Trends in Operative Case Logs of Chief Residents in Surgery by Sex and Race: A 5 - Year National Study.

OBJECTIVES: A recent study of 21 institutions noted significant differences between number of cases reported during general surgery residency by trainees who are Underrepresented in Medicine (URiM) versus trainees who are not Underrepresented in Medicine (non-URiM). This study also identified differences between female residents and male residents. We partnered with the Accreditation Council for Graduate Medical Education to examine case logs reported from all accredited general surgery programs in the United States. This is the first time this data has been examined nationally. METHODS: We examined total case logs submitted by graduating residents between 2017 and 2022. Group differences in mean reported case logs were examined using paired t- tests for female versus male and URiM versus non- URiM overall case numbers. RESULTS: A total of 6,458 residents submitted case logs from 319 accredited programs. Eight-hundred and fifty-four (13%) were URiM and 5,604 (87%) were non-URiM. Over the 5-year study period, URM residents submitted 1096.95 (SD +/- 160.57) major cases versus 1115.96 (+/- 160.53) for non-URiM residents (difference =19 cases, P=0.001). Case logs were submitted by 3,833 (60.1%) male residents and 2,625 (39.9%) female residents over the five-year study period. Male residents reported 1128.56 (SD +/- 168.32) cases versus 1091.38 (+/- 145.98) cases reported by females (difference=37.18, P<0.001). When looking at Surgeon Chief and Teaching Assistant cases, there was no significant difference noted between cases submitted by URiM versus non- URiM residents. However, male residents reported significantly more in both categories than their female peers (P<0.001). CONCLUSIONS: Overall, URiM residents submitted fewer cases in the five- year study period than their non-URiM peers. The gap in submitted cases between male and female residents was more pronounced, with male residents submitting significantly more cases than their female counterparts. This finding was consistent and statistically significant throughout the entire study period, in most case categories, and without narrowing of difference over time. A difference of 30-40 cases can amount to 1-3 months of surgical training and is a concerning national trend deserving the attention of every training program and our governing institutions.

Clinical outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision in locally advanced rectal cancer with mesorectal fascia involvement.

PURPOSE: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. MATERIALS AND METHODS: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of ≤50.4 Gy were defined as the non-boost group, while ≥54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. RESULTS: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). CONCLUSION: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed.

Long-term clinical outcomes of image-guided percutaneous coronary intervention in acute myocardial infarction from the Korea Acute Myocardial Infarction Registry.

Imaging modalities for percutaneous coronary intervention (PCI), such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), have increased in the current PCI era. However, their clinical benefits in acute myocardial infarction (AMI) have not been fully elucidated. This study investigated the long-term outcomes of image-guided PCI in patients with AMI using data from the Korean Acute Myocardial Infarction Registry. A total of 9,271 patients with AMI, who underwent PCI with second-generation drug-eluting stents between November 2011 and December 2015, were retrospectively examined, and target lesion failure (TLF) at 3 years (defined as the composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) was evaluated. From the registry, 2,134 patients (23.0%) underwent image-guided PCI (IVUS-guided: n = 1,919 [20.6%]; OCT-guided: n = 215 patients [2.3%]). Based on propensity score matching, image-guided PCI was associated with a significant reduction in TLF (hazard ratio: 0.76; 95% confidence interval: 0.59-0.98, p = 0.035). In addition, the TLF incidence in the OCT-guided PCI group was comparable to that in the IVUS-guided PCI group (5.3% vs 4.7%, p = 0.903). Image-guided PCI, including IVUS and OCT, is associated with favorable clinical outcomes in patients with AMI at 3 years post-intervention. Additionally, OCT-guided PCI is not inferior to IVUS-guided PCI in patients with AMI.

H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2.

RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.

Transporter Genes and statin-induced Hepatotoxicity.

PURPOSE: Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms. METHODS: This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined. RESULTS: Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55-0.69), and it was increased to 0.71 in Model II (95% CI: 0.64-0.77). CONCLUSION: This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy.

Factors associated with clinical nurses' preconception health behavior in Korea: a cross-sectional survey.

PURPOSE: Nurses have been reported to be at an increased risk for miscarriage and preterm labor. However, there is limited knowledge regarding nurses' preconception health behaviors. Therefore, this study aimed to identify factors influencing these behaviors. METHODS: One hundred sixty nurses, who were planning their first pregnancy within the upcoming year, participated in an online survey from August 11 to October 31, 2021. Data on preconception health behavior, perceived health status, pregnancy anxiety, nursing practice environment, and social support were analyzed using the t-test, Pearson correlation coefficients, and multiple regression analysis. RESULTS: Age (р=.024), educational level (р=.010), marital status (р=.003), work experience (р=.003), satisfaction with the work department (р<.001), smoking status (р=. 039), and previous health problems related to pregnancy outcomes (р=.004) were significantly associated with nurses' preconception health behaviors. Furthermore, perceived health status (р<.001), pregnancy anxiety (р=.011), nursing practice environment (р=.003), and social support (р<.001) showed significant correlations with preconception health behaviors. Social support (ß=. 28, р=.001), satisfaction with the work department (ß=.23, р=.032), marital status (ß=.22, р=.002), and perceived health status (ß=.23, р=.002) were confirmed as factors associated with preconception health behaviors. These factors explained 40.9% of the variance in preconception health behaviors (F=6.64, р<.001). CONCLUSION: Clinical nurses' preconception health behaviors were influenced by social support, perceived health status, satisfaction with the work department, and marital status. Interventions to improve clinical nurses' preconception health behaviors should target social support and perceived health status. A preconception health behavior education program considering clinical nurses' marital status and satisfaction with the workplace can also be implemented.

Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Expanded Access to Video-Based Laparoscopic Skills Assessments: Ease, Reliability, and Accuracy.

OBJECTIVE: Video-based performance assessments provide essential feedback to surgical residents, but in-person and remote video-based assessment by trained proctors incurs significant cost. We aimed to determine the reliability, accuracy, and difficulty of untrained attending staff surgeon raters completing video-based assessments of a basic laparoscopic skill. Secondarily, we aimed to compare reliability and accuracy between 2 different types of assessment tools. DESIGN: An anonymous survey was distributed electronically to surgical attendings via a national organizational listserv. Survey items included demographics, rating of video-based assessment experience (1 = have never completed video-based assessments, 5 = often complete video-based assessments), and rating of favorability toward video-based and in-person assessments (0 = not favorable, 100 = favorable). Participants watched 2 laparoscopic peg transfer performances, then rated each performance using an Objective Structured Assessment of Technical Skill (OSATS) form and the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS). Participants then rated assessment completion ease (1 = Very Easy, 5 = Very Difficult). SETTING: National survey of practicing surgeons. PARTICIPANTS: Sixty-one surgery attendings with experience in laparoscopic surgery from 10 institutions participated as untrained raters. Six experienced laparoscopic skills proctors participated as expert raters. RESULTS: Inter-rater reliability was substantial for both OSATS (k = 0.75) and MISTELS (k = 0.85). MISTELS accuracy was significantly higher than that of OSATS (κ: MISTELS = 0.18, 95%CI = [0.06,0.29]; OSATS = 0.02, 95%CI = [-0.01,0.04]). While participants were inexperienced with completing video-based assessments (median = 1/5), they perceived video-based assessments favorably (mean = 73.4) and felt assessment completion was "Easy" on average. CONCLUSIONS: We demonstrate that faculty raters untrained in simulation-based assessments can successfully complete video-based assessments of basic laparoscopic skills with substantial inter-rater reliability without marked difficulty. These findings suggest an opportunity to increase access to feedback for trainees using video-based assessment of fundamental skills in laparoscopic surgery.

Development of a Risk Score to Predict Short-term Smoking Relapse Following an Inpatient Smoking Cessation Intervention.

This study aimed to investigate the factors affecting smoking relapse and to develop predictive models among Korean national 5-day smoking cessation program participants. The subjects were 518 smokers and follow-up was continued for 6 months after discharge. A predictive logistic model and risk score were developed from the multivariate logistic models and compared using the area under the receiver operating characteristic curve (area under the curve [AUC]). The smoking relapse rate within 6 months after program participation was 38.4%. The AUCs of the logistic regression model and risk score model were similar (odds ratio [OR] = 0.69; 0.69, respectively) in the development data set, and those of the risk score model were similar between the development and validation data sets (OR = 0.68). The risk score used by the six risk factors could predict smoking relapse among participants who attended a 5-day inpatient smoking cessation program.

Accreditation Council for Graduate Medical Education Milestone Training Ratings and Surgeons' Early Outcomes.

Importance: National data on the development of competence during training have been reported using the Accreditation Council for Graduate Medical Education (ACGME) Milestones system. It is now possible to consider longitudinal analyses that link Milestone ratings during training to patient outcomes data of recent graduates. Objective: To evaluate the association of in-training ACGME Milestone ratings in a surgical specialty with subsequent complication rates following a commonly performed operation, endovascular aortic aneurysm repair (EVAR). Design, Setting, and Participants: This study of patient outcomes followed EVAR in the Vascular Quality Initiative (VQI) registry (4213 admissions from 208 hospitals treated by 327 surgeons). All surgeons included in this study graduated from ACGME-accredited training programs from 2015 through 2019 and had Milestone ratings 6 months prior to graduation. Data were analyzed from December 1, 2021, through September 15, 2023. Because Milestone ratings can vary with program, they were corrected for program effect using a deviation score from the program mean. Exposure: Milestone ratings assigned to individual trainees 6 months prior to graduation, based on judgments of surgical competence. Main Outcomes and Measures: Surgical complications following EVAR for patients treated by recent graduates during the index hospitalization, obtained using the nationwide Society for Vascular Surgery Patient Safety Organization's VQI registry, which includes 929 participating centers in 49 US states. Results: The study included outcomes for 4213 patients (mean [SD] age, 73.25 [8.74] years; 3379 male participants [80.2%]). Postoperative complications included 9.5% major (400 of 4213 cases) and 30.2% minor (1274 of 4213 cases) complications. After adjusting for patient risk factors and site of training, a significant association was identified between individual Milestone ratings of surgical trainees and major complications in early surgical practice in programs with lower mean Milestone ratings (odds ratio, 0.50; 95% CI; 0.27-0.95). Conclusions and Relevance: In this study, Milestone assessments of surgical trainees were associated with subsequent clinical outcomes in their early career. Although these findings represent one surgical specialty, they suggest Milestone ratings can be used in any specialty to identify trainees at risk for future adverse patient outcomes when applying the same theory and methodology. Milestones data should inform data-driven educational interventions and trainee remediation to optimize future patient outcomes.

Longitudinal long term follow up investigation on the carcinogenic impact of polyhexamethylene guanidine phosphate in rat models.

Polyhexamethylene guanidine phosphate (PHMG-p) is a major component in humidifier disinfectants, which cause life-threatening lung injuries. However, to our knowledge, no published studies have investigated associations between PHMG-p dose and lung damage severity with long-term follow-up. Therefore, we evaluated longitudinal dose-dependent changes in lung injuries using repeated chest computed tomography (CT). Rats were exposed to low (0.2 mg/kg, n = 10), intermediate (1.0 mg/kg, n = 10), and high (5.0 mg/kg, n = 10) doses of PHMG-p. All rats underwent repeated CT scans after 10 and 40 weeks following the first exposure. All CT images were quantitatively analyzed using commercial software. Inflammation/fibrosis and tumor counts underwent histopathological evaluation. In both radiological and histopathologic results, the lung damage severity increased as the PHMG-p dose increased. Moreover, the number, size, and malignancy of the lung tumors increased as the dose increased. Bronchiolar-alveolar hyperplasia developed in all groups. During follow-up, there was intergroup variation in bronchiolar-alveolar hyperplasia progression, although bronchiolar-alveolar adenomas or carcinomas usually increase in size over time. Thirty-three carcinomas were detected in the high-dose group in two rats. Overall, lung damage from PHMG-p and the number and malignancy of lung tumors were shown to be dose-dependent in a rat model using repeated chest CT scans during a long-term follow-up.

Sequence Alignment-Based Prediction of Myosin 7A: Structural Implications and Protein Interactions.

Myosin, a superfamily of motor proteins, obtain the energy they require for movement from ATP hydrolysis to perform various functions by binding to actin filaments. Extensive studies have clarified the diverse functions performed by the different isoforms of myosin. However, the unavailability of resolved structures has made it difficult to understand the way in which their mechanochemical cycle and structural diversity give rise to distinct functional properties. With this study, we seek to further our understanding of the structural organization of the myosin 7A motor domain by modeling the tertiary structure of myosin 7A based on its primary sequence. Multiple sequence alignment and a comparison of the models of different myosin isoforms and myosin 7A not only enabled us to identify highly conserved nucleotide binding sites but also to predict actin binding sites. In addition, the actomyosin-7A complex was predicted from the protein-protein interaction model, from which the core interface sites of actin and the myosin 7A motor domain were defined. Finally, sequence alignment and the comparison of models were used to suggest the possibility of a pliant region existing between the converter domain and lever arm of myosin 7A. The results of this study provide insights into the structure of myosin 7A that could serve as a framework for higher resolution studies in future.

National Profile of the ACGME Milestones 1.0 and 2.0 within General Surgery: A Seven-Year National Study from 2014 to 2021.

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) introduced General Surgery Milestones 1.0 in 2014 and Milestones 2.0 in 2020 as steps toward competency-based training. Analysis will inform residency programs on curriculum development, assessment, feedback, and faculty development. This study describes the distributions and trends for Milestones 1.0 and 2.0 ratings and proportion of residents not achieving the level 4.0 graduation target. METHODS: A deidentified dataset of milestone ratings for all ACGME-accredited General Surgery residency programs in the United States was used. Medians and interquartile ranges (IQR) were reported for milestone ratings at each PGY level. Percentages of PGY-5s receiving final year ratings of less than 4.0 were calculated. Wilcoxon rank sum tests were used to compare 1.0 and 2.0 median ratings. Kruskal-Wallis and Bonferroni post-hoc tests were used to compare median ratings across time periods and PGY levels. Chi-squared tests were used to compare the proportion of level 4.0 nonachievement under both systems. RESULTS: Milestones 1.0 data consisted of 13,866 residents and Milestones 2.0 data consisted of 7,633 residents. For 1.0 and 2.0, all competency domain median ratings were higher for subsequent years of training. Milestones 2.0 had significantly higher median ratings at all PGY levels for all competency domains except Medical Knowledge. Percentages of PGY-5 residents not achieving the graduation target in Milestones 1.0 ranged from 27% to 42% and in 2.0 from 5% to 13%. For Milestones 1.0, all subcompetencies showed an increased number of residents achieving the graduation target from 2014 to 2019. CONCLUSIONS: This study of General Surgery Milestones 1.0 and 2.0 data uncovered significant increases in average ratings and significantly fewer residents not achieving the graduation target under the 2.0 system. We hypothesize that these findings may be related more to rating bias given the change in rating scales, rather than a true increase in resident ability.

Transcriptional corepressor activity of CtBP1 is regulated by ISG15 modification.

C-terminal binding protein 1 (CtBP1) is a critical transcriptional corepressor of many tumor suppressor genes and plays diverse roles in the progression of cancers. The transcriptional repression function of CtBP1 is mediated by recruiting histone-modifying enzymes, such as histone deacetylases and histone methyltransferases, to target genes by binding with DNA-interacting factors. Several post-translational modifications of CtBP1 have been identified, including ubiquitination, phosphorylation, and SUMOylation. This paper reports that CtBP1 is conjugated by ISG15. Endogenous CtBP1 was modified by ISG15 after interferon-α treatment in HeLa cells. The ISGylation process of CtBP1 was regulated by deISGylation enzyme USP18 and ISG15 E3 ligase EFP. Interestingly, CtBP1 ISGylation affected the binding affinity between CtBP1 and some components of CtBP1-associated transcriptional complexes. HDAC1 and LSD1 bound more efficiently to ISG15-conjugated CtBP1 than non-conjugated CtBP1. On the other hand, binding between CtBP1 and HDAC4 was unaffected by ISG15 modification. Furthermore, ISG15 modification enhanced the transcriptional repression activity of CtBP1 on several target genes related to EMT and apoptosis. These findings suggest that the ISG15 modification of CtBP1 modulates the function and activity of CtBP1 and that CtBP1 ISGylation may provide a new insight for CtBP1-mediated cancers.

Is Robotic Surgery Beneficial for Rectal Cancer Patients with Unfavorable Characteristic After Neoadjuvant Chemoradiotherapy?

BACKGROUND: The objective of this study was to compare long-term oncologic outcomes of robot and laparoscopic surgeries for patients with advanced rectal cancer who underwent neoadjuvant chemoradiotherapy (nCRT) followed by radical resection. METHODS: This study analyzed 3240 rectal cancer patients who underwent radical surgery from 2008 to 2019. Among them, 1204 patients who received nCRT (robotic, n = 316; laparoscopic, n = 888) were analyzed. The oncological outcome according to the number of unfavorable factors (male, body mass index ≥ 25, receiving CCRT) present in patients also was analyzed. We used 1:1 propensity score matching (PSM) to adjust for potential baseline confounders between groups. RESULTS: After PSM, two groups showed similar demographics and pathological results. After PSM analysis, the robotic group showed higher 5-year disease-free survival (DFS) and local recurrence-free survival rates than the laparoscopic group, whereas 5-year overall survival and distant recurrence-free survival rates were similar between the two groups. In addition, by comparing survival rates for each yp stage, it was found 5-year DFS and local recurrence-free survival of the robotic group in yp stage III were significantly higher than those of the laparoscopic group. Five-year DFS was conducted according to the number of unfavorable factors (male, body mass index ≥ 25 kg/m2, and undergoing nCRT) as a subgroup analysis. In patients with all three unfavorable factors, the robotic group showed significantly higher DFS than the laparoscopic group. CONCLUSIONS: Robotic approach for rectal cancer after nCRT, especially for patients with yp stage III and unfavorable factors, have the advantage of improving oncologic outcomes even for surgeons specializing in colorectal cancer.

The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.

The Associations between Intakes of One-Carbon Metabolism-Related Vitamins and Breast Density among Young Women.

BACKGROUND: Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism-related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer. METHODS: Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years. RESULTS: Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04). CONCLUSIONS: Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings. IMPACT: Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.

LAMMER Kinase Governs the Expression and Cellular Localization of Gas2, a Key Regulator of Flocculation in Schizosaccharomyces pombe.

It was reported that LAMMER kinase in Schizosaccharomyces pombe plays an important role in cation-dependent and galactose-specific flocculation. Analogous to other flocculating yeasts, when cell wall extracts of the Δlkh1 strain were treated to the wild-type strain, it displayed flocculation. Gas2, a 1,3-ß-glucanosyl transferase, was isolated from the EDTA-extracted cell-surface proteins in the Δlkh1 strain. While disruption of the gas2+ gene was not lethal and reduced the flocculation activity of the ∆lkh1 strain, the expression of a secreted form of Gas2, in which the GPI anchor addition sequences had been removed, conferred the ability to flocculate upon the WT strain. The Gas2-mediated flocculation was strongly inhibited by galactose but not by glucose. Immunostaining analysis showed that the cell surface localization of Gas2 was crucial for the flocculation of fission yeast. In addition, we identified the regulation of mbx2+ expression by Lkh1 using RT-qPCR. Taken together, we found that Lkh1 induces asexual flocculation by regulating not only the localization of Gas2 but also the transcription of gas2+ through Mbx2.

The Association of ACGME Milestones With Performance on American Board of Surgery Assessments: A National Investigation of Surgical Trainees.

OBJECTIVE: To determine the relationship between, and predictive utility of, milestone ratings and subsequent American Board of Surgery (ABS) vascular surgery in-training examination (VSITE), vascular qualifying examination (VQE), and vascular certifying examination (VCE) performance in a national cohort of vascular surgery trainees. BACKGROUND: Specialty board certification is an important indicator of physician competence. However, predicting future board certification examination performance during training continues to be challenging. METHODS: This is a national longitudinal cohort study examining relational and predictive associations between Accreditation Council for Graduate Medical Education (ACGME) Milestone ratings and performance on VSITE, VQE, and VCE for all vascular surgery trainees from 2015 to 2021. Predictive associations between milestone ratings and VSITE were conducted using cross-classified random-effects regression. Cross-classified random-effects logistic regression was used to identify predictive associations between milestone ratings and VQE and VCE. RESULTS: Milestone ratings were obtained for all residents and fellows(n=1,118) from 164 programs during the study period (from July 2015 to June 2021), including 145,959 total trainee assessments. Medical knowledge (MK) and patient care (PC) milestone ratings were strongly predictive of VSITE performance across all postgraduate years (PGYs) of training, with MK ratings demonstrating a slightly stronger predictive association overall (MK coefficient 17.26 to 35.76, ß = 0.15 to 0.23). All core competency ratings were predictive of VSITE performance in PGYs 4 and 5. PGY 5 MK was highly predictive of VQE performance [OR 4.73, (95% CI, 3.87-5.78), P <0.001]. PC subcompetencies were also highly predictive of VQE performance in the final year of training [OR 4.14, (95% CI, 3.17-5.41), P <0.001]. All other competencies were also significantly predictive of first-attempt VQE pass with ORs of 1.53 and higher. PGY 4 ICS ratings [OR 4.0, (95% CI, 3.06-5.21), P <0.001] emerged as the strongest predictor of VCE first-attempt pass. Again, all subcompetency ratings remained significant predictors of first-attempt pass on CE with ORs of 1.48 and higher. CONCLUSIONS: ACGME Milestone ratings are highly predictive of future VSITE performance, and first-attempt pass achievement on VQE and VCE in a national cohort of surgical trainees.