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Immune checkpoint inhibitor-associated colitis (ICIC) affects approximately 15% of cancer patients treated with immunotherapy. Although histological evaluation is potentially valuable for both the diagnosis of ICIC and evaluation of disease activity, use in clinical practice is heterogeneous. We aimed to develop expert recommendations to standardize histological assessment of disease activity in patients with ICIC. Using the modified Research and Development/University of California Los Angeles (RAND/UCLA) appropriateness methodology, an international panel of 11 pathologists rated the appropriateness of 99 statements on a 9-point Likert scale during two rounds of anonymous voting. Results were discussed between rounds using moderated videoconferences. There are currently no disease-specific instruments for assessing histological features of ICIC. The panel considered that colonoscopy with at least three biopsies per segment from a total of at least five segments, including both endoscopically normal and inflamed areas, was appropriate for tissue acquisition. They agreed that biopsies should be oriented such that the long axis of the colonic crypts is visualized and should be stained with hematoxylin and eosin. Histological items that the panel voted were appropriate to evaluate in ICIC included the degree of structural/architectural change, chronic inflammatory infiltrate, lamina propria and intraepithelial neutrophils, crypt abscesses and destruction, erosions/ulcerations, apoptosis, surface intraepithelial lymphocytosis, and subepithelial collagen thickness. The appropriateness of routine immunohistochemistry was uncertain. These expert recommendations will help standardize assessment of histological activity in patients with ICIC. The panel also identified the development and validation of an ICIC-specific histological index as a research priority.

Research summary: The concern of crime in New York City public housing complexes motivated heightened police patrol of buildings and the enforcement of trespass laws. The 2013 federal court settlement of Davis et al. v. City of New York et al. mandated that the New York City Police Department (NYPD) implement a series of reforms, including the deployment of body‐worn cameras (BWCs) on officers, to address unconstitutional use of criminal trespass enforcement and stop and frisk practices in public housing developments. This study employed a stepped wedge quasi‐experimental design that involved the sequential crossover of public housing service area clusters from control to BWC implementation until all NYPD housing bureau officers were equipped with BWCs. Panel regression models at the individual officer and service area levels were used to estimate BWC program impacts on outcomes between 2015 and 2019. Logistic regression models were used to estimate the impact of the BWCs on the lawfulness of officer stop reports that were randomly selected for audit between 2017 and 2019. Results show that BWC deployment in public housing reduced excessive enforcement, citizen complaints, and use of force by NYPD housing officers. Findings further suggest that BWCs can help reduce constitutionally problematic stops and frisks of citizens. Policy implications: Problematic police activities in public housing contexts can be reformed using BWCs. When coupled with routine supervisory review of video footage, the deployment of BWCs on public housing officers can improve compliance with department directives to reduce enforcement actions and increase documentation of citizen stops. [ABSTRACT FROM AUTHOR]

Research Summary Policy Implications The evaluation literature suggests that focused deterrence strategies are effective in reducing gun violence. However, focused deterrence is notoriously difficult to implement and sustain. The history of focused deterrence implementation failure raises questions about its viability as a gun violence prevention strategy. Stockton, California, implemented focused deterrence three times during the past 25 years. In its most recent version, Stockton officials explicitly designed the strategy to be a permanent feature of the city's violence prevention portfolio. Although program caseloads diminished over the course of the COVID‐19 pandemic and the strategy faced leadership and resource challenges, Stockton's efforts prevented the program from being discontinued and, for those gang members who did receive treatment, delivered a robust gun violence prevention strategy. A quasi‐experimental evaluation shows that treated gang members were less likely to be shot and reduced their violent offending relative to similar untreated gang members. The focused deterrence impacts also appear to spill over to gang members who were socially connected to treated gang members. Although Stockton experienced an increase in homicides over the course of the COVID‐19 pandemic, the increase was not as steep as other comparable California cities.Focused deterrence strategies can be effective responses to gun violence problems when implemented properly. A priori planning is essential when jurisdictions prepare to adopt focused deterrence. Strategic management actions, such as maintaining a robust network of partnering agencies, developing accountability structures and sustainability plans, and conducting upfront and ongoing problem analysis, are critical elements that must be in place for focused deterrence to be effective and sustainable. [ABSTRACT FROM AUTHOR]

CO2 mineralization in slag has been widely investigated as a potential solution for offsetting steelmaking industry emissions. However, it can be associated with ecotoxic elements release (e.g., V and Cr). The presence of such elements in heterogenous slag at the micro‐scale remains difficult for analysis since microstructural features can be missed during microscopy data inspection, thereby presenting a challenge in understanding how ecotoxic elements exist in slag. Here, an unsupervised machine learning‐based technique is used to analyze slag's microstructural features. Energy Dispersive Spectroscopy (EDS) data are analyzed through Hierarchical Density‐Based Spatial Clustering of Applications with Noise (HDBSCAN) method. Results show that passive CO2 mineralization has occurred in situ in the studied samples, on the surface, and within their pores. Additionally, V and Cr regions with equivalent diameters < 42 µm can exist within slag, potentially making such elements prone to mobilization due to slag pulverization. Interrogation of the samples with Laser Ablation Inductively Coupled Plasma Mass Spectroscopy (LA‐ICP‐MS) confirms the distribution of the elements obtained from the clustering algorithm and further demonstrates that up to 84 and 9 ppm of V and Cr are incorporated in the precipitated calcite, respectively. This implies that ecotoxic elements may be immobilized through calcite precipitation. [ABSTRACT FROM AUTHOR]

O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression. [ABSTRACT FROM AUTHOR]

Background and Aims In this systematic review we summarise existing scoring indices for assessing disease activity and quality of life in perianal fistulising Crohn's disease [PFCD], and highlight gaps in the literature. Methods MEDLINE, EMBASE, and CENTRAL were searched from August 24, 2022, to identify studies evaluating clinical, radiological, or patient-reported outcome measures [PROMS] in PFCD. The primary objective was to identify all available scoring indices and describe the operating properties of these indices. Results A total of 53 studies reported on the use of one clinical index [Perianal Disease Activity Index: PDAI], three PROMs, and 10 radiological indices; 25 studies evaluated the operating properties of these indices. The PDAI demonstrated content validity, construct validity, and responsiveness but criterion validity or reliability were not assessed. The Van Assche Index [VAI], modified VAI, and the Magnetic Resonance Index for Assessing Fistulas in Patients with CD [MAGNIFI-CD] were the most studied radiological indices. These indices demonstrated responsiveness and reliability. The VAI and MAGNIFI-CD demonstrated construct validity; criterion and content validity and feasibility have not been assessed. Among the three PROMs, the Crohn's Anal Fistula Quality of Life index demonstrated content and construct validity, inter-observer reliability, and responsiveness; criterion validity, intra-observer reliability, and feasibility have not been assessed for this index. Conclusions There are no fully valid, reliable, and responsive clinical disease or radiological indices for PFCD. Although the radiological indices demonstrated responsiveness and reliability, well-defined cut-offs for response and remission are lacking. Future research should focus on establishing standardised definitions and thresholds for outcomes. [ABSTRACT FROM AUTHOR]

Background Fistulas are a debilitating complication of Crohn's disease [CD]. We conducted a systematic review to assess the efficacy of medical therapies for fistulizing CD. Methods MEDLINE, Embase, and CENTRAL were searched on May 26, 2022, for randomized controlled trials [RCTs] of pharmacological therapy in adults with fistulizing CD. The primary outcome was induction and maintenance of fistula response. Pooled risk ratios [RRs] and 95% confidence intervals [CIs] were calculated. GRADE was used to assess the certainty of evidence. Results Thirty-eight RCTs were included. Nineteen trials [50%] exclusively involved perianal fistula. The remaining studies included some participants with non-perianal fistula. Pooled RRs for anti-tumour necrosis factor [TNF] agents were not statistically significant for induction [RR 1.36, 95% CI 0.97–1.91] or maintenance of fistula response [RR 1.48, 95% CI 0.97–2.27]. However, in a sensitivity analysis of studies with fistula response as the primary outcome, anti-TNFs were superior to placebo for induction [RR 1.94, 95% CI 1.10–3.41] and maintenance [RR 1.88, 95% CI 1.23–2.88] of fistula response. Oral small molecules [RR 2.56, 95% CI 1.18–5.53] and mesenchymal stem cell [MSC] therapy [RR 1.26, 95% CI 1.01–1.57] were effective for induction of fistula response. Ustekinumab was associated with maintenance of fistula response [RR 1.80, 95% CI 1.04–3.11]. Vedolizumab was not superior to placebo. The certainty of evidence ranged from very low to moderate. Conclusion Very low- to moderate-certainty evidence suggests that anti-TNF therapy, oral small molecules, ustekinumab, and MSCs are effective for perianal fistulizing CD. Dedicated fistula studies evaluating biologics and small molecules are needed. [ABSTRACT FROM AUTHOR]