The LexA-RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation.

The bacterial SOS response plays a key role in adaptation to DNA damage, including genomic stress caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament that forms on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete Escherichia coli SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS gene induction. We further find that the interface involves three RecA subunits, with a single residue in the central engaged subunit acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance.

Primary prevention of venous thromboembolism for cancer patients in randomized controlled trials: a bibliographical analysis of funding and trial characteristics.

Background: The majority of randomized controlled trials (RCTs) investigating venous thromboembolism (VTE) prophylaxis in patients with cancer involve commercial sponsorship. Commercial sponsorship overcomes feasibility limitations inherent in RCTs, such as recruitment and funding, but has attracted scrutiny for its potential for bias. Objectives: In RCTs of VTE prophylaxis in patients with cancer, how do trial characteristics compare between commercially sponsored RCTs and noncommercially sponsored RCTs? Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched for RCTs that investigated at least 1 pharmacologic intervention for VTE prophylaxis in adult patients with cancer. Screening and data extraction were conducted by independent reviewers. Outcomes included trial characteristics, reporting of favorable outcomes, protocol-manuscript discrepancies, and appraisal of spin. Outcomes were compared using the independent t-test, Mann-Whitney U-test, Pearson chi-squared test, and Fisher's exact test. Logistic regression was performed to identify factors associated with possible bias. Results: Of the 54 trials analyzed, 34 (63%) reported commercial sponsorship. Commercial sponsorship was not associated with the reporting of favorable outcomes, presence of spin, retrospective registration, or protocol-manuscript discrepancy. Spin was most prevalent in the abstract conclusions (9 out of 17 [53.3%]) and manuscript conclusions (8 out of 17 [46.7%]).Commercially sponsored trials had a higher rate of intention-to-treat analysis. Noncommercially sponsored trials were more likely to report retrospective registration of trial protocol and the use of composite primary outcomes. Conclusion: There were few significant differences between trial characteristics, suggesting that the evidence from commercially sponsored trials investigating VTE prophylaxis in patients with cancer is unlikely to be subject to bias attributable to commercial sponsorship.

Assessing the robustness of positive vascular surgery randomized controlled trials using their fragility index.

OBJECTIVE: The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. METHODS: In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. RESULTS: Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P = .035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P = .01, respectively). The FI did not vary between disease states (P = .285) or between index and follow-up trials (P = .147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). CONCLUSIONS: A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery.

Development of an Artificial Intelligence Tool for Intraoperative Guidance During Endovascular Abdominal Aortic Aneurysm Repair.

BACKGROUND: Adverse events during surgery can occur in part due to errors in visual perception and judgment. Deep learning is a branch of artificial intelligence (AI) that has shown promise in providing real-time intraoperative guidance. This study aims to train and test the performance of a deep learning model that can identify inappropriate landing zones during endovascular aneurysm repair (EVAR). METHODS: A deep learning model was trained to identify a "No-Go" landing zone during EVAR, defined by coverage of the lowest renal artery by the stent graft. Fluoroscopic images from elective EVAR procedures performed at a single institution and from open-access sources were selected. Annotations of the "No-Go" zone were performed by trained annotators. A 10-fold cross-validation technique was used to evaluate the performance of the model against human annotations. Primary outcomes were intersection-over-union (IoU) and F1 score and secondary outcomes were pixel-wise accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The AI model was trained using 369 images procured from 110 different patients/videos, including 18 patients/videos (44 images) from open-access sources. For the primary outcomes, IoU and F1 were 0.43 (standard deviation ± 0.29) and 0.53 (±0.32), respectively. For the secondary outcomes, accuracy, sensitivity, specificity, NPV, and PPV were 0.97 (±0.002), 0.51 (±0.34), 0.99 (±0.001). 0.99 (±0.002), and 0.62 (±0.34), respectively. CONCLUSIONS: AI can effectively identify suboptimal areas of stent deployment during EVAR. Further directions include validating the model on datasets from other institutions and assessing its ability to predict optimal stent graft placement and clinical outcomes.

Direct oral anticoagulants for the treatment of splanchnic vein thrombosis - A systematic review and meta-analysis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism in the splanchnic venous system, with scarce evidence surrounding its management. We assessed the efficacy and safety of direct oral anticoagulant (DOAC) to low-molecular-weight heparins (LMWH), vitamin-k antagonists (VKAs), or no anticoagulation. METHODS: We conducted a systematic review and meta-analysis with the primary efficacy outcome being complete recanalization of affected vessels and primary safety outcome being major bleeding. Meta-analysis was done using a random-effects model, with dichotomous outcomes being synthesized with odds ratios (ORs) and corresponding 95 % CIs. RESULTS: Seven non-randomized and one randomized study involving 883 participants were included for analysis. DOACs were more effective than VKAs (OR = 4.33; 95 % CI: 2.4, 7.83; n = 1 study) in non-cirrhotic patients and no anticoagulation in cirrhotic patients (OR = 3.86; 95 % CI: 1.49, 10.03; n = 3 studies). DOACs had a statistically significant reduction in major bleeding compared to observation [OR = 0.09; 95 % CI: 0.03, 0.29; n = 3 studies], LMWHs [OR = 0.13; 95 % CI: 0.03, 0.29; n = 1 study] and VKAs [OR = 0.12; 95 % CI: 0.02, 0.69; n = 2 studies] in non-cirrhotic patients. No difference in major bleeding was found between DOACs and observation, LMWH, or VKAs in cirrhotic patients. CONCLUSION: DOACs appear to be a favorable alternative to VKAs and LMWHs in non-cirrhotic patients. This avenue of research would benefit from larger studies that adjust for SVT etiologies, patient risk factors, and overall bleeding risk.

Evaluating YouTube as a Source of Education for Patients Undergoing Surgery: A Systematic Review.

OBJECTIVE: The objective of this systematic review is to characterize the peer-reviewed literature investigating YouTube as a source of patient education for patients undergoing surgery. SUMMARY BACKGROUND DATA: YouTube is the largest online video sharing platform and has become a substantial source of health information that patients are likely to access before surgery, yet there has been no systematic assessment of peer-reviewed studies. A comprehensive literature search was conducted using EMBASE, MEDLINE, and Ovid HealthStar from inception through to December of 2021. METHODS: All primary studies evaluating YouTube as a source of patient education relating to surgical procedures (general, cardiac, urology, otolaryngology, plastic, vascular) were included. Study screening and data extraction occurred in duplicate with two reviewers. Characteristics extracted included video length, view count, upload source, overall video educational quality, and quality of individual studies. RESULTS: Among 6,453 citations, 56 studies were identified that examined 6,797 videos with 547 hours of content and 1.39 billion views. There were 49 studies that evaluated the educational quality of the videos. A total of 43 quality assessment tools were used, with each study using a mean of 1.90 assessment tools. Per the global rating for assessments, 34/49 studies (69%) concluded that the overall quality of educational content was poor. CONCLUSIONS: While the impact of non-peer-reviewed YouTube videos on patient knowledge for surgery is unclear, the large amount of online content suggests that they are in demand. The overall educational content of these videos is poor, however, and there is substantial heterogeneity in the quality assessment tools used in their evaluation. A peer-reviewed and standardized approach to online education with video content is needed to better support patients.

Role of intrapulmonary lymph nodes in patients with NSCLC and visceral pleural invasion. The VPI 1314 multicenter registry study protocol.

BACKGROUND: In the lung cancer classification (TNM), the involvement of thoracic lymph nodes is relevant from a diagnostic and prognostic point of view. Even if imaging modality could help in selecting patients who should undergo surgery, a systematic lymph node dissection during lung surgery is mandatory to identify the subgroup of patients who can benefit from an adjuvant treatment. METHODS: Patients undergoing elective lobectomy/bilobectomy/segmentectomy) for non-small cell lung cancer and lymphadenectomy with lymph nodes station 10-11-12-13-14 sampling that meet the inclusion and exclusion criteria will be recorded in a multicenter prospective database. The overall incidence of N1 patients (subclassified in: Hilar Lymph nodes, Lobar Lymph nodes and Sublobar Lymph nodes) will be examined as well as the incidence of visceral pleural invasion. DISCUSSION: The aim of this multicenter prospective study is to evaluate the incidence of intrapulmonary lymph nodes metastases and the possible relation with visceral pleural invasion. Identifying patients with lymph node station 13 and 14 metastases and/or a link between visceral pleural invasion and presence of micro/macro metastases in intrapulmonary lymph nodes may have an impact on decision-making process. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05596578.

Completeness of reporting in systematic reviews and meta-analyses in vascular surgery.

OBJECTIVE: Systematic reviews (SRs) and meta-analyses are essential in informing clinical guidelines and decision-making. Complete reporting of SRs through compliance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines promotes transparency, reproducibility, and consistency across the literature. The purpose of this meta-epidemiological study is to assess the completeness of reporting of SRs in the vascular surgery literature. METHODS: MEDLINE and Embase were used to search through four major vascular surgery journals and four high impact general medical journals for SRs published between 2018 and October 2022 evaluating clinical treatments for any pathology treated by a vascular surgeon. Data screening and extraction were conducted in duplicate. The reporting completeness of each included SR was measured with reference to the 27-item PRISMA checklist, and methodological quality was evaluated using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) tool. Parametric tests were used to evaluate for associations between PRISMA score and study funding, protocol registration, publication in a higher impact factor journal, and AMSTAR 2 score. The protocol is available online: 10.17605/OSF.IO/VBC5N. RESULTS: Of 1653 articles captured in the initial search, 162 SRs were included in the final analysis. All SRs had more than one incomplete PRISMA item. The mean PRISMA score was 21.2/27 (standard deviation: 2.9, 78.5% compliance), and the mean AMSTAR 2 score was 11.7/16 (standard deviation: 1.9, 73%). SRs that had a prospectively registered protocol had a higher PRISMA score (22.9 vs 20.6, P < .001) as did those that were published in higher impact factor journals (23.3 vs 21.0, P = .017). There was a large positive correlation between an SR's PRISMA and AMSTAR 2 scores (Pearson r = 0.655, 95% confidence interval: 0.55-0.74). There were no associations between the PRISMA score and publication year (P = .067) or funding status (P = .076). CONCLUSIONS: Overall, the reporting of SRs and meta-analyses in vascular surgery is less than ideal, with several key items being consistently under-reported. Prospective registration and methodological quality as measured by AMSTAR 2 scores are positively associated with improved reporting. Authors, reviewers, and journal editors should consider these findings moving forward to encourage completeness of SR reporting. Raising awareness surrounding the value of complete reporting of SRs can aid in enhancing the quality of evidence, and journals should consider these findings in methods used to promote SR reporting.

FRETing about the details: Case studies in the use of a genetically encoded fluorescent amino acid for distance-dependent energy transfer.

Förster resonance energy transfer (FRET) is a valuable method for monitoring protein conformation and biomolecular interactions. Intrinsically fluorescent amino acids that can be genetically encoded, such as acridonylalanine (Acd), are particularly useful for FRET studies. However, quantitative interpretation of FRET data to derive distance information requires careful use of controls and consideration of photophysical effects. Here we present two case studies illustrating how Acd can be used in FRET experiments to study small molecule induced conformational changes and multicomponent biomolecular complexes.

Convalescent plasma therapy for coronavirus disease 2019 in ambulatory versus hospitalized patients: Efficacy and risk of thromboembolism.

Background: Although early evidence concluded a lack of clinical benefit of convalescent plasma therapy (CPT) in COVID-19 management, recent trials have demonstrated the therapeutic potential of CPT in ambulatory care. CPT may also potentiate thromboembolic events, given the presence of coagulation factors and the prothrombotic state of COVID-19. Objectives: The present study aimed to assess and compare the clinical efficacy and the risk of venous thromboembolism (VTE)/arterial thromboembolism (ATE) of CPT in ambulatory versus hospitalized patients with COVID-19. Methods: MEDLINE, Embase, and Cochrane CENTRAL were searched from December 2019 to December 2022 for randomized controlled trials that investigated the use of CPT against placebo or standard of care in adult patients with COVID-19. The primary outcome was nonmortality disease progression. Secondary outcomes include VTE, ATE, 28-day mortality, clinical improvement, length of hospitalization, sepsis/fever, and major adverse cardiovascular events. Results: Twenty randomized controlled trials, with 21,340 patients, were included. CPT significantly reduced nonmortality disease progression in ambulatory patients (odds ratio [OR], 0.72; 95% CI, 0.56-0.92; P = .009) but not in hospitalized patients (OR, 1.03; 95% CI, 0.94-1.12; P = .58). The risk of VTE and ATE did not differ between the CPT and the control group (OR, 1.16; 95% CI, 0.82-1.66; P = .40; and OR, 1.01; 95% CI, 0.37-2.79; P = .98, respectively). No conclusive differences between CPT and control groups were noted in 28-day mortality, clinical improvement, length of hospitalization, risk of sepsis/fever, and major adverse cardiovascular events. Conclusion: In conclusion, treatment of COVID-19 with CPT prevents the progression of COVID-19 in the ambulatory care. It is not associated with an increased risk of VTE, ATE, or other adverse events.

Deficiency of RAB39B Activates ER Stress-Induced Pro-apoptotic Pathway and Causes Mitochondrial Dysfunction and Oxidative Stress in Dopaminergic Neurons by Impairing Autophagy and Upregulating α-Synuclein.

Deletion and missense or nonsense mutation of RAB39B gene cause familial Parkinson's disease (PD). We hypothesized that deletion and mutation of RAB39B gene induce degeneration of dopaminergic neurons by decreasing protein level of functional RAB39B and causing RAB39B deficiency. Cellular model of deletion or mutation of RAB39B gene-induced PD was prepared by knocking down endogenous RAB39B in human SH-SY5Y dopaminergic cells. Transfection of shRNA-induced 90% reduction in RAB39B level significantly decreased viability of SH-SY5Y dopaminergic neurons. Deficiency of RAB39B caused impairment of macroautophagy/autophagy, which led to increased protein levels of α-synuclein and phospho-α-synucleinSer129 within endoplasmic reticulum (ER) and mitochondria. RAB39B deficiency-induced increase of ER α-synuclein and phospho-α-synucleinSer129 caused activation of ER stress, unfolded protein response, and ER stress-induced pro-apoptotic cascade. Deficiency of RAB39B-induced increase of mitochondrial α-synuclein decreased mitochondrial membrane potential and increased mitochondrial superoxide. RAB39B deficiency-induced activation of ER stress pro-apoptotic pathway, mitochondrial dysfunction, and oxidative stress caused apoptotic death of SH-SY5Y dopaminergic cells by activating mitochondrial apoptotic cascade. In contrast to neuroprotective effect of wild-type RAB39B, PD mutant (T168K), (W186X), or (G192R) RAB39B did not prevent tunicamycin- or rotenone-induced increase of neurotoxic α-synuclein and activation of pro-apoptotic pathway. Our results suggest that RAB39B is required for survival and macroautophagy function of dopaminergic neurons and that deletion or PD mutation of RAB39B gene-induced RAB39B deficiency induces apoptotic death of dopaminergic neurons via impairing autophagy function and upregulating α-synuclein.

"Spin" in Plastic Surgery Randomized Controlled Trials with Statistically Nonsignificant Primary Outcomes: A Systematic Review.

BACKGROUND: "Spin" refers to a manipulation of language that implies benefit for an intervention when none may exist. Randomized controlled trials (RCTs) in other fields have been demonstrated to employ spin, which can mislead clinicians to use ineffective or unsafe interventions. This study's objective was to determine the strategies, severity, and extent of spin in plastic surgery RCTs with nonsignificant primary outcomes. METHODS: A literature search of the top 15 plastic surgery journals using MEDLINE was performed (2000 through 2020). Parallel 1:1 RCTs with a clearly identified primary outcome showing statistically nonsignificant results ( P > 0.05) were included. Screening, data extraction, and spin analysis were performed by two independent reviewers. The spin analysis was then independently assessed in duplicate by two plastic surgery residents with graduate-level training in clinical epidemiology. RESULTS: From 3497 studies identified, 92 RCTs were included in this study. Spin strategies were identified in 78 RCTs (85%), including 64 abstracts (70%) and 77 main texts (84%). Severity of spin was rated moderate or high in 43 abstract conclusions (47%) and 42 main text conclusions (46%). The most identified spin strategy in the abstract was claiming equivalence for statistically nonsignificant results (26%); in the main text, focusing on another objective (24%). CONCLUSIONS: This study suggests that 85% of statistically nonsignificant RCTs in plastic surgery employ spin. Readers of plastic surgery research should be aware of strategies, whether intentional or unintentional, used to manipulate language in reports of statistically nonsignificant RCTs when applying research findings to clinical practice.

Assessing the robustness of negative vascular surgery randomized controlled trials using their reverse fragility index.

OBJECTIVE: The reverse fragility index (RFI) describes the number of event conversions needed to convert a statistically nonsignificant dichotomous outcome to a significant one. The objective of the present study was to assess the RFI of vascular surgery randomized controlled trials (RCTs) comparing endovascular vs open surgery for the treatment of abdominal aortic aneurysms (AAAs), carotid artery stenosis (CAS), and peripheral artery disease (PAD). METHODS: MEDLINE and Embase were searched for RCTs that had investigated AAAs, CAS, or PAD with statistically nonsignificant binary primary outcomes. The primary outcome for the present study was the median RFI. Calculation of the RFI was performed by creating two-by-two contingency tables and subtracting events from the group with fewer events and adding nonevents to the same group until a two-tailed Fisher exact test had produced a statistically significant result (P ≤ .05). RESULTS: Of 4187 reports, 49 studies reporting 103 different primary end points were included. The overall median RFI was 7 (interquartile range [IQR], 5-13). The specific RFIs for AAA, CAS, and PAD were 10 (IQR, 6-15.5), 6 (IQR, 5-9.5), and 7 (IQR, 5.5-10), respectively. Of the 103 end points, 42 (47%) had had a loss to follow-up greater than the RFI, of which 10 were AAA trials (24%), 23 were CAS trials (55%), and 9 were PAD trials (21%). The Pearson correlation demonstrated a significant positive relationship between a study's RFI and the impact factor of its publishing journal (r = 0.38; 95% confidence interval [CI], 0.20-0.54; P < .01), length of follow-up (r = 0.43; 95% CI, 0.26-0.58; P < .01), and sample size (r = 0.28; 95% CI, 0.09-0.45; P < .01). CONCLUSIONS: A small number of events (median, 7) was required to change the outcome of negative RCTs from statistically nonsignificant to significant, with 47% of the studies having missing data that could have reversed the finding of its primary outcome. Reporting of the RFI relative to the loss to follow-up could be of benefit in future trials and provide confidence regarding the robustness of the P value.

Outcomes After Neuraxial or Regional Anaesthesia Instead of General Anaesthesia for Lower Limb Revascularisation Surgery: A Systematic Review and Meta-Analysis of Randomised and Non-Randomised Studies.

OBJECTIVE: To determine whether receipt of neuraxial or regional anaesthesia instead of general anaesthesia for lower limb revascularisation surgery affects patient outcomes. DATA SOURCES: MEDLINE, EMBASE, Evidence Based Medicine Reviews, and Google Scholar. REVIEW METHODS: After protocol registration, the data sources were searched for randomised and non-randomised studies comparing neuraxial or regional anaesthesia with general anaesthesia for lower limb revascularisation surgery in adults. Two investigators independently selected articles, extracted data, and assessed risks of bias. Data were pooled using random effects models. GRADE was used to assess certainty in cumulative evidence. RESULTS: From 10 755 citations identified, five randomised (n = 970) and 13 non-randomised (n = 96 800) studies were included. Use of neuraxial instead of general anaesthesia for lower limb revascularisation surgery was associated with no statistically significant reduction in short term (in hospital or 30 day) mortality in randomised studies (pooled odds ratio [OR] 0.77; 95% confidence interval [CI] 0.33 - 1.81; low certainty) and a statistically significant reduction in adjusted short term mortality in non-randomised studies (pooled OR 0.67; 95% CI 0.56 - 0.81; low certainty). Adults allocated to neuraxial anaesthesia in randomised studies had fewer pulmonary complications (pooled OR 0.35; 95% CI 0.16 - 0.76; low certainty). In non-randomised studies, neuraxial instead of general anaesthesia was associated with a lower adjusted odds of any morbidity (pooled OR 0.66; 95% CI 0.52 - 0.84), cardiac complications (pooled OR 0.68; 95% CI 0.58 - 0.79), pneumonia (pooled OR 0.81; 95% CI 0.64 - 1.02), prolonged mechanical ventilation (OR 0.09; 95% CI 0.002 - 0.55), and bypass graft thrombosis (OR 0.70; 95% CI 0.59 - 0.85), as well as a shorter operative duration (low certainty for all). Use of a nerve block instead of general anaesthesia was associated with a lower adjusted odds of delirium (OR 0.16; 95% CI 0.06 - 0.42) and a shorter operative duration (low certainty for both). CONCLUSION: Randomised and non-randomised data suggest that neuraxial anaesthesia for lower limb revascularisation surgery reduces morbidity and possibly mortality. Until randomised trials with a low risk of bias become available, this study supports use of neuraxial anaesthesia for these procedures where appropriate.

Prognostic significance of lymph nodes assessment during pulmonary metastasectomy: a systematic review and meta-analysis.

Background: Lung metastasectomy is an accepted treatment modality worldwide. Whether the addition of lymph node dissection to the procedure is useful remains, however, unknown. Methods: We performed a systematic review of the literature analyzing MEDLINE, Embase, until 31st October 2021. We included all studies which met the inclusion criteria aiming to determine if the addition of lymph node tissue dissection/sampling to lung metastasectomy offers survival benefits when compared to patients who do receive lymph node tissue dissection. Secondary outcomes were 3- and 5-year overall survival (OS) and disease-free survival (DFS). Each study was assessed for risk of bias. The data collected from the included studies were pooled using reconstruction of individual-level patient data and pooling of reported 5-year odds ratios (ORs). Interstudy heterogeneity was estimated with visual inspection of forest plots and calculation of the I2 inconsistency statistic. Results: We found 11 eligible studies that included a total of 3,310 patients. The most common primary tumor type was colorectal cancer (1,740 patients) and the most commonly performed operative procedure was wedge resection (57%) followed by lobectomy (39%). When resection status was reported, R0 resection was achieved in 90% of the cases. Nine studies did not show a statistically significant effect of lymph nodes dissection or sampling on the 5-year OS with a pooled hazard ratio (HR) of 0.94 [95% confidence interval (CI): 0.82, 1.08; I2=26%; 95% prediction interval (PI): 0.70, 1.24]. Regarding DFS, the pooled HR 0.60 (95% CI: 0.44, 0.80; I2=31%; 95% PI: 0.12, 2.09). Conclusions: The addition of lymph node tissue dissection during lung metastasectomy was not associated with a significant benefit in OS and showed a slight tendency towards a better DFS.

Engineered RecA Constructs Reveal the Minimal SOS Activation Complex.

The SOS response is a bacterial DNA damage response pathway that has been heavily implicated in bacteria's ability to evolve resistance to antibiotics. Activation of the SOS response is dependent on the interaction between two bacterial proteins, RecA and LexA. RecA acts as a DNA damage sensor by forming lengthy oligomeric filaments (RecA*) along single-stranded DNA (ssDNA) in an ATP-dependent manner. RecA* can then bind to LexA, the repressor of SOS response genes, triggering LexA degradation and leading to induction of the SOS response. Formation of the RecA*-LexA complex therefore serves as the key "SOS activation signal." Given the challenges associated with studying a complex involving multiple macromolecular interactions, the essential constituents of RecA* that allow LexA cleavage are not well defined. Here, we leverage head-to-tail linked and end-capped RecA constructs as tools to define the minimal RecA* filament that can engage LexA. In contrast to previously postulated models, we found that as few as three linked RecA units are capable of ssDNA binding, LexA binding, and LexA cleavage. We further demonstrate that RecA oligomerization alone is insufficient for LexA cleavage, with an obligate requirement for ATP and ssDNA binding to form a competent SOS activation signal with the linked constructs. Our minimal system for RecA* highlights the limitations of prior models for the SOS activation signal and offers a novel tool that can inform efforts to slow acquired antibiotic resistance by targeting the SOS response.

Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis.

Objective: To determine the safety and efficacy of vedolizumab for the prophylaxis and treatment of gastrointestinal involvement of acute graft-versus-host disease (GVHD) (GI-aGVHD). Methods: Literature search within PubMed, EMBASE, Web of Science, and Cochrane Library for observational studies and clinical trials that evaluated the effect of vedolizumab on GI-aGVHD was done through 17 May 2022. A bivariate and random-effect meta-analysis derived the pooled observational percentages and pooled risk ratios (RRs) from baseline of primary endpoints including overall response, complete response, mortality, and adverse events. Results: There was a total of 122 participants in eight eligible studies, including one study on the prophylactic use of vedolizumab and seven studies on vedolizumab for the treatment of GI-aGVHD. Of seven studies that reported details on baseline grades of GI-aGVHD, a total of 47 patients (47.95%) were of stage 4, 31 patients (31.63%) were of stage 3, 10 patients (10.2%) were of stage 2, and 10 patients (10.2%) were of stage 1. The use of vedolizumab for the treatment of GI-aGVHD yielded a significantly improved objective response rate (ORR) at 14 days (pooled ORR = 60.53%, pooled RR = 14.14, 95% CI: 2.95-67.71), 28 days (pooled ORR = 50%, RR = 7.36, 95% CI = 2.14-25.37), and 12 months (pooled ORR = 76.92%, RR = 13.66, 95% CI = 3.5-53.35) from baseline. Likewise, the use of vedolizumab was followed by a significantly improved complete response (CR) at 12 months (pooled CR = 27.27%, RR = 5.50, 95% CI = 1.01-29.95), yet the CR at 14 days and 28 days did not reach statistical significance. Fifty-seven out of 87 (pooled overall survival, OS = 34.5%) and 46 out of 65 (pooled OS = 29.2%) patients expired at 6 and 12 months after the use of vedolizumab, respectively. Prophylactic use of vedolizumab was not associated with any specific type of reported adverse events, while patients with GI-aGVHD on vedolizumab presented with significantly increased risks of adverse events including infections (RR = 7.55) and impaired metabolism or nutritional complications (RR = 9.00). All analyses were of a low heterogeneity (all I-squares = 0%). Conclusion: Vedolizumab was safe and effective for the prophylaxis and management of early grade GI-aGVHD. More clinical evidence is warranted to validate these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345584, identifier CRD42022345584.

Pictorial review of computed tomography features of diffuse cystic lung disease.

Diffuse cystic lung disease represents a diverse group of uncommon disorders that has been increasingly diagnosed due to the increasing use of computed tomography. It poses a frequent diagnostic challenge to radiologists due to the similar clinical and radiological features these diseases share. This pictorial review includes selected cases from the Hospital Authority New Territories West Cluster (NTWC) in Hong Kong from the past 3 years. It will illustrate the spectrum of diffuse cystic lung diseases, including some rarer entities in our locality, and identify the pertinent differentiating imaging features on CT. A flowchart to summarize these features is provided at the end to aid in diagnosis.

Exploration of inhibitors of the bacterial LexA repressor-protease.

Resistant and tolerant bacterial infections lead to billions in healthcare costs and cause hundreds of thousands of deaths each year. The bulk of current antibiotic research efforts focus on molecules which, although novel, are not immune from acquired resistance and seldomly affect tolerant populations. The bacterial SOS response has been implicated in several resistance and tolerance mechanisms, making it an attractive antibiotic target. Using small molecule inhibitors targeting a key step in the deployment of the SOS response, our approach focused on preventing the deployment of mechanisms such as biofilm formation, horizontal gene transfer, and error-prone DNA repair. Herein we report the synthesis and testing of analogs of a triazole-containing tricyclic inhibitor of LexA proteolysis, the key event in the SOS response. Our results hint that our inhibitor's may function by adopting a ß-hairpin conformation, reminiscent of the native cleavage loop of LexA.