An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFß.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFß. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFß signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFß at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFß-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

Uterine rupture of an unscarred gravid uterus at term attributed to adenomyosis.

Uterine rupture is a rare obstetric emergency that is typically associated with the presence of scar tissue such as in the case of previous caesarean section. In this case report, a primigravid patient presented to the hospital in cardiac arrest with massive haemoperitoneum secondary to a posterior uterine rupture. The histological specimen was found to have diffuse adenomyosis at the site of rupture. On review of the literature, there is insufficient evidence to suggest we as clinicians should alter the antenatal care for patients with known adenomyosis; however, this case highlights how we should have a high index of suspicion for those presenting with signs and symptoms of uterine rupture with known adenomyosis in the absence of other risk factors.

Development of "Baby, Me, & NRT": A Behavioral Intervention to Improve the Effectiveness of Nicotine Replacement Therapy in Pregnancy.

BACKGROUND: The effectiveness of Nicotine Replacement Therapy (NRT) for smoking cessation in pregnancy is limited by inconsistent and incorrect use. This paper describes the development process for "Baby, Me, & NRT", a novel pregnancy-specific intervention aimed at enhancing adherence to NRT. METHODS: An integrated approach to intervention development was used, combining evidence, theory, stakeholders' feedback, and tailoring principles. The process involved six iterative steps: (1) synthesizing relevant published evidence and guidance, (2) collecting primary qualitative data on barriers and facilitators to NRT adherence along with potential intervention design features, (3) identifying relevant behavioral theories and mapping the evidence against these, (4) prioritizing behavioral determinants identified in steps 1 and 2, generating intervention objectives, and identifying behavior change techniques which target the prioritized determinants, (5) consulting with stakeholders on intervention components, key content and tailoring features, and (6) producing a prototype intervention along with implementation guidance. RESULTS: The prototype intervention comprises of a multi-component, 1-month cessation programme, which includes six enhanced behavioral support sessions delivered by a trained advisor, tailored text messages, a website, and an illustrated booklet. It promotes the uptake of high-dose and combination NRT, emphasizes the importance of adherence, addresses motivation to use NRT, proactively helps problem solve NRT use issues, and provides guidance on preventing and managing smoking lapses. CONCLUSION: The development process generated an evidence- and theory-guided intervention, designed with stakeholder input, aimed at improving NRT effectiveness for smoking cessation in pregnancy. The prototype intervention has since been optimized and is being evaluated in a randomized controlled trial.

Comparison of a Daily Smartphone App and Retrospective Questionnaire Measures of Adherence to Nicotine Replacement Therapy Among Pregnant Women: Observational Study.

BACKGROUND: Few studies have investigated how to best measure adherence to smoking cessation medications, but continuous usage measures are recommended. OBJECTIVE: In this first study of its kind, we compared methods for measuring adherence to nicotine replacement therapy (NRT) among pregnant women, investigating the completeness and validity of data collected from daily assessments using a smartphone app versus data collected from retrospective questionnaires. METHODS: Women aged ≥16 years who were daily smokers and <25 weeks pregnant were offered smoking-cessation counseling and encouraged to use NRT. For 28 days after setting a quit date (QD), women were asked to report NRT use daily to a smartphone app and to questionnaires administered in person or remotely at 7 and 28 days. For both data collection methods, we provided up to £25 (~US $30) as compensation for the time taken providing research data. Data completeness and NRT use reported to the app and in questionnaires were compared. For each method, we also correlated mean daily nicotine doses reported within 7 days of the QD with Day 7 saliva cotinine concentrations. RESULTS: Of the 438 women assessed for eligibility, 40 participated and 35 accepted NRT. More participants (31/35) submitted NRT usage data to the app by Day 28 (median 25, IQR 11 days) than completed the Day 28 questionnaire (24/35) or either of the two questionnaires (27/35). Data submitted to the app showed a lower reported duration of NRT use compared to that indicated in the questionnaire (median for app 24 days, IQR 10.25; median for questionnaire 28 days, IQR 4.75; P=.007), and there appeared to be specific cases of overreporting to the questionnaire. Mean daily nicotine doses between the QD and Day 7 were lower when calculated using app data (median for app 40 mg, IQR 52.1; median for questionnaire 40 mg, IQR 63.1; P=.001), and some large outliers were evident for the questionnaire. Mean daily nicotine doses, adjusted for cigarettes smoked, were not associated with cotinine concentrations for either method (app rs=0.184, P=.55; questionnaire rs=0.031, P=.92), but the small sample size meant that the analysis was likely underpowered. CONCLUSIONS: Daily assessment of NRT use via a smartphone app facilitated more complete data (a higher response rate) than questionnaires, and reporting rates over 28 days were encouraging among pregnant women. App data had better face validity; retrospective questionnaires appeared to overestimate NRT use for some participants.

Development and Content Validation of a Questionnaire for Measuring Beliefs About Using Nicotine Replacement Therapy for Smoking Cessation in Pregnancy.

INTRODUCTION: Improving adherence to nicotine replacement therapy (NRT) in pregnancy may result in higher smoking cessation rates. Informed by the Necessities and Concerns Framework, we developed an intervention targeting pregnancy NRT adherence. To evaluate this, we derived the NRT in pregnancy necessities and concerns questionnaire (NiP-NCQ), which measures perceived need for NRT and concerns about potential consequences. AIMS AND METHODS: Here we describe the development and content validation of NiP-NCQ. From qualitative work, we identified potentially modifiable determinants of pregnancy NRT adherence and classed these as necessity beliefs or concerns. We translated these into draft self-report items and piloted items on 39 pregnant women offered NRT and a prototype NRT adherence intervention, assessing distributions and sensitivity to change. After removing poorly performing items, smoking cessation experts (N = 16) completed an online discriminant content validation (DCV) task to determine whether retained items measure a necessity belief, concern, both, or neither construct. RESULTS: Draft NRT concern items encompassed safety for the baby, side effects, too much or insufficient nicotine, and addictiveness. Draft necessity belief items included perceived need for NRT for short- and longer-term abstinence, and desire to minimize or cope without NRT. Of 22 out of 29 items retained after piloting, four were removed following the DCV task: three were judged to measure neither construct and one possibly both. The final NiP-NCQ comprised nine items per construct (18 total). CONCLUSIONS: The NiP-NCQ measures potentially modifiable determinants of pregnancy NRT adherence within two distinct constructs and may have research and clinical utility for evaluating interventions targeting these. IMPLICATIONS: Poor adherence to NRT in pregnancy may result from low perceived need and concerns about consequences; interventions challenging these beliefs may yield higher smoking cessation rates. To evaluate an NRT adherence intervention informed by the Necessities and Concerns Framework, we developed the NiP-NCQ. Through the content development and refinement processes described in this paper, we derived an evidence-based, 18-item questionnaire measuring two distinct constructs within two nine-item subscales. Higher concerns and lower necessity beliefs indicate more negative NRT beliefs; NiP-NCQ may have research and clinical utility for interventions targeting these.

A systematic review and meta-analysis of suicidality in autistic and possibly autistic people without co-occurring intellectual disability.

BACKGROUND: Suicidality is highly prevalent in autistic people without co-occurring intellectual disabilities, and high autistic traits are found in adults who have attempted suicide. However, prevalence rates for both autistic and possibly autistic people have not been synthesised meta-analytically. AIMS: To (1) calculate pooled prevalence estimates of suicidality in autistic people and possibly autistic people without co-occurring intellectual disability; (2) evaluate the influence of participant and study level characteristics on heterogeneity; and (3) determine the quality of evidence. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. PsycINFO, Embase, MEDLINE and Web of Science were systematically searched from 1992 to January 25, 2022. Empirical quantitative studies reporting prevalence of suicidal ideation, suicide plans, or suicide attempts and behaviours were considered for inclusion. Random effects models were used to estimate pooled prevalence of each suicidality outcome with 95% confidence intervals. Heterogeneity was explored using sensitivity and moderator analyses. RESULTS: Data from 48,186 autistic and possibly autistic participants in 36 primary studies were meta-analysed. Pooled prevalence of suicidal ideation was 34.2% (95% CI 27.9-40.5), suicide plans 21.9% (13.4-30.4), and suicidal attempts and behaviours 24.3% (18.9-29.6). High levels of heterogeneity (I2 > 75) were observed in all three analyses. Estimates did not differ between autistic or possibly autistic samples. Geographical location (p = 0.005), transgender or gender non-conforming samples (p < 0.001) and type of report (p < 0.001) significantly moderated suicidal ideation, whereas age group (p = 0.001) and measure of suicidality (p = 0.001) significantly moderated suicide plans. There was a significant association between the proportion of male participants and prevalence of suicide plans, with a decrease in the proportion of males for every unit change of suicide plan prevalence (p = 0.013). No variables were found to moderate estimates of suicide attempts and behaviours. CONCLUSIONS: The results confirm suicidality is highly prevalent in both autistic and possibly autistic people without co-occurring intellectual disability and highlights potential moderators. Possibly autistic individuals require more attention in clinical and research considerations going forward to further understand and prevent suicide in both groups.

Developing a taxonomy to describe offspring outcomes in studies involving pregnant mammals' exposure to non-tobacco nicotine: A systematic scoping review.

INTRODUCTION: Many countries recommend Nicotine Replacement Therapy (NRT) for smoking cessation in pregnancy. Preclinical studies of nicotine exposure to pregnant mammals could indicate how nicotine may adversely affect the developing fetus. As a first step towards summarising this literature, we undertook a systematic scoping review to determine the number and nature of offspring outcomes studied. METHODS: We searched MEDLINE and EMBASE databases for papers reporting empirical data on offspring outcomes following nicotine exposure to pregnant non-human mammals. We excluded studies that investigated exposure to only smoking, e-cigarettes, nicotine vaccines, or studies with no 'nicotine only' group. We developed a draft taxonomy and using this, described and quantified outcomes reported. RESULTS: We identified 476 studies, which reported 729 offspring outcomes. The draft taxonomy classified outcomes as being measured in i) whole animals, ii) body systems and iii) 'other'. Body system outcomes were further categorised as being functional changes, or changes at macroscopic or cellular levels. The most frequently used outcomes were those detecting changes in the brain (n = 265), physical parameters measured in whole animals (n = 122) and any respiratory system changes (n = 97). CONCLUSIONS: This scoping review quantifies the nature and frequency of outcomes used in preclinical studies investigating the potential impacts of nicotine administration in pregnancy on offspring. Systematic reviews of studies investigating outcomes involving animal brains, respiratory system, or 'whole animal' outcomes may have greatest potential for further advancing knowledge regarding impacts of gestational nicotine exposure on offspring. PROTOCOL AND REGISTRATION: Protocol for this review can be found on Open Science Framework (https://osf.io/ptmzc/).

Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here, we define a critical role of epiregulin-EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target.

Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells.

The development and acceptability testing of an app-based smart survey system to record smoking behaviour, use of nicotine replacement therapy (NRT) and e-cigarettes.

OBJECTIVE: Nicotine replacement therapy (NRT) helps people stop smoking. Monitoring treatment adherence is important as poor adherence to NRT limits its effectiveness. As e-cigarettes contain nicotine, their use ('vaping') is likely to affect both NRT use and smoking. We wished to measure adherence to NRT, and to investigate relationships between NRT, vaping and smoking so we developed 'NicUse', a smartphone App linked to a cloud database for collecting data relevant to NRT adherence. We report user-acceptability and investigate data validity among pregnant people by comparing heaviness of smoking reported to NicUse surveys with contemporaneous exhaled carbon monoxide readings. RESULTS: Thirty five pregnant women participating in a pilot study were asked to install and use NicUse on their smartphones. 32/35 (91%) logged into NicUse, 31 (89%) completed one or more surveys, and 22 (63%) completed these on ≥ 20 of 28 study days. Twenty-four gave end-of-study user acceptability ratings; 23 (96%) agreed or strongly agreed NicUse was 'Easy to use' and 'Instructions were clear'. There was a strong correlation between the number of daily cigarettes reported on NicUse and exhaled CO readings taken on study Day 7 (Pearson's r = 0.95, p < 0.001). NicUse appears highly acceptable, and smoking data reported to it shows validity.

Quantitative in vivo micro-computed tomography for monitoring disease activity and treatment response in a collagen-induced arthritis mouse model.

A painful, chronic condition, Rheumatoid Arthritis, is marked by bone erosion and soft tissue swelling at the joint. As treatments are investigated in pre-clinical models, characterizing disease progression is integral to assessing treatment efficacy. Here, in vivo and ex vivo micro-computed tomography (µCT) are used in parallel with traditional caliper score measurement to quantify physiological changes in the tarsal region in a murine, collagen-induced arthritis model. In vivo imaging methods, which are validated here through comparison to ex vivo and caliper methods, afford longitudinal analysis of both bone and soft tissue through a single image acquisition. This method removes the subjectivity of swelling quantification which is inherently associated with traditional caliper measurements. Histopathology offers an additional assessment of bone erosion and inflammation by providing a microscopic characterization of disease activity. In comparison to untreated animals, daily prednisolone (glucocorticoid) treatment is shown to restore bone volume, as reflected through in vivo and ex vivo µCT images, as well as histopathology. Prednisolone-associated reduction in inflammation is shown through in vivo µCT soft tissue volume measurements, paw caliper measurements, and histopathology. The findings reported here provide a comprehensive validation of in vivo µCT with a sensitivity that enables characterization of pre-clinical disease assessment in response to treatment in a murine, collagen-induced arthritis model.

Smoking Cessation Support for Pregnant Women Provided by English Stop Smoking Services and National Health Service Trusts: A Survey.

Reducing smoking rates in pregnancy continues to be a public health priority. Given a recent UK government policy change resulting in The National Health Service (NHS) making a significant new contribution to cessation support in pregnancy in England, in addition to that of Local Authorities (LA), an up-to-date assessment of national support offered to pregnant women is needed. LA Stop Smoking Service (SSS) managers and representatives from maternity services in NHS Trusts were invited to participate in an online survey in autumn 2020. Topics included service configuration, staffing, practitioner consultations and treatments offered. The survey response rate was 66% (99/151) of LAs and 68% (95/140) of Trusts. Most LAs provided smoking support for pregnant smokers (78%), whereas under half (43%) of NHS Trusts did. Combination nicotine replacement therapy, i.e., a combination of a patch and short-acting product, was offered by LAs (92%) and Trusts (95%) and most commonly for 12 weeks duration, at 53% and 50%, respectively. Similar national online training was undertaken by those supporting women, with the majority undertaking the specialist pregnancy-specific module: LAs 60% and Trusts 79%. However, clinicians were reported to deliver specialist stop smoking support in over 50% of Trusts, whereas this was reported in only 16% of LAs. In England, both LA and NHS Trusts are currently delivering similar stop smoking support to pregnant women. Having nationally recognised treatment programmes and training allows for the delivery of consistent, evidence-based smoking cessation to pregnant women in different healthcare settings.

Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models.

Col4a3-/- Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3-/- mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.

Comparison of saliva cotinine and exhaled carbon monoxide concentrations when smoking and after being offered dual nicotine replacement therapy in pregnancy.

BACKGROUND AND AIMS: Although English Stop Smoking Services routinely offer dual nicotine replacement therapy (NRT) to help pregnant women to quit smoking, little is known about how nicotine and tobacco smoke exposures following this compare with that from smoking. We compared, in pregnant women when smoking and after being offered dual NRT, saliva cotinine and exhaled carbon monoxide (CO) concentrations and numbers of daily cigarettes smoked. DESIGN AND SETTING: Secondary analysis of data from three sequential, observational, mixed-methods cohort studies conducted as part of the Nicotine Replacement Effectiveness and Delivery in Pregnancy programme. Participants were recruited on-line or in Nottingham University Hospitals (UK) antenatal clinics between June 2019 and September 2020. PARTICIPANTS: Forty pregnant women, who agreed to try stopping smoking. INTERVENTION: Participants were offered dual NRT, agreed a smoking quit date and received an intervention to improve adherence to NRT. MEASUREMENTS: Saliva cotinine and exhaled CO concentrations and reported number of cigarettes smoked per day. FINDINGS: There were no differences in saliva cotinine concentrations at baseline and day 7 post quit date [n = 20, mean difference = -32.31 ng/ml, 95% confidence interval (CI) = -68.11 to 3.5 ng/ml; P = 0.074, Bayes factor = 0.04]. There were reductions in the reported number of cigarettes smoked per day (n = 26, mean difference = -7 cigarettes, 95% CI = -8.35 to -5.42 cigarettes, P < 0.001) and concurrently in exhaled CO concentrations (n = 17, ratio of geometric means = 0.30 p.p.m., 95% CI = 0.17-0.52 p.p.m.; P < 0.001). CONCLUSION: Pregnant women who smoke and are offered dual nicotine replacement therapy (NRT) appear to show no change in their exposure to cotinine compared with their pre-NRT exposure levels but they report smoking fewer cigarettes, as validated by reductions in exhaled carbon monoxide concentrations.

Barriers and Facilitators to Staying Smoke-Free after Having a Baby, a Qualitative Study: Women's Views on Support Needed to Prevent Returning to Smoking Postpartum.

BACKGROUND: Postpartum return to smoking (PPRS) is a common and important public health problem. Interventions to prevent PPRS have not been shown to be effective. We aimed to qualitatively explore the barriers and facilitators to staying smoke-free after having a baby, and women's views on the support needed to avoid PPRS to inform future intervention development. METHODS: We conducted semi-structured telephone interviews (n = 26) with pregnant women who quit smoking (n = 9), and postpartum women who were abstinent at delivery and returned to smoking (n = 7) or stayed smoke-free (n = 10). Inductive thematic analysis was used. RESULTS: Five overarching themes were identified: (i) smoking intentions; (ii) facilitators to staying smoke-free; (iii) barriers to staying smoke-free; (iv) support to avoid relapse; and (v) e-cigarettes, nicotine replacement therapy, and varenicline. Facilitators to staying smoke-free were the health benefits to their baby, whilst barriers included stress, cravings, and being in environments where they would previously have smoked. Women wanted continuous offers of support to stay smoke-free throughout the extended postpartum period, with a particular interest in support for partners to quit smoking and self-help support. Women expressed safety concerns for e-cigarettes, nicotine replacement therapy, and varenicline. CONCLUSIONS: Offers of support to stay smoke-free should continue throughout the postpartum and engage with partners or other household members who smoke. Reassuring women about the relative safety of nicotine replacement therapy and e-cigarettes by a health professional, particularly for those who are breastfeeding, could be beneficial.

Smoking and vaping patterns during pregnancy and the postpartum: A longitudinal UK cohort survey.

INTRODUCTION: There is limited information about longitudinal patterns of vaping during pregnancy and the postpartum. We describe the prevalence, frequency, and reasons for vaping throughout pregnancy and postpartum. We also describe temporal patterns in pregnant women's vaping. METHODS: A longitudinal cohort study across England and Scotland, with questionnaires in early pregnancy (8-24 weeks gestation), late pregnancy (34-38 weeks) and 3 months postpartum. A total of 750 women, aged 16 years or over, who were either current smokers, vapers or had smoked in the 3 months before pregnancy, were recruited between June and November 2017. RESULTS: Vaping prevalence was 15.9% (n = 119/750) in early pregnancy: 12.4% (n = 93/750) were dual users and 3.5% (n = 26/750) exclusive vapers. Late pregnancy vaping prevalence was 17.8% (n = 68/383): 12.5% (n = 48/383) were dual users and 5.2% (n = 20/383) exclusive vapers. Postpartum vaping prevalence was 23.1% (n = 95/411): 14.6% (n = 60/411) were dual users and 8.5% (n = 35/411) exclusive vapers. The most frequently reported reason to vape among all vapers was to quit smoking. A total of 316 women completed all three surveys: 2.6% (n = 8/316) were exclusive vapers in early pregnancy with most remaining exclusive vapers postpartum (n = 6/8, 75%). Of the 11.5% (n = 35/316) dual users in early pregnancy, 31.4% (n = 11/35) were exclusive smokers by the postpartum. CONCLUSION: Vaping prevalence was between 15.9% and 23.1% during pregnancy and the postpartum period, and the majority were dual users. Vaping habits of exclusive vapers remains stable throughout pregnancy and the postpartum. However, the vaping habits of dual users varies, with a third exclusively smoking in the postpartum.

Agreement and Disparities between Women and Stop-Smoking Specialists about How to Promote Adherence to Nicotine Replacement Therapy in Pregnancy.

Evidence for the effectiveness of nicotine replacement therapy (NRT) for smoking-cessation in pregnancy is weak. This has been attributed to insufficient dosing and low adherence. This study investigated the acceptability of key messages and delivery modes for a behavioral intervention to increase NRT adherence in pregnancy. Semi-structured telephone interviews were carried out with pregnant or postpartum women aged ≥16 from across England, who had been offered NRT during pregnancy as part of a quit attempt and who struggled to quit (n = 10), and a focus group with stop-smoking specialists from across England (n = 6). The two data sources were coded separately using a thematic approach and then integrated to compare perspectives. Women and specialists agreed on message tone and delivery modes. However, views diverged on the most influential sources for certain messages and whether some information should be given proactively or reactively. There was also disagreement over which messages were novel and which were routinely delivered. This study demonstrates the value of capturing and integrating different perspectives and informational requirements when developing behavior-change interventions. The findings provide useful insights for designing a pregnancy-specific NRT adherence intervention that is acceptable to both those who will deliver and receive it.

Mechanisms and regulation of IL-22-mediated intestinal epithelial homeostasis and repair.

AIMS: Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the intestine for which key elements in disease initiation and perpetuation are defects in epithelial barrier integrity. Achieving mucosal healing is essential to ameliorate disease outcome and so new therapies leading to epithelial homeostasis and repair are under investigation. This study was designed to determine the mechanisms by which IL-22 regulates intestinal epithelial cell function. MAIN METHODS: Human intestinal organoids and resections, as well as mice were used to evaluate the effect of IL-22 on stem cell expansion, proliferation and expression of mucus components. IL-22 effect on barrier function was assessed in polarized T-84 cell monolayers. Butyrate co-treatments and organoid co-cultures with immune cells were performed to monitor the impact of microbial-derived metabolites and inflammatory environments on IL-22 responses. KEY FINDINGS: IL-22 led to epithelial stem cell expansion, proliferation, barrier dysfunction and anti-microbial peptide production in human and mouse models evaluated. IL-22 also altered the mucus layer by inducing an increase in membrane mucus but a decrease in secreted mucus and goblet cell content. IL-22 had the same effect on anti-microbial peptides and membrane mucus in both healthy and IBD human samples. In contrast, this IL-22-associated epithelial phenotype was different when treatments were performed in presence of butyrate and organoids co-cultured with immune cells. SIGNIFICANCE: Our data indicate that IL-22 promotes epithelial regeneration, innate defense and membrane mucus production, strongly supporting the potential clinical utility of IL-22 as a mucosal healing therapy in IBD.

Understanding pregnant women's adherence-related beliefs about Nicotine Replacement Therapy for smoking cessation: A qualitative study.

INTRODUCTION: Reducing smoking during pregnancy is a public health priority. Nicotine replacement therapy (NRT) is offered routinely to pregnant women who smoke in the United Kingdom. However, evidence of treatment efficacy in this population is weak, most likely due to poor adherence. Guided by the Necessity-Concerns Framework, we conducted a qualitative study to better understand pregnant women's perceived needs and concerns regarding NRT use, with consideration of combination NRT. METHODS: Semi-structured interviews were conducted by telephone with 18 pregnant or recently pregnant women in England and Wales, purposively sampled for different NRT-related experiences. Participants were recruited online via Facebook adverts and through a Stop Smoking Service. A hybrid approach of deductive and inductive thematic coding was used for analysis. RESULTS: Findings were organized around three themes: 1) the role of motivation to stop smoking; 2) necessity beliefs about using NRT; and 3) concerns about NRT. Some women reported fluctuating motivation for stopping smoking which undermined their NRT use. Others used NRT to cut down the number of cigarettes they smoked. Reasons for low NRT necessity beliefs included a preference for quitting unassisted, low or unrealistic expectations of efficacy, and overconfidence in achieving cessation (necessity testing). Concerns included safety, particularly around increased nicotine exposure with combination NRT, addictiveness, side effects, and capability to use. CONCLUSION: Pregnant women have multiple necessity beliefs and concerns that influence their use of NRT. Targeting these, alongside increasing and maintaining motivation to quit smoking, will likely help optimize NRT use in pregnancy and improve quit rates.