Biologics, small molecule therapies and surgery in small bowel Crohn's disease.

PURPOSE OF REVIEW: The terminal ileum and small bowel (SB) are involved in 30-45% of patients with Crohn's disease, while 20% have both small and large bowel involvement. Ileal Crohn's is associated with higher risk of progression to stricturing and penetrating disease 1 , hence it's imperative to utilize effective therapies to induce and maintain clinical and endoscopic remission and prevent intestinal complications. We review the available data of biologics and upadacitinib in small bowel disease, and the emerging data on the role of surgery as first line therapy for isolated Crohn's ileitis. RECENT FINDINGS: Most trials assessing drug efficacy do not report efficacy by disease location, and robust data on efficacy of therapies in isolated small bowel Crohn's is sparse. Several studies indicate that small bowel disease is generally less responsive to biologics, and could require higher drug trough levels to achieve endoscopic healing. SUMMARY: Current therapies for induction and maintenance of remission in moderate to severe Crohn's disease include several classes of monoclonal antibodies and a Janus Kinase inhibitor, upadacitinib. While small bowel Crohn's disease is generally less responsive to treatment, anti-TNFs are still preferred as first line therapy, and the option of early ileocecal resection in early limited ileal disease is gaining interest.

Research Review: The internalizing paradox - youth anxiety and depression symptoms, psychotherapy outcomes, and implications for research and practice.

BACKGROUND: Youth anxiety and depression have long been combined within the empirically derived internalizing syndrome. The two conditions show substantial comorbidity, symptom co-occurrence, and overlap in treatment procedures, but paradoxically diverge in psychotherapy outcomes: strong, positive effects for anxiety and weak effects for depression. METHODS: Drawing on recent research, we examine candidate explanations for this paradox to help identify strategies for addressing it by improving outcomes for youth depression. RESULTS: Candidate explanations include that youth depression, compared with youth anxiety, has more varied comorbidities and more heterogeneous symptom combinations, has greater uncertainty regarding mediators and mechanisms of change, is treated with more complex and potentially confusing protocols, and has characteristics that may impede client engagement. Candidate strategies for shrinking the psychotherapy effectiveness gap include personalizing through transdiagnostic modular treatment, simplifying therapy by focusing on empirically supported principles of change, developing effective strategies for engaging family members as intervention allies, using shared decision-making to inform clinical decisions and boost client engagement, capitalizing on youth-friendly technological advances, and shortening and digitizing treatments to enhance their accessibility and appeal. CONCLUSIONS: Recent advances suggest explanations for the internalizing paradox, which in turn suggest strategies for shrinking the youth anxiety-depression psychotherapy outcome gap; these form an agenda for a promising new era of research.

Endo-histologic Normalization Is Achievable with Tofacitinib and Is Associated with Improved Clinical Outcomes.

BACKGROUND: Recent real-world effectiveness studies investigating tofacitinib have been encouraging. Questions remain regarding the long-term effectiveness and safety of tofacitinib, effect on endoscopic remission rates, histologic changes, and alterations in fecal calprotectin levels. METHODS: This retrospective study includes consecutive patients with inflammatory bowel disease (IBD) who initiated tofacitinib therapy. We reviewed electronic medical records for demographic and clinical data, as well as all adverse events and hospitalizations. All patients receiving tofacitinib were included in the safety analysis and only patients with ulcerative colitis (UC) were included in the effectiveness analysis. RESULTS: 119 patients with IBD (97 UC, 12 CD, and 10 pouchitis) seen at our center between 2014 and 2020 were included in this study. Median follow-up was 32 weeks (interquartile range (IQR) 3-252). Clinical response and remission were observed in 70% and 21%, 59% and 33%, and 49%, and 37% at weeks 8, 24, and 52, respectively. Endo-histologic healing was achieved by 11%, 25%, and 37.5% of patients at weeks 8, 24, and 52, respectively. Histologic normalization occurred as early as 24 weeks in this cohort and was achieved by 26% of patients in endoscopic remission. Overall, there were 27 (25%) adverse events with 6 (5%) resulting in treatment discontinuation. There were 11 (10%) infections, none required treatment discontinuation. Ten (10.3%) patients underwent colectomy during the follow-up period. There were no cardiovascular adverse events in the cohort during follow-up. CONCLUSION: This study demonstrates the effectiveness and long-term safety of tofacitinib in patients with UC. Importantly, we show that the endpoint of endo-histologic healing is achievable with tofacitinib and can occur as early as week 8 of therapy.

'Excessive and Unreasonable': The Relation Between Clinical Insight and Clinical Correlates and Treatment Outcomes in Obsessive-Compulsive Disorder Across the Life Course.

Individuals with mental disorders possess varying levels of clinical insight-the degree to which one understands that they are afflicted with a mental disorder and that their symptoms are manifestations of this psychopathology. Although clinical insight in OCD is thought to play an especially important role in determining various clinical characteristics and treatment outcomes, insight has not been sufficiently addressed developmentally, the importance of which this review will elucidate. Findings from this review suggest that clinical insight is typically associated with more complex cases and worse treatment outcomes across the life course, and also reveal nuances between pediatric and adult OCD cases with low insight. Implications of these findings, future research directions, and recommendations for the field are discussed.

Sustaining a nurse-led community partnership to promote environmental justice.

The Westlawn Partnership for a Healthier Environment (WPHE) is a longstanding group of community stakeholders that was formed over a decade ago to identify, prioritize, and address environmental health (EH) concerns in a low-income, predominantly African American, urban neighborhood, which faces a disproportionate burden of EH risks, particularly asthma. Launched by the University of Wisconsin-Milwaukee College of Nursing, which established a nurse-managed health center within the community 30 years ago, WPHE utilized the Protocol of Assessing Community Excellence in Environment Health methodology to develop, implement, and sustain the partnership. WPHE implemented programs for Healthy Homes, Healthy Day Cares, and bicycling, and made system and infrastructure changes within the community to address the top identified EH concerns: indoor and outdoor air pollution, mold exposure, access to safe and healthy food, and pesticide exposure. WPHE's efforts have resulted in significant local, state, and national policy impacts to promote environmental justice. This brief report shares how the partnership was formed, its priorities, major activities and accomplishments, and insights into sustaining a community-based EH partnership, including recommendations for the key role that public health nurses can play to promote environmental justice.

The Management Approach to the Adolescent IBD Patient: Health Maintenance and Medication Considerations.

PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) is often diagnosed during adolescence and can have a deep impact on the physical, hormonal, developmental, and psychosocial changes associated with this life period. The purpose of this review is to address the particular manifestations of IBD (such as growth and pubertal delay), health maintenance issues, and treatment considerations in the adolescent. RECENT FINDINGS: The need for a multidisciplinary approach to recognize and address growth and pubertal delay, bone health, as well as the psychosocial impact of IBD on the adolescent has been increasingly recognized as an integral part of IBD care in this population. Vaccinations schedule, preventive health measures, and promoting compliance with care are particularly important during adolescence. Replacing nutrients deficits is also crucial: in particular, vitamin D has been shown to play a role in the gut immune system, and adequate vitamin D levels might promote IBD remission. Iron replacement should be done by intravenous route since oral iron is poorly absorbed in chronic inflammatory states. Finally, recent data have shed light on the increased risk of particular types of lymphoma in adolescent on thiopurines, whereas biologic therapies, in particular, anti-TNF, now are positioned as a preferred and effective steroid-sparing agents in moderate to severe IBD. Management of adolescents with IBD is not without significant challenges. An early implementation of steroid-sparing therapies, a multidisciplinary treatment approach, and a dynamic physician-patient relationship are essential to achieve remission, prevent disease-related complications but also optimize developmental, physical, and psychosocial health, and encourage compliance and transition to adult care.

Hepatotoxicty of Agents Used in the Management of Inflammatory Bowel Disease: a 2020 Update.

PURPOSE OF REVIEW: As treatment options for inflammatory bowel disease (IBD) continue to expand, the opportunity for hepatotoxicity remains a clinical concern. This review looks to update the current literature on drug-induced liver injury (DILI) and liver-related complications from current and emerging treatments for Crohn's disease (CD) and ulcerative colitis (UC). RECENT FINDINGS: An extensive literature review on currently used medications to treat IBD and their liver-related side effects that includes mesalamine, thiopurines, certain antibiotics, methotrexate, anti-TNF agents including recently introduced biosimilars, anti-integrin therapy, anti-IL 12/IL 23 therapy, and small molecule JAK inhibitors. Hepatotoxicity remains an important clinical issue when managing patients with IBD. Clinicians need to remain aware of the potential for liver-related adverse events with various medication classes and adjust their clinical monitoring as appropriate based on the agents being used.

Type 2 Diabetes Therapies: A STEPS Approach.

A concise way to evaluate pharmacotherapy options for type 2 diabetes mellitus is to use the five patient-oriented STEPS criteria: safety, tolerability, efficacy, price, and simplicity. The first-line treatment option, metformin, is safe and fairly well-tolerated, has excellent long-term efficacy for patient-oriented outcomes, is moderately priced, and has a simple dosing regimen. However, most patients with type 2 diabetes require more than one medication. The STEPS approach can help choose subsequent medications if metformin does not provide adequate glycemic control.

Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons.

The accumulation of Tau into aggregates is associated with key pathological events in frontotemporal lobe degeneration (FTD-Tau) and Alzheimer disease (AD). Recent data have shown that misfolded Tau can be internalized by cells in vitro (Frost, B., Jacks, R. L., and Diamond, M. I. (2009) J. Biol. Chem. 284, 12845-12852) and propagate pathology in vivo (Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., and Tolnay, M. (2009) Nat. Cell Biol. 11, 909-913; Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., and Kayed, R. (2012) Sci. Rep. 2, 700). Here we show that recombinant Tau misfolds into low molecular weight (LMW) aggregates prior to assembly into fibrils, and both extracellular LMW Tau aggregates and short fibrils, but not monomers, long fibrils, nor long filaments purified from brain extract are taken up by neurons. Remarkably, misfolded Tau can be internalized at the somatodendritic compartment, or the axon terminals and it can be transported anterogradely, retrogradely, and can enhance tauopathy in vivo. The internalized Tau aggregates co-localize with dextran, a bulk-endocytosis marker, and with the endolysosomal compartments. Our findings demonstrate that exogenous Tau can be taken up by cells, uptake depends on both the conformation and size of the Tau aggregates and once inside cells, Tau can be transported. These data provide support for observations that tauopathy can spread trans-synaptically in vivo, via cell-to-cell transfer.

Children's knowledge and feelings align in response to emotional music.

Examining emotion recognition and response to music can isolate recognition of and resonance with emotion from the confounding effects of other social cues (e.g., faces). In a within-sample design, participants aged 5-6 years in the eastern region of the United States (N = 135, Mage = 5.98, SDage = .54; 78 female, 56 male; eight Asian, 43 Black, 62 White, 13 biracial, and nine "other") listened to clips of calm, scary, and sad music. In separate sessions, participants identified the emotional content of the music or reported on the feelings elicited by the music clip, with above-chance accuracy. Emotion recognition was associated with age and higher levels of child emotional verbal expressivity. Children with higher parent-reported empathy reported greater resonance with the emotion conveyed by music, specifically for sad music. Recognition and resonance were correlated (i.e., alignment), although the relationship varied as a function of the emotion expressed, with the greatest alignment for sad music. Results provide insights into emotion recognition and resonance in the absence of direct social signals and provide evidence that children's ability to recognize and resonate with emotion differs depending on characteristics of the music and the child. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Availability of Internet-Based Cognitive-Behavioral Therapies for Depression: A Systematic Review.

We examined the availability and components of internet-based cognitive-behavioral therapies (iCBTs) for depression tested in randomized-controlled trials (RCTs). The objectives of this literature review were to determine the extent to which research-validated iCBTs were available to the public, as well as to determine their therapeutic content. A literature review of RCTs for iCBTs was conducted on July 30, 2021. For each iCBT, interventions were rated by content and compared to commercially available smartphone apps. Our search yielded 80 studies using 41 unique iCBTs. Of these, only 6 (15%) were completely available to the public, more than half were not publicly available (46%), and the remaining 39% were available to the public with some restrictions (e.g., those based on the user's geographical location). When comparing iCBTs evaluated in RCTs to commercially available smartphone apps, we found that iCBTs were more likely to contain psychoeducation, cognitive restructuring, behavioral activation, problem solving, and interpersonal communication components. iCBTs from RCTs contain evidence-based content but few are available to the public. Extending beyond efficacy, attention should be paid to the dissemination of iCBTs.

Pregnancy and medications for inflammatory bowel disease: An updated narrative review.

Inflammatory bowel disease (IBD) is often diagnosed during the peak reproductive years of young women. Women with active IBD around conception are at a significantly increased risk of disease relapse during pregnancy, which is associated with poor pregnancy and neonatal outcomes. Given these substantial risks, it is prudent that disease remission should ideally be achieved before conception. Unfortunately, some patients may experience a disease flare-up even if they are in a state of remission before pregnancy. Patients must continue their IBD medications to reduce the risk of disease flare and subsequent poor outcomes during the gestational and postpartum periods. When treating IBD flare-ups during pregnancy, the management is quite similar to the therapeutic approach for non-pregnant patients with IBD, including 5-aminosalicylate, steroids, calcineurin inhibitors (CNIs), and biologic therapies. While the data regarding the safety of CNIs in pregnant women with IBD is limited, the findings in our recent meta-analysis suggest that CNIs may be safer to use in those with IBD than in solid organ transplant recipients. There are several types of biologics and small-molecule therapies currently approved for IBD, and physicians should thoroughly understand their clinical benefits and safety profiles when utilizing these treatments in the context of pregnancy. This review highlights recent studies, including our systematic review and meta-analysis, and discusses the clinical advantages and safety considerations of biologics and small molecules for pregnant women with IBD.

Death and Disability Reported with Cases of Vaccine Anaphylaxis Stratified by Administration Setting: An Analysis of the Vaccine Adverse Event Reporting System from 2017 to 2022.

The serious nature of post-vaccination anaphylaxis requires healthcare professionals to be adequately trained to respond to these hypersensitivity emergencies. The aim of this study was to compare outcomes reported with cases of vaccine anaphylaxis stratified by administration setting. We queried reports in the Vaccine Adverse Event Reporting System (VAERS) database from 2017 to 2022 and identified cases involving anaphylaxis with an onset within one day of vaccine administration. The primary outcome was the combined prevalence of death or disability for each setting while the secondary outcome was the prevalence of hospitalization. Adjusted (age, sex, prior history of allergy, vaccine type) odds ratios (aOR) and associated 95% confidence intervals (CI) were calculated using logistic regression analysis. A total of 2041 cases of anaphylaxis comprised the primary study cohort with representation in the sample from all 50 US states and the District of Columbia. The mean age was 43.3 ± 17.5 years, and most cases involved women (79.9%). Cases of anaphylaxis were reported after receiving a coronavirus vaccine (85.2%), influenza vaccine (5.9%), tetanus vaccine (2.2%), zoster vaccine (1.6%), measles vaccine (0.7%), and other vaccine (4.5%). Outcomes associated with reports of vaccine anaphylaxis included 35 cases of death and disability and 219 hospitalizations. Compared with all other settings, the aOR of death and disability when anaphylaxis occurred was 1.92 (95% CI, 0.86-4.54) in a medical provider's office, 0.85 (95% CI, 0.26-2.43) in a pharmacy and 1.01 (95% CI, 0.15-3.94) in a public health clinic. Compared with all other settings, the aOR of hospitalization when anaphylaxis occurred was 1.02 (95% CI, 0.71-1.47) in a medical provider's office, 1.06 (95% CI, 0.72-1.54) in a pharmacy, and 1.12 (95% CI, 0.61-1.93) in a public health clinic. An analysis of a national database across six years revealed no significant differences in the odds of death/disability and odds of hospitalization associated with post-vaccination anaphylaxis in the medical office, pharmacy, and public health clinic compared with all other settings. This study expands our understanding of the safety of immunization services and reinforces that all settings must be prepared to respond to such an emergency.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

Nivolumab-associated Nasal Polyposis and Eosinophilic Asthma Responsive to Benralizumab, An Anti-IL5R Biologic.

We present a case report of nivolumab-aggravated treatment-resistant chronic rhinosinusitis with nasal polyposis with asthma, suggestive of aspirin-exacerbated respiratory disease, normalized with the IL-5R antagonist benralizumab. For patients experiencing symptomatic complications of immunotherapy-associated eosinophilia, this case suggests anti-IL-5(R) biologics may durably resolve nasal polyposis and asthma symptoms, permitting continuity of checkpoint inhibitor therapy and sparing of systemic corticosteroids. Postulated mechanisms of checkpoint inhibition favoring eosinophilia and polyposis, and the uncertain effect of eosinophil reduction upon malignancy progression, are reviewed.