Conception, pregnancy and inflammatory bowel disease-Current concepts for the practising clinician.

The peak incidence of inflammatory bowel disease (IBD) coincides with a woman's prime reproductive years. The management of IBD during pregnancy can be challenging for healthcare professionals, underpinning the need for a multi-disciplinary approach with shared decision-making with the patient. Pre-conception counselling can address patient concerns, improve pregnancy specific IBD patient knowledge and provide a personalized risk assessment, to ensure optimal maternal and fetal outcomes. Most women with IBD have fertility rates comparable with the general population, although voluntary childlessness is common among women with IBD. IBD disease activity at conception and during pregnancy is a key determinant of the course of IBD during pregnancy. Active IBD during pregnancy is associated with adverse pregnancy-related outcomes, including spontaneous abortion, small for gestational age baby and preterm birth, emphasizing the importance of ensuring disease remission prior to conception. Most IBD medications (5-aminosalicylates, thiopurines if already initiated pre-conception, corticosteroids and biologic medications) are considered safe and low risk during pregnancy and breastfeeding, except for methotrexate, JAK-inhibitors, ozanimod and allopurinol and maintaining remission throughout gestation should be the priority. Most women with IBD can have a vaginal delivery, but cesarean section should be considered in active perianal disease and history of ileal pouch surgery. This narrative review outlines the current evidence for the management of IBD in pregnancy, as well as considering the pre-conceptual and post-partum period.

Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.

Managing Inflammatory Bowel Disease in Pregnancy: Health Care Professionals' Involvement, Knowledge, and Decision Making.

BACKGROUND: The management of pregnant women with inflammatory bowel disease (IBD) is complex. We aimed to assess health care professionals' (HCPs) theoretical and applied knowledge of pregnancy-related IBD issues. METHODS: A cross-sectional international survey was distributed to HCPs providing IBD care between October 2020 and March 2021. Knowledge was assessed using the validated Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow; range, 0-17). Decision-making was assessed by free text responses to 3 clinical scenarios scored against predetermined scoring criteria (maximum score 70). RESULTS: Among 81 participants, median CCPKnow score was 16 (range, 8-17), and median total scenario score was 29 (range, 9-51). Health care professionals who treat >10 IBD patients per week (CCPKnow P = .03; scenarios P = .003) and are more regularly involved in pregnancy care (CCPKnow P = .005; scenarios P = .005) had significantly better scores. Although CCPKnow scoring was consistently high (median score ≥15) across all groups, consultants scored better than trainees and IBD nurses (P = .008 and P = .031). Median scenario scores were higher for consultants (32) and IBD nurses (33) compared with trainees (24; P = .018 and P = .022). There was a significant positive correlation between caring for greater numbers of pregnant IBD patients and higher CCPKnow (P = .001, r = .358) and scenario scores (P = .001, r = .377). There was a modest correlation between CCPKnow and scenario scores (r = .356; P < 0.001). CONCLUSIONS: Despite "good" theoretical pregnancy-related IBD knowledge as assessed by CCPKnow, applied knowledge in the scenarios was less consistent. There is need for further HCP education and clinical experience to achieve optimal standardized care for IBD in pregnancy.

Objective assessment of pregnancy-specific IBD knowledge among gastroenterology health care professionals is good; however, clinician application of knowledge in decision-making is less consistent. There is need for further clinician education to provide optimal standardized care for IBD in pregnancy.

Ustekinumab and Vedolizumab Are Equally Safe and Effective in Elderly Crohn's Disease Patients.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) agents are associated with increased infection risk among elderly inflammatory bowel disease (IBD) patients, and thus, alternative biologics may be preferable. However, little comparative data exist on the safety and efficacy of vedolizumab and ustekinumab in elderly IBD patients. AIMS: To compare the safety and effectiveness of ustekinumab and vedolizumab in elderly Crohn's disease patients. METHODS: Patients ≥ 60 years old who commenced ustekinumab or vedolizumab for Crohn's disease (CD) were included. Primary outcome was serious infections, defined as requiring hospitalisation. Efficacy was assessed by treatment persistence and clinical response rates. We appropriately adjusted for confounders using propensity score-matched analysis weighted by the inverse predicted probability of treatment weighing and performed a logistic regression analysis to assess factors associated with serious infections and treatment persistence. RESULTS: Eighty-three patients commencing ustekinumab and 42 commencing vedolizumab therapy were included. In a propensity adjusted cohort, the rate of serious infection and treatment persistence were comparable between ustekinumab and vedolizumab. There was a significant reduction in HBI at 6 and 12 months compared to baseline in both groups. Male gender was positively associated with serious infection risk at 12 months, and penetrating disease behaviour was positively associated with 12-month treatment persistence. Baseline HBI score was negatively associated with 12-month treatment persistence. Cox regression analysis showed no overall difference in treatment discontinuation-free and serious infection-free survival by 12 months. CONCLUSIONS: We observed comparable safety and effectiveness for ustekinumab and vedolizumab in treating elderly CD patients.

Safety and effectiveness of ustekinumab in elderly Crohn's disease patients.

OBJECTIVE: Anti-tumour necrosis factor (TNF) agents are associated with increased infection risk among elderly IBD patients, but little is known about non anti-TNF biologics in this cohort. We examined the safety and effectiveness of ustekinumab in elderly Crohn's patients. METHODS: This retrospective multi-centre cohort study included Crohn's patients ≥60-years old who commenced ustekinumab. We recorded Harvey-Bradshaw index (HBI), concomitant steroid therapy, treatment persistence and new infections or malignancies. Primary outcome was serious infections requiring hospitalisation. RESULTS: Seventy patients were included, with median age of 68 years. 43 (61.4%) had prior anti-TNF exposure, and 15 (21.4%) vedolizumab. Median treatment duration was 12 months, totalling 84 patient-years. Nine serious infections were reported, incidence 106.7/1000 patient-years. Systemic steroids were associated with increased risk of serious infections [odds ratio (OR) 7.83, 95% confidence interval (CI): 1.44-44.32, P = 0.02]. There were 27 "non-serious" infections; 321.4/1000 patient-years. Charlson co-morbidity index (OR 1.49, 95% CI: 1.05-2.12, P = 0.03) and steroid exposure (OR 44.10, 95% CI: 1.75-1112.10, P = 0.02) increased non-serious infection risk (P &lt; 0.05). Mean HBI improved from 8.13 to 4.64 at 6 months and 4.10 at last follow up (P &lt; 0.0001). 12-month treatment persistence was 55.7% (N = 39); 34 (48.6%) were steroid-free. CONCLUSION: Ustekinumab was safe and effective in a cohort of elderly Crohn's disease patients. Infections were mostly mild, not resulting in therapy discontinuation. Serious infection risk was comparable to previously reported rates with anti-TNF agents. Steroid exposure was associated with an increased serious infection risk.

Tofacitinib and newer JAK inhibitors in inflammatory bowel disease-where we are and where we are going.

Inflammatory bowel diseases, comprising ulcerative colitis (UC) and Crohn's disease, are chronic, immune-mediated and progressive inflammatory disorders affecting the gastrointestinal tract. Tofacitinib is the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved by the National Institute for Health and Care Excellence (NICE) for use in moderately-to-severely active UC after intolerance, inadequate response, or loss of response to conventional treatment or biologic therapy. The pivotal OCTAVE studies demonstrated the efficacy and safety of tofacitinib for the induction and maintenance of remission in UC. A growing body of evidence from real-world data supports the positive clinical and endoscopic benefits observed with tofacitinib treatment in the OCTAVE trials. This narrative review summarizes the current literature regarding the mechanism of action of tofacitinib, data from registrational trials, emerging real-world evidence, and an overview of the most recent safety evidence. We explore evolving treatment paradigms, including the use of tofacitinib in the COVID-19 era, pregnancy and extraintestinal manifestations, as well as the emerging concept of combining tofacitinib with biological therapy. We will also present a brief overview of the next generation of JAK inhibitors in the pipeline.

Gastroenterology team members' knowledge and practices with fertility therapy for women with inflammatory bowel disease.

Introduction: Fecundity may be reduced in women with active inflammatory bowel disease (IBD) or prior IBD-related surgery, and these women may require assisted reproductive technology (ART). There are no guidelines for women with IBD to outline referral criteria for ART. Methods: We performed a prospective, multicentre, international questionnaire of gastroenterologists, gastroenterology trainees, and IBD nurses. The primary outcome was to establish clinical practices and fertility therapy referral patterns among gastroenterology team members. We hypothesised that the lack of knowledge and awareness may delay or prevent initiation of fertility consultation referrals. Discussion: Of 182 participants, most had never initiated a referral for fertility therapy (69.8%), and of respondents who do initiate referrals, 50% wait until the patient has been unsuccessfully attempting conception for 12 months. Participants were significantly more likely to initiate a fertility therapy referral if they believed ART was effective (p = 0.038), not impeded by IBD-related surgery (p = 0.053), and if they had access to a dedicated IBD-pregnancy clinic (p = 0.027). Superior pregnancy knowledge was predictive of a greater likelihood of fertility therapy referrals (p = 0.037). All participants thought they had inadequate knowledge about ART in IBD, and 96.2% expressed desire to improve their knowledge. Conclusion: Gastroenterology team members infrequently initiate referrals for fertility therapy consultation in women with IBD, increasing their risk of remaining childless. Implementation of dedicated IBD pregnancy clinics and targeted education programmes to increase awareness of ART in women with IBD might increase referral rates and reduce infertility.

A real-world, long-term experience on effectiveness and safety of vedolizumab in adult patients with inflammatory bowel disease: The Cross Pennine study.

BACKGROUND: Real-life data on vedolizumab effectiveness in inflammatory bowel disease (IBD) are still emerging. Data on the comparative safety of the gut selective profile are of particular interest. AIMS: To assess clinical outcome and safety in IBD patients treated with vedolizumab. METHODS: We retrospectively collected data of patients treated with vedolizumab at eight UK hospitals (August 2014-January 2018). Clinical response and remission at 14 and 52 weeks evaluated through Physician Global Assessment (PGA) and adverse events were recorded. Possible predictors of clinical response were examined. RESULTS: Two hundred and three IBD patients (mean treatment 16 ±â€¯8 months) were included. Of these, 135 patients (mean age 40.6 ±â€¯16.0 years; F:M 1.9:1) had CD and 68 (mean age 44.5 ±â€¯18.1 years; F:M 1:1.2) had UC. According to PGA, 106/135 (78.5%) CD and 62/68 (91.2%) UC patients (p = 0.02) had a clinical response/remission at 14 weeks, whereas 76/119 (63.9%) CD and 52/63 (82.5%) UC patients (p < 0.01) showed a sustained response or remission at 52 weeks, with a high adherence rate (97%). No predictors of clinical response were found. The cumulative incidence of infectious diseases was 11.9 per 100 person-years. CONCLUSION: Vedolizumab is an effective therapy for inducing and maintaining remission of IBD, with better results for UC, and with a good safety profile.

Elucidating the Role of Residue 67 in IMP-Type Metallo-ß-Lactamase Evolution.

Antibiotic resistance in bacteria is ever changing and adapting, as once-novel ß-lactam antibiotics are losing their efficacy, primarily due to the production of ß-lactamases. Metallo-ß-lactamases (MBLs) efficiently inactivate a broad range of ß-lactam antibiotics, including carbapenems, and are often coexpressed with other antibacterial resistance factors. The rapid dissemination of MBLs and lack of novel antibacterials pose an imminent threat to global health. In an effort to better counter these resistance-conferring ß-lactamases, an investigation of their natural evolution and resulting substrate specificity was employed. In this study, we elucidated the effects of different amino acid substitutions at position 67 in IMP-type MBLs on the ability to hydrolyze and confer resistance to a range of ß-lactam antibiotics. Wild-type ß-lactamases IMP-1 and IMP-10 and mutants IMP-1-V67A and IMP-1-V67I were characterized biophysically and biochemically, and MICs for Escherichia coli cells expressing these enzymes were determined. We found that all variants exhibited catalytic efficiencies (kcat/Km) equal to or higher than that of IMP-1 against all tested ß-lactams except penicillins, against which IMP-1 and IMP-1-V67I showed the highest kcat/Km values. The substrate-specific effects of the different amino acid substitutions at position 67 are discussed in light of their side chain structures and possible interactions with the substrates. Docking calculations were employed to investigate interactions between different side chains and an inhibitor used as a ß-lactam surrogate. The differences in binding affinities determined experimentally and computationally seem to be governed by hydrophobic interactions between residue 67 and the inhibitor and, by inference, the ß-lactam substrates.

Meropenem and chromacef intermediates observed in IMP-25 metallo-ß-lactamase-catalyzed hydrolysis.

Metallo-ß-lactamases inactivate most ß-lactam antibacterials, and much attention has been paid to their catalytic mechanism. One issue of controversy has been whether ß-lactam hydrolysis generally proceeds through an anionic intermediate bound to the active-site Zn(II) ions or not. The formation of an intermediate has not been shown conclusively in imipenemase (IMP) enzymes to date. Here, we provide evidence that intermediates are formed during the hydrolysis of meropenem and chromacef catalyzed by the variant IMP-25 and, to a lesser degree, IMP-1.

In their own words: the place of faith in the lives of young people with autism and intellectual disability.

Abstract Although the prominence of spirituality and religious connections among the people of the United States is well documented, little is known about the place of faith in the lives of youth with developmental disabilities. In this qualitative interview study, we examined the perspectives of 20 young people with intellectual disability or autism on their faith, spiritual expressions, and disability. Participants identified key spiritual expressions and themes reflecting the importance of faith in their lives. They also shared perceptions of their disability in the context of their faith, highlighting affirmation and acceptance of their disability. We offer recommendations to families, faith communities, and service systems for supporting the spiritual formation, expression, and connections of young people with disabilities.

Understanding the determinants of substrate specificity in IMP family metallo-ß-lactamases: the importance of residue 262.

In Gram-negative bacteria, resistance to ß-lactam antibacterials is largely due to ß-lactamases and is a growing public health threat. One of the most concerning ß-lactamases to evolve in bacteria are the Class B enzymes, the metallo-ß-lactamases (MBLs). To date, penams and cephems resistant to hydrolysis by MBLs have not yet been found. As a result of this broad substrate specificity, a better understanding of the role of catalytically important amino acids in MBLs is necessary to design novel ß-lactams and inhibitors. Two MBLs, the wild type IMP-1 with serine at position 262, and an engineered variant with valine at the same position (IMP-1-S262V), were previously found to exhibit very different substrate spectra. These findings compelled us to investigate the impact of a threonine at position 262 (IMP-1-S262T) on the substrate spectrum. Here, we explore MBL sequence-structure-activity relationships by predicting and experimentally validating the effect of the S262T substitution in IMP-1. Using site-directed mutagenesis, threonine was introduced at position 262, and the IMP-1-S262T enzyme, as well as the other two enzymes IMP-1 and IMP-1-S262V, were purified and kinetic constants were determined against a range of ß-lactam antibacterials. Catalytic efficiencies (kcat /KM ) obtained with IMP-1-S262T and minimum inhibitory concentrations (MICs) observed with bacterial cells expressing the protein were intermediate or comparable to the corresponding values with IMP-1 and IMP-1-S262V, validating the role of this residue in catalysis. Our results reveal the important role of IMP residue 262 in ß-lactam turnover and support this approach to predict activities of certain novel MBL variants.

Biochemical characterization of IMP-30, a metallo-ß-lactamase with enhanced activity toward ceftazidime.

IMP-type enzymes constitute a clinically important family of metallo-ß-lactamases that has grown dramatically in the past decade to its current 45 known members. Here, we report the biochemical characterization of IMP-30 in comparison to IMP-1, from which it deviates by a single E59K mutation. Kinetics, MIC assays, docking, and molecular dynamics simulations support a scenario in which Lys59 interacts with the ceftazidime R1 group, resulting in increased water access and enhanced turnover and MIC of ceftazidime.

Centre for Addiction and Mental Health Inventory of Gambling Situations: Evaluation of the Factor Structure, Reliability, and External Correlations.

The development and evaluation of the Centre for Addiction and Mental Health Inventory of Gambling Situations (CAMH-IGS) is described. The CAMH-IGS is based on a cognitive-behavioural approach to addiction that sees excessive gambling as a pattern of behaviour which is learned, and which can be changed. The CAMH-IGS is designed to determine the patterns of behaviour, thoughts or feelings which may trigger problematic gambling, with the goal of developing tailored treatment and relapse-prevention approaches for clients. The information can be used in treatment planning. A sample of 524 gamblers that included 323 problem and probable pathological gamblers was used to evaluate the factor structure, reliability, and external correlations of the CAMH-IGS. The results show that the CAMH-IGS consists of 10 internally reliable subscales that can identify individual differences between clients.

The sequence-activity relationship between metallo-ß-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary adaptation to meropenem exposure.

Metallo-ß-lactamases are important determinants of antibacterial resistance. In this study, we investigate the sequence-activity relationship between the closely related enzymes IMP-1, IMP-6, and IMP-25. While IMP-1 is the more efficient enzyme across the overall spectrum of tested ß-lactam antibacterial agents, IMP-6 and IMP-25 seem to have evolved to specifically inactivate the newer carbapenem meropenem. Molecular modeling indicates that the G235S mutation distinguishing IMP-25 from IMP-1 and IMP-6 may affect enzyme activity via Asn233.

Evaluación y tratamiento de las urgencias de suicidalidad en los trastornos de personalidad / Assessment and emergency management of suicidality in personality disorders

En diversos estudios se ha ilustrado una relación entre los trastornos de la personalidad, la conducta suicida y el suicidio. La investigación es más robusta en el campo del trastorno límite de la personalidad. Éste es un diagnóstico habitual y difícil, caracterizado por suicidalidad crónica, y hemos tratado de diferenciar entre pacientes en riesgo de suicidio de alta letalidad en comparación con los de baja letalidad. Aunque la evaluación y el tratamiento de la suicidalidad en pacientes con este trastorno pueden ser frustrantes incluso para los médicos con más experiencia, es posible reconocer el aumento agudo del riesgo y utilizar técnicas que contribuyan a crear una alianza terapéutica y reducir la intensidad de las situaciones de crisis (AU)

Several studies have illustrated a link between personality disorders, suicidal behavior, and suicide. The research is most robust in the field of BPD. BPD is a common and challenging diagnosis characterized by chronic suicidality, and we have attempted to differentiate between patients at risk for high versus low lethality suicide attempts. Although assessing and managing suicidality in patients who have BPD can be frustrating for even the most experienced clinicians, it is possible to recognize acutely elevated risk and use techniques to help create a therapeutic alliance and de-escalate the crisis situation (AU)

Interpersonal group psychotherapy for comorbid alcohol dependence and non-psychotic psychiatric disorders.

Alcohol-dependent patients (N = 15) with comorbid non-psychotic psychiatric disorders were treated with Modified Interpersonal Group Therapy (MIGT) for eight weeks, 16 sessions, in a pilot intervention trial. Analysis of the group participants demonstrated that they achieved statistically significant improvements at post-treatment in four of five self-report outcome measures: number of drinking days, number of heavy drinking days, the Brief Symptom Inventory, and the Beck Depression Inventory. Furthermore, the improvements in heavy drinking days and the Brief Symptom Inventory were maintained at two and eight months post-treatment. This study yields preliminary evidence in support of MIGT as a useful treatment approach for an alcohol-dependent population with psychiatric comorbidity.

Assessment and emergency management of suicidality in personality disorders.

This article examines the association between suicidal behavior and personality disorders. It updates the review of epidemiological evidence for the association between suicidal behavior and suicide in individuals who have a personality disorder diagnosis, particularly in borderline personality disorder (BPD). The second part of the article presents new empirical evidence that characterizes suicidal behavior in patients who have BPD, specifically examining patient characteristics that differentiate patients who have BPD with a history of high versus low lethality suicide attempts. Finally, the article discusses the approach to a patient who has BPD and presents to the emergency department because of an increased risk of suicide.

Family medicine residents' beliefs, attitudes and performance with problem drinkers: a survey and simulated patient study.

Fifty-six second-year family medicine residents completed a survey on their knowledge and beliefs about problem drinkers. Most residents felt responsible for screening and counseling, were confident in their clinical skills in these areas, and scored well on related knowledge questions. However, only 18% felt that problem drinkers would often respond to brief counseling sessions with physicians while 36% felt that moderate drinking was a reasonable goal for patients with severe alcohol dependence. Residents were then visited by unannounced simulated patients (SPs) presenting with alcohol-induced hypertension or insomnia. Residents detected the SP in 45 out of 104 visits. In the 59 undetected SP visits, residents asked about alcohol consumption in 47 visits (80%), discussed the relationship between alcohol use and the presenting complaint in 37 visits (63%), and recommended a specific weekly consumption in 35 visits (59%). Only 31% offered reduced drinking strategies, and most did not ask about features of alcohol dependence. These results suggest that residents have the fundamental clinical skills required to manage the problem drinker who gives a clear history and is receptive to advice. Educational efforts with residents should focus on the importance of systematic screening, taking an alcohol history under more challenging conditions, identifying the subtler presentations of alcohol problems, counselling the less receptive patient at an earlier stage of change, distinguishing the problem drinker from the alcohol-dependent patient, and offering specific behavioral strategies for the problem drinker.

Family Medicine Residents' Performance with Detected Versus Undetected Simulated Patients Posing as Problem Drinkers.

BACKGROUND: Simulated patients are commonly used to evaluate medical trainees. Unannounced simulated patients provide an accurate measure of physician performance. PURPOSE: To determine the effects of detection of SPs on physician performance, and identify factors leading to detection. METHODS: Fixty-six family medicine residents were each visited by two unannounced simulated patients presenting with alcohol-induced hypertension or insomnia. Residents were then surveyed on their detection of SPs. RESULTS: SPs were detected on 45 out of 104 visits. Inner city clinics had higher detection rates than middle class clinics. Residents' checklist and global rating scores were substantially higher on detected than undetected visits, for both between-subject and within-subject comparisons. The most common reasons for detection concerned SP demographics and behaviour; the SP "did not act like a drinker" and was of a different social class than the typical clinic patient. CONCLUSIONS: Multi-clinic studies involving residents experienced with SPs should ensure that the SP role and behavior conform to physician expectations and the demographics of the clinic. SP station testing does not accurately reflect physicians' actual clinical behavior and should not be relied on as the primary method of evaluation. The study also suggests that physicians' poor performance in identifying and managing alcohol problems is not entirely due to lack of skill, as they demonstrated greater clinical skills when they became aware that they were being evaluated. Physicians' clinical priorities, sense of responsibility and other attitudinal determinants of their behavior should be addressed when training physicians on the management of alcohol problems.