Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9.

Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells. Importantly, RNA-targeting Cas9 (RCas9) reverses hallmark features of disease including elimination of RNA foci among all conditions studied (DM1, DM2, C9-ALS, polyglutamine diseases), reduction of polyglutamine protein products, relocalization of repeat-bound proteins to resemble healthy controls, and efficient reversal of DM1-associated splicing abnormalities in patient myotubes. Finally, we report a truncated RCas9 system compatible with adeno-associated viral packaging. This effort highlights the potential of RCas9 for human therapeutics.

Cryo-EM structure of the human cardiac myosin filament.

Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly1. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years2. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state3; how titin and cMyBP-C may contribute to length-dependent activation4; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease5,6. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.

FACT is recruited to the +1 nucleosome of transcribed genes and spreads in a Chd1-dependent manner.

The histone chaperone FACT occupies transcribed regions where it plays prominent roles in maintaining chromatin integrity and preserving epigenetic information. How it is targeted to transcribed regions, however, remains unclear. Proposed models include docking on the RNA polymerase II (RNAPII) C-terminal domain (CTD), recruitment by elongation factors, recognition of modified histone tails, and binding partially disassembled nucleosomes. Here, we systematically test these and other scenarios in Saccharomyces cerevisiae and find that FACT binds transcribed chromatin, not RNAPII. Through a combination of high-resolution genome-wide mapping, single-molecule tracking, and mathematical modeling, we propose that FACT recognizes the +1 nucleosome, as it is partially unwrapped by the engaging RNAPII, and spreads to downstream nucleosomes aided by the chromatin remodeler Chd1. Our work clarifies how FACT interacts with genes, suggests a processive mechanism for FACT function, and provides a framework to further dissect the molecular mechanisms of transcription-coupled histone chaperoning.

Spatiotemporal coordination of transcription preinitiation complex assembly in live cells.

Transcription initiation by RNA polymerase II (RNA Pol II) requires preinitiation complex (PIC) assembly at gene promoters. In the dynamic nucleus, where thousands of promoters are broadly distributed in chromatin, it is unclear how multiple individual components converge on any target to establish the PIC. Here we use live-cell, single-molecule tracking in S. cerevisiae to visualize constrained exploration of the nucleoplasm by PIC components and Mediator's key role in guiding this process. On chromatin, TFIID/TATA-binding protein (TBP), Mediator, and RNA Pol II instruct assembly of a short-lived PIC, which occurs infrequently but efficiently within a few seconds on average. Moreover, PIC exclusion by nucleosome encroachment underscores regulated promoter accessibility by chromatin remodeling. Thus, coordinated nuclear exploration and recruitment to accessible targets underlies dynamic PIC establishment in yeast. Our study provides a global spatiotemporal model for transcription initiation in live cells.

Molecular architecture of the ATP-dependent chromatin-remodeling complex SWR1.

The ATP-dependent chromatin-remodeling complex SWR1 exchanges a variant histone H2A.Z/H2B dimer for a canonical H2A/H2B dimer at nucleosomes flanking histone-depleted regions, such as promoters. This localization of H2A.Z is conserved throughout eukaryotes. SWR1 is a 1 megadalton complex containing 14 different polypeptides, including the AAA+ ATPases Rvb1 and Rvb2. Using electron microscopy, we obtained the three-dimensional structure of SWR1 and mapped its major functional components. Our data show that SWR1 contains a single heterohexameric Rvb1/Rvb2 ring that, together with the catalytic subunit Swr1, brackets two independently assembled multisubunit modules. We also show that SWR1 undergoes a large conformational change upon engaging a limited region of the nucleosome core particle. Our work suggests an important structural role for the Rvbs and a distinct substrate-handling mode by SWR1, thereby providing a structural framework for understanding the complex dimer-exchange reaction.

Two ARGONAUTE proteins loaded with transposon-derived small RNAs are associated with the reproductive cell lineage in Arabidopsis.

In sexually propagating organisms, genetic, and epigenetic mutations are evolutionarily relevant only if they occur in the germline and are hence transmitted to the next generation. In contrast to most animals, plants are considered to lack an early segregating germline, implying that somatic cells can contribute genetic information to progeny. Here we demonstrate that 2 ARGONAUTE proteins, AGO5 and AGO9, mark cells associated with sexual reproduction in Arabidopsis (Arabidopsis thaliana) throughout development. Both AGOs are loaded with dynamically changing small RNA populations derived from highly methylated, pericentromeric, long transposons. Sequencing of single stem cell nuclei revealed that many of these transposons are co-expressed within an AGO5/9 expression domain in the shoot apical meristem (SAM). Co-occurrence of transposon expression and specific ARGONAUTE (AGO) expression in the SAM is reminiscent of germline features in animals and supports the existence of an early segregating germline in plants. Our results open the path to investigating transposon biology and epigenome dynamics at cellular resolution in the SAM stem cell niche.

Salicylic acid and RNA interference mediate antiviral immunity of plant stem cells.

Stem cells are essential for the development and organ regeneration of multicellular organisms, so their infection by pathogenic viruses must be prevented. Accordingly, mammalian stem cells are highly resistant to viral infection due to dedicated antiviral pathways including RNA interference (RNAi). In plants, a small group of stem cells harbored within the shoot apical meristem generate all postembryonic above-ground tissues, including the germline cells. Many viruses do not proliferate in these cells, yet the molecular bases of this exclusion remain only partially understood. Here, we show that a plant-encoded RNA-dependent RNA polymerase, after activation by the plant hormone salicylic acid, amplifies antiviral RNAi in infected tissues. This provides stem cells with RNA-based virus sequence information, which prevents virus proliferation. Furthermore, we find RNAi to be necessary for stem cell exclusion of several unrelated RNA viruses, despite their ability to efficiently suppress RNAi in the rest of the plant. This work elucidates a molecular pathway of great biological and economic relevance and lays the foundations for our future understanding of the unique systems underlying stem cell immunity.

Electronic Health Record-Based Algorithm for Monitoring Respiratory Virus-Like Illness.

Viral respiratory illness surveillance has traditionally focused on single pathogens (e.g., influenza) and required fever to identify influenza-like illness (ILI). We developed an automated system applying both laboratory test and syndrome criteria to electronic health records from 3 practice groups in Massachusetts, USA, to monitor trends in respiratory viral-like illness (RAVIOLI) across multiple pathogens. We identified RAVIOLI syndrome using diagnosis codes associated with respiratory viral testing or positive respiratory viral assays or fever. After retrospectively applying RAVIOLI criteria to electronic health records, we observed annual winter peaks during 2015-2019, predominantly caused by influenza, followed by cyclic peaks corresponding to SARS-CoV-2 surges during 2020-2024, spikes in RSV in mid-2021 and late 2022, and recrudescent influenza in late 2022 and 2023. RAVIOLI rates were higher and fluctuations more pronounced compared with traditional ILI surveillance. RAVIOLI broadens the scope, granularity, sensitivity, and specificity of respiratory viral illness surveillance compared with traditional ILI surveillance.

Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

Continuity of primary care for type 2 diabetes and hypertension and its association with health outcomes and disease control: insights from Central Vietnam.

BACKGROUND: Vietnam is undergoing a rapid epidemiological transition with a considerable burden of non-communicable diseases (NCDs), especially hypertension and diabetes (T2DM). Continuity of care (COC) is widely acknowledged as a benchmark for an efficient health system. This study aimed to determine the COC level for hypertension and T2DM within and across care levels and to investigate its associations with health outcomes and disease control. METHODS: A cross-sectional study was conducted on 602 people with T2DM and/or hypertension managed in primary care settings. We utilized both the Nijmegen continuity of care questionnaire (NCQ) and the Bice - Boxerman continuity of care index (COCI) to comprehensively measure three domains of COC: interpersonal, informational, and management continuity. ANOVA, paired-sample t-test, and bivariate and multivariable logistic regression analysis were performed to examine the predictors of COC. RESULTS: Mean values of COC indices were: NCQ: 3.59 and COCI: 0.77. The proportion of people with low NCQ levels was 68.8%, and that with low COCI levels was 47.3%. Primary care offered higher informational continuity than specialists (p < 0.01); management continuity was higher within the primary care team than between primary and specialist care (p < 0.001). Gender, living areas, hospital admission and emergency department encounters, frequency of health visits, disease duration, blood pressure and blood glucose levels, and disease control were demonstrated to be statistically associated with higher levels of COC. CONCLUSIONS: Continuity of primary care is not sufficiently achieved for hypertension and diabetes mellitus in Vietnam. Strengthening robust primary care services, improving the collaboration between healthcare providers through multidisciplinary team-based care and integrated care approach, and promoting patient education programs and shared decision-making interventions are priorities to improve COC for chronic care.

An integrated knowledge translation (iKT) approach to advancing community-based depression care in Vietnam: lessons from an ongoing research-policy collaboration.

BACKGROUND: Evidence-based mental health policies are key to supporting the expansion of community-based mental health care and are increasingly being developed in low and middle-income countries (LMICs). Despite this, research on the process of mental health policy development in LMICs is limited. Engagement between researchers and policy makers via an integrated Knowledge Translation (iKT) approach can help to facilitate the process of evidence-based policy making. This paper provides a descriptive case study of a decade-long policy and research collaboration between partners in Vietnam, Canada and Australia to advance mental health policy for community-based depression care in Vietnam. METHODS: This descriptive case study draws on qualitative data including team meeting minutes, a focus group discussion with research team leaders, and key informant interviews with two Vietnamese policy makers. Our analysis draws on Murphy et al.'s (2021) findings and recommendations related to stakeholder engagement in global mental health research. RESULTS: Consistent with Murphy et al.'s findings, facilitating factors across three thematic categories were identified. Related to 'the importance of understanding context', engagement between researchers and policy partners from the formative research stage provided a foundation for engagement that aligned with local priorities. The COVID-19 pandemic acted as a catalyst to further advance the prioritization of mental heath by the Government of Vietnam. 'The nature of engagement' is also important, with findings demonstrating that long-term policy engagement was facilitated by continuous funding mechanisms that have enabled trust-building and allowed the research team to respond to local priorities over time. 'Communication and dissemination' are also crucial, with the research team supporting mental health awareness-raising among policy makers and the community, including via capacity building initiatives. CONCLUSIONS: This case study identifies factors influencing policy engagement for mental health system strengthening in an LMIC setting. Sustained engagement with policy leaders helps to ensure alignment with local priorities, thus facilitating uptake and scale-up. Funding agencies can play a crucial role in supporting mental health system development through longer term funding mechanisms. Increased research related to the policy engagement process in global mental health will further support policy development and improvement in mental health care in LMICs.

Effects of Shrimp Shell-Derived Chitosan on Growth, Immunity, Intestinal Morphology, and Gene Expression of Nile Tilapia (Oreochromis niloticus) Reared in a Biofloc System.

Chitosan (CH) shows great potential as an immunostimulatory feed additive in aquaculture. This study evaluates the effects of varying dietary CH levels on the growth, immunity, intestinal morphology, and antioxidant status of Nile tilapia (Oreochromis niloticus) reared in a biofloc system. Tilapia fingerlings (mean weight 13.54 ± 0.05 g) were fed diets supplemented with 0 (CH0), 5 (CH5), 10 (CH10), 20 (CH20), and 40 (CH40) mL·kg-1 of CH for 8 weeks. Parameters were assessed after 4 and 8 weeks. Their final weight was not affected by CH supplementation, but CH at 10 mL·kg-1 significantly improved weight gain (WG) and specific growth rate (SGR) compared to the control (p < 0.05) at 8 weeks. Skin mucus lysozyme and peroxidase activities were lower in the chitosan-treated groups at weeks 4 and 8. Intestinal villi length and width were enhanced by 10 and 20 mL·kg-1 CH compared to the control. However, 40 mL·kg-1 CH caused detrimental impacts on the villi and muscular layer. CH supplementation, especially 5-10 mL·kg-1, increased liver and intestinal expressions of interleukin 1 (IL-1), interleukin 8 (IL-8), LPS-binding protein (LBP), glutathione reductase (GSR), glutathione peroxidase (GPX), and glutathione S-transferase (GST-α) compared to the control group. Overall, dietary CH at 10 mL·kg-1 can effectively promote growth, intestinal morphology, innate immunity, and antioxidant capacity in Nile tilapia fingerlings reared in biofloc systems.

Review of quorum-quenching probiotics: A promising non-antibiotic-based strategy for sustainable aquaculture.

The emergence of antibiotic-resistant bacteria (ARBs) and genes (ARGs) in aquaculture underscores the urgent need for alternative veterinary strategies to combat antimicrobial resistance (AMR). These measures are vital to reduce the likelihood of entering a post-antibiotic era. Identifying environmentally friendly biotechnological solutions to prevent and treat bacterial diseases is crucial for the sustainability of aquaculture and for minimizing the use of antimicrobials, especially antibiotics. The development of probiotics with quorum-quenching (QQ) capabilities presents a promising non-antibiotic strategy for sustainable aquaculture. Recent research has demonstrated the effectiveness of QQ probiotics (QQPs) against a range of significant fish pathogens in aquaculture. QQ disrupts microbial communication (quorum sensing, QS) by inhibiting the production, replication, and detection of signalling molecules, thereby reducing bacterial virulence factors. With their targeted anti-virulence approach, QQPs have substantial promise as a potential alternative to antibiotics. The application of QQPs in aquaculture, however, is still in its early stages and requires additional research. Key challenges include determining the optimal dosage and treatment regimens, understanding the long-term effects, and integrating QQPs with other disease control methods in diverse aquaculture systems. This review scrutinizes the current literature on antibiotic usage, AMR prevalence in aquaculture, QQ mechanisms and the application of QQPs as a sustainable alternative to antibiotics.

Consulting the Digital Doctor: Google Versus ChatGPT as Sources of Information on Breast Implant-Associated Anaplastic Large Cell Lymphoma and Breast Implant Illness.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare complication associated with the use of breast implants. Breast implant illness (BII) is another potentially concerning issue related to breast implants. This study aims to assess the quality of ChatGPT as a potential source of patient education by comparing the answers to frequently asked questions on BIA-ALCL and BII provided by ChatGPT and Google. METHODS: The Google and ChatGPT answers to the 10 most frequently asked questions on the search terms "breast implant associated anaplastic large cell lymphoma" and "breast implant illness" were recorded. Five blinded breast plastic surgeons were then asked to grade the quality of the answers according to the Global Quality Score (GQS). A Wilcoxon paired t-test was performed to evaluate the difference in GQS ratings for Google and ChatGPT answers. The sources provided by Google and ChatGPT were also categorized and assessed. RESULTS: In a comparison of answers provided by Google and ChatGPT on BIA-ALCL and BII, ChatGPT significantly outperformed Google. For BIA-ALCL, Google's average score was 2.72 ± 1.44, whereas ChatGPT scored an average of 4.18 ± 1.04 (p < 0.01). For BII, Google's average score was 2.66 ± 1.24, while ChatGPT scored an average of 4.28 ± 0.97 (p < 0.01). The superiority of ChatGPT's responses was attributed to their comprehensive nature and recognition of existing knowledge gaps. However, some of ChatGPT's answers had inaccessible sources. CONCLUSION: ChatGPT outperforms Google in providing high-quality answers to commonly asked questions on BIA-ALCL and BII, highlighting the potential of AI technologies in patient education. LEVEL OF EVIDENCE: Level III, comparative study LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

What Is the Risk? Epidemiology and Evidence for Surveillance Regimens.

Patients with inflammatory bowel disease (IBD) have increased risk of colorectal cancer (CRC). The risk for CRC is positively correlated to the duration of disease, extent of colonic involvement, and severity of inflammation. After 8 to 10 years of IBD diagnosis, the risk for CRC rises substantially and screening colonoscopy is recommended. Surveillance colonoscopy interval ranges from 1 to 5 years depending on patient and disease-specific risk factors. IBD patients with high risk factors such as having concomitant primary sclerosing cholangitis, moderate-to-severe inflammation, first-degree relative with CRC at early age, or history of invisible dysplasia or high-risk visible dysplasia should undergo surveillance colonoscopy in 1 year. Meanwhile, those with minimal colonic involvement or ≥2 consecutive unremarkable examinations while in continuous remission may consider extending the surveillance interval to 5 years. Advance in colonoscopy technique such as chromoendoscopy using dyes and/or image digital processing (virtual chromoendoscopy) may enhance dysplasia detection and is the preferred method for IBD surveillance. In the era of high-definition colonoscope, the practice of obtaining extensive biopsies throughout the colon remains controversial but is generally recommended to improve the detection rate of invisible dysplasia. Endoscopic surveillance in IBD has been shown to result in earlier detection of CRC and improved prognosis.

Amyloid beta and its naturally occurring N-terminal variants are potent activators of human and mouse formyl peptide receptor 1.

Formyl peptide receptors (FPRs) may contribute to inflammation in Alzheimer's disease through interactions with neuropathological Amyloid beta (Aß) peptides. Previous studies reported activation of FPR2 by Aß1-42, but further investigation of other FPRs and Aß variants is needed. This study provides a comprehensive overview of the interactions of mouse and human FPRs with different physiologically relevant Aß-peptides using transiently transfected cells in combination with calcium imaging. We observed that, in addition to hFPR2, all other hFPRs also responded to Aß1-42, Aß1-40, and the naturally occurring variants Aß11-40 and Aß17-40. Notably, Aß11-40 and Aß17-40 are very potent activators of mouse and human FPR1, acting at nanomolar concentrations. Buffer composition and aggregation state are extremely crucial factors that critically affect the interaction of Aß with different FPR subtypes. To investigate the physiological relevance of these findings, we examined the effects of Aß11-40 and Aß17-40 on the human glial cell line U87. Both peptides induced a strong calcium flux at concentrations that are very similar to those obtained in experiments for hFPR1 in HEK cells. Further immunocytochemistry, qPCR, and pharmacological experiments verified that these responses were primarily mediated through hFPR1. Chemotaxis experiments revealed that Aß11-40 but not Aß17-40 evoked cell migration, which argues for a functional selectivity of different Aß peptides. Together, these findings provide the first evidence that not only hFPR2 but also hFPR1 and hFPR3 may contribute to neuroinflammation in Alzheimer's disease through an interaction with different Aß variants.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

Comparative Safety of Biologic Agents in Patients With Inflammatory Bowel Disease With Active or Recent Malignancy: A Multi-Center Cohort Study.

BACKGROUND & AIMS: Safety of biologic agents is a key consideration in patients with inflammatory bowel disease (IBD) and active or recent cancer. We compared the safety of tumor necrosis factor (TNF)-α antagonists vs non-TNF biologics in patients with IBD with active or recent cancer. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD and either active cancer (cohort A) or recent prior cancer (within ≤5 years; cohort B) who were treated with TNFα antagonists or non-TNF biologics after their cancer diagnosis. Primary outcomes were progression-free survival (cohort A) or recurrence-free survival (cohort B). Safety was compared using inverse probability of treatment weighting with propensity scores. RESULTS: In cohort A, of 125 patients (483.8 person-years of follow-up evaluation) with active cancer (age, 54 ± 15 y, 75% solid-organ malignancy), 10 of 55 (incidence rate [IR] per 100 py, 4.4) and 9 of 40 (IR, 10.4) patients treated with TNFα antagonists and non-TNF biologics had cancer progression, respectively. There was no difference in the risk of progression-free survival between TNFα antagonists vs non-TNF biologics (hazard ratio, 0.76; 95% CI, 0.25-2.30). In cohort B, of 170 patients (513 person-years of follow-up evaluation) with recent prior cancer (age, 53 ± 15 y, 84% solid-organ malignancy; duration of remission, 19 ± 19 mo), 8 of 78 (IR, 3.4) and 5 of 66 (IR 3.7) patients treated with TNFα antagonists and non-TNF biologics had cancer recurrence, respectively. The risk of recurrence-free survival was similar between both groups (hazard ratio, 0.94; 95% CI, 0.24-3.77). CONCLUSIONS: In patients with IBD with active or recent cancer, TNFα antagonists and non-TNF biologics have comparable safety. The choice of biologic should be dictated by IBD disease severity in collaboration with an oncologist.

Varied Trainee Competence in Cold Snare Polypectomy: Results of the COMPLETE Randomized Controlled Trial.

INTRODUCTION: Cold snare polypectomy (CSP) is strongly recommended as the optimal technique for the complete removal of small polyps. Though significant variability in polypectomy technique and quality has been established, the learning curve and impact of targeted training on CSP are unknown. Video feedback has shown promise as an effective pedagogy to improve performance among surgical trainees. We aimed to compare CSP performance between trainees who received video-based feedback and those who received conventional apprentice-based concurrent feedback. We hypothesized that video-based feedback would accelerate competence. METHODS: We conducted a single-blinded, randomized controlled trial on competence for CSP of polyps <1 cm, comparing video-based feedback with conventional feedback. We randomly assigned deidentified consecutively recorded CSP videos to blinded raters to assess using the CSP Assessment Tool. We shared cumulative sum learning curves every 25 CSP with each trainee. The video feedback trainees also received biweekly individualized terminal feedback. Control trainees received conventional feedback during colonoscopy. The primary outcome was CSP competence. We also assessed competence across domains and change over polypectomy volume. RESULTS: We enrolled and randomized 22 trainees, 12 to video-based feedback and 10 to conventional feedback, and evaluated 2,339 CSP. The learning curve was long; 2 trainees (16.7%) in the video feedback achieved competence, after a mean of 135 polyps, and no one in the control ( P = 0.481) achieved competence. Overall and in all steps of CSP, a higher percentage of the video feedback group met competence, increasing 3% every 20 CSP ( P = 0.0004). DISCUSSION: Video feedback aided trainees to competence in CSP. However, the learning curve was long. Our findings strongly suggest that current training methods are not sufficient to support trainees to competency by the completion of their fellowship programs. The impact of new training methods, such as simulation-based mastery learning, should be assessed to determine whether such methods can result in achievement of competence at a faster rate; ClinicalTrials.gov : NCT03115008.

Long-Term Outcomes of Open Versus Laparoscopic Distal Gastrectomy for T4a Gastric Cancer: A Propensity Score-Matched Cohort Study.

BACKGROUND: Laparoscopic gastrectomy for advanced gastric cancer (GC) has been applied more frequently worldwide but is still controversial for patients with serosal invasion (T4a). This study compared short- and long-term outcomes of laparoscopic distal radical gastrectomy (LDG) with open distal gastrectomy (ODG) for T4a GC. PATIENTS AND METHODS: We retrospectively studied 472 patients with T4a gastric adenocarcinoma in the lower or middle third of the stomach: 231 underwent LDG and 241 underwent ODG between 2013 and 2020. Short-term outcomes included operative characteristics and complications. Long-term outcomes included overall survival (OS) and disease-free survival (DFS). Propensity score-matched (PSM) analysis was used to adjust for imbalances in baseline characteristics between groups. RESULTS: The PSM strategy resulted in 294 patients (147 in each group). The LDG group had a significantly longer operating time (mean: 200 vs 190 min, p = 0.001) but reduced blood loss (mean: 50 vs 100 ml, p = 0.001). The LDG group had a higher rate of any postoperative complication (23.1% vs 12.2%, p = 0.021) but most were classified as grades I-II according to Clavien-Dindo classification. Grade III-V complications were similar between groups. Five-year OS was 69% versus 60% (p = 0.109) and 5-year DFS was 58% vs 53% (p = 0.3) in LDG and ODG groups, respectively. For tumor size < 5 cm, LDG was better in reduction of blood loss, postoperative hospital length of stay, and OS. CONCLUSIONS: LDG is feasible and safe for patients with T4a GC and is comparable to ODG regarding short- and long-term outcomes. Furthermore, LDG can be a favorable option for T4a GC smaller than 5 cm.