal homeostasis. In the embryo, fetus, and adult, intestinal Hh signaling is paracrine: Hh ligands are expressed in the endodermally derived epithelium, while signal transduction is confined to the mesenchymal compartment, where at least a dozen distinct cell types are capable of responding to Hh signals. Epithelial Hh ligands not only regulate a variety of mesenchymal cell behaviors, but they also direct these mesenchymal cells to secrete additional soluble factors (e.g., Wnts, Bmps, inflammatory mediators) that feed back to regulate the epithelial cells themselves. Evolutionary conservation of the core Hh signaling pathway, as well as conservation of epithelial/mesenchymal cross talk in the intestine, has meant that work in many diverse model systems has contributed to our current understanding of the role of this pathway in intestinal organogenesis, which is reviewed here.

Social endophenotypes in autism spectrum disorder: A scoping review.

Endophenotypes are measurable markers of genetic vulnerability to current or future disorder. Autism spectrum disorder (ASD) is well-suited to be examined within an endophenotype framework given past and current emphases on the broader autism phenotype and early detection. We conducted a scoping review to identify potential socially-related endophenotypes of ASD. We focused on paradigms related to sociality (e.g., theory of mind (TOM), social attention), which comprise most of this literature. We integrated findings from traditional behavioral paradigms with brain-based measures (e.g., electroencephalography, functional magnetic resonance imaging). Broadly, infant research regarding social attention and responsivity (Research Domain Criteria (RDoC) domain of affiliation) and attention to faces and voices (social communication) finds consistent abnormality in vulnerable infant siblings. Several additional paradigms that have shown differences in vulnerable infants and young children include animacy perception tasks (perception and understanding of others), measures of recognition and response to familiar faces (attachment), and joint attention and false-belief tasks (understanding mental states). Research areas such as alexithymia (the perception and understanding of self), empathic responding, and vocal prosody may hold interest; however, challenges in measurement across populations and age ranges is a limiting factor. Future work should address sex differences and age dependencies, specificity to ASD, and heterogeneous genetic pathways to disorder within samples individuals with ASD and relatives.

RYK-mediated filopodial pathfinding facilitates midgut elongation.

Between embryonic days 10.5 and 14.5, active proliferation drives rapid elongation of the murine midgut epithelial tube. Within this pseudostratified epithelium, nuclei synthesize DNA near the basal surface and move apically to divide. After mitosis, the majority of daughter cells extend a long, basally oriented filopodial protrusion, building a de novo path along which their nuclei can return to the basal side. WNT5A, which is secreted by surrounding mesenchymal cells, acts as a guidance cue to orchestrate this epithelial pathfinding behavior, but how this signal is received by epithelial cells is unknown. Here, we have investigated two known WNT5A receptors: ROR2 and RYK. We found that epithelial ROR2 is dispensable for midgut elongation. However, loss of Ryk phenocopies the Wnt5a-/- phenotype, perturbing post-mitotic pathfinding and leading to apoptosis. These studies reveal that the ligand-receptor pair WNT5A-RYK acts as a navigation system to instruct filopodial pathfinding, a process that is crucial for continuous cell cycling to fuel rapid midgut elongation.

Brief report: Does "healthy" family functioning look different for families who have a child with autism?

BACKGROUND: For families of typically developing children, extremes of family cohesion (enmeshed and disengaged) and flexibility (rigid and chaotic) are associated with negative outcomes (Olson, 2011). Some work suggests that this may not be true for families of children with autism spectrum disorder (ASD; Altiere & von Kluge 2009). Specifically, regimented daily routines (increased rigidity) and highly involved caregivers (increased enmeshment) might theoretically be associated with positive outcomes. OBJECTIVES: This study examined whether families who have a child with ASD report different family dynamics than families with typically developing children, and if these dynamics are equally predictive of outcomes for both groups. METHOD: Regression-based interaction analyses using data from an online survey (n = 235) were used to examine how diagnostic group (typically-developing child or child with ASD) affected the relationships between elements of family functioning and parent outcomes of happiness, depression, and satisfaction with family life. RESULTS: Higher parent-reported enmeshment was associated with decreased parent-reported happiness in typical families only; these variables were unrelated in families with a child with ASD. In addition, the relationship between disengagement and parent happiness was marginally weaker in the ASD group. Other scales (rigid and chaotic) exhibited similar relationships with family outcomes across both diagnostic groups. CONCLUSION: In alignment with previous findings (Altiere & von Kluge 2009), elevated levels of enmeshment were not predictive of poorer outcomes in families of children with ASD. There is a need to critically consider whether behaviors traditionally thought of as "enmeshed" may represent different, more adaptive support strategies for families who have a child with ASD.

Elevated urine IL-10 concentrations associate with Escherichia coli persistence in older patients susceptible to recurrent urinary tract infections.

BACKGROUND: Age is a significant risk factor for recurrent urinary tract (rUTI) infections, but the clinical picture is often confused in older patients who also present with asymptomatic bacteriuria (ASB). Yet, how bacteriuria establishes in such patients and the factors underpinning and/or driving symptomatic UTI episodes are still not understood. To explore this further a pilot study was completed in which 30 male and female community based older patients (mean age 75y) presenting clinically with ASB / rUTIs and 15 control volunteers (72y) were recruited and monitored for up to 6 months. During this period symptomatic UTI episodes were recorded and urines collected for urinary cytokine and uropathogenic Escherichia coli (UPEC) analyses. RESULTS: Eighty-six per cent of patients carried E. coli (102 ≥ 105 CFU/ml urine) at some point throughout the study and molecular typing identified 26 different E. coli strains in total. Analyses of urine samples for ten different cytokines identified substantial patient variability. However, when examined longitudinally the pro-inflammatory markers, IL-1 and IL-8, and the anti-inflammatory markers, IL-5 and IL-10, were significantly different in the patient urines compared to those of the controls (P < 0.0001). Furthermore, analysing the cytokine data of the rUTI susceptible cohort in relation to E. coli carriage, showed the mean IL-10 concentration to be significantly elevated (P = 0.04), in patients displaying E. coli numbers ≥105 CFU/ml. CONCLUSIONS: These pilot study data suggest that bacteriuria, characteristic of older rUTI patients, is associated with an immune homeostasis in the urinary tract involving the synthesis and activities of the pro and anti-inflammatory cytokines IL-1, IL-5, IL-8 and IL-10. Data also suggests a role for IL-10 in regulating bacterial persistence.

Meta-analysis of naturalistic developmental behavioral interventions for young children with autism spectrum disorder.

Naturalistic developmental behavioral intervention is an emerging class of interventions for young children with autism spectrum disorder. The present article is a meta-analysis of outcomes of group-design studies (n = 27) testing interventions using naturalistic developmental behavioral intervention strategies. Small, significant positive effects of naturalistic developmental behavioral intervention were found for expressive language (g = 0.32), reduction in symptoms of autism spectrum disorder (g = -0.38), and play skills (g = 0.23). Larger effects were found for social engagement (g = 0.65) and overall cognitive development (g = 0.48). A marginal effect was found for joint attention (g = 0.14) and receptive language (g = 0.28). For joint attention, improvement was moderated by hours of professional involvement. Evidence of publication and reporting bias was present for language outcomes. This meta-analysis grows the evidence base for naturalistic developmental behavioral interventions, particularly in the key areas of social engagement and cognition.

Signals and forces shaping organogenesis of the small intestine.

The adult gastrointestinal tract (GI) is a series of connected organs (esophagus, stomach, small intestine, colon) that develop via progressive regional specification of a continuous tubular embryonic organ anlage. This chapter focuses on organogenesis of the small intestine. The intestine arises by folding of a flat sheet of endodermal cells into a tube of highly proliferative pseudostratified cells. Dramatic elongation of this tube is driven by rapid epithelial proliferation. Then, epithelial-mesenchymal crosstalk and physical forces drive a stepwise cascade that results in convolution of the tubular surface into finger-like projections called villi. Concomitant with villus formation, a sharp epithelial transcriptional boundary is defined between stomach and intestine. Finally, flask-like depressions called crypts are established to house the intestinal stem cells needed throughout life for epithelial renewal. New insights into these events are being provided by in vitro organoid systems, which hold promise for future regenerative engineering of the small intestine.

Leisure time and family functioning in families living with autism spectrum disorder.

Family leisure can provide opportunities for both enjoyment and family growth. However, families of children with autism spectrum disorder experience multiple barriers to engaging in satisfying family leisure activities. This study surveyed parents of children with autism spectrum disorder (n = 112) and parents of children with typical development (n = 123) to examine relationships among family leisure involvement, leisure satisfaction, family functioning, and satisfaction with family life. Parents of children with autism spectrum disorder reported a similar amount of leisure involvement as families of typically developing children. However, they reported lower leisure satisfaction, poorer family functioning, and less satisfaction with family life. Mediation models suggested that low leisure satisfaction was related to less effective family communication, which in turn led to poorer family functioning and less satisfaction with family life. Amount of time spent in leisure made relatively small contributions to predicting other family variables. These results suggest that leisure-focused interventions for families of children with autism spectrum disorder should focus on improving quality, rather than quantity, of family leisure time.

ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in women (ALTAR): study protocol for a multicentre, pragmatic, patient-randomised, non-inferiority trial.

BACKGROUND: At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the 'gold standard' preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention. DESIGN /METHODS: This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants' and recruiting clinicians' views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study. DISCUSSION: The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a 'Type A' study. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016.