Development of a Risk Score for Long-term Survival and MACCE After Coronary Artery Bypass Grafting Surgery.

OBJECTIVE: To develop risk scoring models predicting long-term survival and major adverse cardiovascular and cerebrovascular events (MACCE) including myocardial infarction and stroke after coronary artery bypass grafting (CABG). METHODS: All-consecutive 4,821 patients undergoing isolated CABG at Lankenau between 01/2005-07/2021 were included. MACCE was defined as all-cause mortality+myocardial infarction (MI)+stroke. Variable selection for both outcomes was obtained using a double selection logit Lasso with adaptive selection. Models performance was internally evaluated by calibration and accuracy using bootstrap cross-validation. Mortality and MACCE were compared among patients split into three groups based on the predicted risk scores for all-cause mortality and MACCE. An external validation of our database was performed with 665 patients from the University of Brescia, Italy. RESULTS: Pre-operative risk predictors were found to be predictors for all-cause mortality and MACCE. In addition, being of African American ethnicity is a significant predictor for MACCE after isolated CABG. The AUC which measures the discrimination of the models were 80.4%, 79.1%, 81.3%, and 79.2% for mortality at 1,2,3, and 5 years follow-up. The AUC for MACCE were 75%, 72.5%, 73,8%, and 72.7% at 1, 2, 3, and 5-years follow-up. For external validation, AUC for all-cause mortality and MACCE at 1, 2, 3, and 5 years was 73.7%, 70.8%, 68.7%, and 72.2% and 72.3%, 68.2%, 65.6%, 69.6%, respectively. CONCLUSIONS: The Advanced (AD) Coronary Risk Score for All-Cause Mortality and MACCE provide good discrimination of long-term mortality and MACCE after isolated CABG. External validation observed a more AUC's above 70%.

Continental-scale migration patterns and origin of Helicoverpa zea (Lepidoptera: Noctuidae) based on a biogeochemical marker.

Insect migrations have ecological and economic impacts, particularly in agriculture. However, there is limited knowledge about the migratory movements of pests at the continental scale, which is an important factor influencing the spread of resistance genes. Understanding the migratory patterns of economic pests, like Helicoverpa zea (Boddie), is essential for improving Integrated Pest Management (IPM) and Insect Resistance Management (IRM) strategies. In this study, we used stable hydrogen isotopic ratios in wing tissue as a biogeochemical marker to examine migratory patterns and estimate the native origins of H. zea individuals collected across a wide latitudinal gradient in North America. Samples collected at higher latitudes (Ontario, Canada and Minnesota, USA) exhibited a greater proportion (60%-96%) of nonlocal individuals, with an increased probability of origin from the southeastern United States. Populations from mid-latitudes (Florida, North Carolina, and South Carolina) showed a blend of local and nonlocal (40%-60%) individuals. Finally, 15% of the southernmost population individuals (Puerto Rico) were classified as migratory, with some having a probability of origin at higher latitudes (>30°). Overall, our results provide evidence of a northward spring/summer migration of H. zea in North America and underscore the significance of the southeastern United States as a hub for genetic flow. In addition, based on stable hydrogen isotopic ratios, there is strong evidence of reverse (southward) migration of H. zea from the continental United States to Puerto Rico. Our study highlights the implications for IPM and IRM programs and the need for management strategies that account for both northward and southward migration patterns.

Post-traumatic stress, depression, and anxiety during the 2021 Myanmar conflict: a nationwide population-based survey.

Background: The UN warns that Myanmar faces the 'triple crises' of mass conflict, uncontrolled COVID-19, and economic collapse. Therefore, we aimed to assess the population mental health burden, healthcare needs, and the associated risk factors in Myanmar. Methods: We established a nationwide random sample and recruited 1038 adults via random digit dialling from July 3-Aug 9, 2021, during the ongoing conflict since Feb 1, 2021, and surge in SARS-CoV-2 infections. Probable post-traumatic stress disorder (PTSD) was assessed using the PTSD Checklist-Civilian Version. Probable depression and anxiety were assessed using the Patient Health Questionnaire-2 and the Generalized Anxiety Disorder-2. We calculated population attributable fractions for probable mental disorders using multivariable logistic regression models. Based on the mental health burden and healthcare-seeking patterns, we projected the need for mental health services. Findings: During the 'triple crises', a third of adults in Myanmar (34.9%, 95% CI 32.0-37.7) reported a probable mental disorder. Prevalence of probable PTSD, depression, and anxiety were 8.1% (6.6-9.7), 14.3% (12.0-16.6), and 22.2% (19.7-24.7), respectively. We estimated that up to 79.9% (43.8-97.9) of probable PTSD was attributable to political stress. This corresponds to 2.1 million (1.1-3.2 million) fewer adults with probable PTSD if political stress was removed from the population. The mental health burden could translate into roughly 5.9 million adults seeking mental health services. Interpretation: The mental health burden in Myanmar is substantial, and population mental health might only be restored when the three crises have ended. An accelerated peace process is critical to protecting Myanmar's population mental health. Funding: This research was supported the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 17606122) and the Michele Tansella Award.

Seed-Mediated Electrodeposition of Silver Nanowires and Nanorods.

Here, we compare the amount and morphology of silver (Ag) nanostructures electrodeposited at varied potentials and times in the presence of cetyltrimethylammonium bromide (CTAB) onto glass/indium tin oxide (glass/ITO) electrodes functionalized with mercaptopropyltrimethoxysilane (MPTMS) and coated or not coated with 4 nm average diameter Au nanoparticle (Au NP) seeds. There is a significantly larger amount of Ag deposited on the seeded electrode surface compared to that in the nonseeded electrode at potentials of -150 to -300 mV (vs Ag/AgCl) since the Au NP seeds act as catalysts for Ag deposition. At more negative overpotentials of -400 to -500 mV, the amount of Ag deposited on both electrodes is similar because the deposition kinetics are fast enough on glass/ITO that the Au seed catalyst does not make as big of a difference. Ag nanorods (NRs) and nanowires (NWs) form on the seeded surfaces, especially at more positive potentials, where deposition primarily occurs on the Au seed catalysts. Deposition of Ag onto the Au seeds appears as a separate peak in the voltammetry. This procedure mimics the seed-mediated growth of Ag NRs observed in solution in the presence of CTAB using ascorbic acid as a reducing agent. The yield, length, and aspect ratio of the Ag NRs/NWs depend on the deposition time and potential with the average length ranging from 300 nm to 3 µm for times of 30-120 min and potentials of -150 to -200 mV. The electrochemical seed-mediated growth of Ag NRs/NWs across electrode gaps could find use for resistive and surface-enhanced Raman-based sensing and molecular electronic applications.

A humanized mouse model for adeno-associated viral gene therapy.

Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg-/-/Rag2-/-/Fah-/-/Aavr-/- (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.

Periprocedural Risk Predictors Affecting Long-Term Prognosis in Patients With Chronic Obstructive Pulmonary Disease Undergoing Coronary Artery Bypass Grafting.

OBJECTIVE: This study sought to identify periprocedural risk predictors that affect long-term prognosis in patients with chronic obstructive pulmonary disease (COPD) undergoing isolated coronary artery bypass grafting (CABG). METHODS: All consecutive 4,871 patients undergoing isolated CABG between May 2005 and June 2021 were included. Patients with and without COPD were compared for baseline demographics and preoperative characteristics. A propensity-matched analysis was used to compare the 2 groups. The primary outcome was long-term incidence of all-cause death. RESULTS: After matching, 767 patients each were included in the COPD and non-COPD groups; mean age was 71.6 and 71.4 years (P = .7), respectively; 29.3% and 32% (P = .2) were women, respectively. Intraoperatively, median (IQR) operating room time was higher in the COPD group than in the non-COPD group (5.9 [5.2-7.0] hours vs 5.8 [5.1-6.7] hours, respectively; P = .01). Postoperatively, intensive care unit stay (P = .03), hospital length of stay (P = .0004), and fresh frozen plasma transfusion units (P = .012) were higher in the COPD group than in the non-COPD group. Thirty-day mortality was not different between groups (1.3% in the COPD group vs 1% in the non-COPD group; P = .4). Median follow-up time was 4.0 years. The rate of all-cause death was higher in the COPD group than in the non-COPD group (138 patients [18.3%] vs 109 patients [14.5%], respectively; P = .042). Periprocedural risk predictors for all-cause death in patients with COPD were atrial fibrillation, diabetes, male sex, dialysis, ejection fraction less than 50%, peripheral vascular disease, and Society of Thoracic Surgeons Predicted Risk of Mortality score greater than 4%. CONCLUSION: Patients with COPD undergoing isolated CABG had a significantly higher incidence of all-cause death than those without COPD. Herein, risk predictors are provided for all-cause death in patients undergoing isolated CABG.

Upfront neck dissection for treatment selection and improvement in quality of life as a novel treatment paradigm for deintensification in HPV+ OPSCC.

PURPOSE: Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II de-escalation trial for patients with HPV+OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve quality of life without compromising survival. METHODS: Patients with T1-3, N0-2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Patients with a single lymph node less than six centimeters, with no extracapsular spread(ECS), and no primary site adverse features underwent transoral surgery (Arm A). Patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone (Arm B). Patients who had ECS in any lymph node were treated with chemoradiation (Arm C). The primary endpoint was quality of life at 1 year compared to a matched historical control. RESULTS: Thirty-four patients were enrolled and underwent selective neck dissection. Based on pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in HNQOL compared to historical controls (-2.6 vs -11.9, p=0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression free survival was 96% (95% CI: 76-99%). CONCLUSION: A neck dissection driven treatment paradigm warrants further research as a de-intensification strategy.

RTF2 controls replication repriming and ribonucleotide excision at the replisome.

DNA replication through a challenging genomic landscape is coordinated by the replisome, which must adjust to local conditions to provide appropriate replication speed and respond to lesions that hinder its progression. We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2), regulate Replication Termination Factor 2 (RTF2) levels at stalled replisomes, allowing fork stabilization and restart. Here, we show that during unperturbed replication, RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme that removes RNA from RNA-DNA heteroduplexes. RTF2, like RNase H2, is essential for mammalian development and maintains normal replication speed. However, persistent RTF2 and RNase H2 at stalled replication forks prevent efficient replication restart, which is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for RTF2-dependent regulation of replication-coupled ribonucleotide removal and reveal the existence of PRIM1-mediated direct replication restart in mammalian cells.

Hybrid robotic-assisted coronary revascularization and transcatheter aortic valve replacement: a single-center experience.

OBJECTIVES: The efficacy of hybrid robotic-assisted coronary artery bypass grafting (CABG) and transcatheter aortic valve replacement (TAVR) for coronary and aortic valve disease is poorly reported. Herein, we report our experience with this hybrid approach. METHODS: Between January 2018 and June 2022, 10 (7 male, 3 female) patients with a mean age of 81 years underwent the hybrid procedure. Coronary revascularization was performed prior to TAVR with robotic-assisted left internal mammary artery-to-left anterior descending (LAD) bypass grafting for left main or proximal LAD lesions with or without multivessel disease with or without hybrid percutaneous coronary intervention (PCI). RESULTS: Five patients had left main disease, and 5 had proximal LAD disease with or without multivessel disease. All patients tolerated the robotic-assisted CABG procedure well; 9 patients were extubated in the operating room and all patients were ambulatory on postoperative day 1. Five patients underwent hybrid PCI for non-LAD lesions. TAVR was subsequently performed at intervals ranging from 3 days to 5 months after CABG. One patient with end-stage renal disease on hemodialysis required hospitalization for heart failure during the interval period. The 1-year mortality rate was 0%, and 3 patients died during late follow-up (24-43 months). CONCLUSIONS: This innovative, less invasive approach demonstrates the potential for early recovery in appropriately selected patients with complex coronary and aortic valve disease with promising mid-term outcomes.

The skin-brain connection and pleasant touch as supportive care for psychocutaneous disorders.

Psychodermatology is a subdiscipline of dermatology at the intersection of dermatology, psychiatry, and psychology. In dermatology clinical practice, patients may present with skin disease that affects their mental health, or skin disorders induced or worsened by psychological/psychiatric problems so there is a need for specialised education of dermatologists, as well as multidisciplinary teams, to achieve better management of these patients. Understanding the interaction between the central nervous system and the skin underlying psychocutaneous disorders could help identify alternative therapies that may improve patient well-being. The concept of pleasurable touch has received increasing attention following the discovery of C-tactile (CT) fibres. While afferent C-fibre stimulation is usually associated with pain, temperature, or itch, CT-fibres are stimulated optimally by a stimulus not in the nociceptor range but by a gentle, low-force stroking. As this affective touch may counteract unpleasurable sensations, such as pain and itch, and elicit positive feelings, the potential benefits of gentle touch and massage are interesting for dermatological, especially psychocutaneous, disorders. Here we provide an overview of the skin-brain connection to help understand the benefits of touch and massage, as illustrated with studies on atopic dermatitis and burns, as an adjunct to dermatological treatment for improving patient well-being and optimising treatment outcomes.

SUMO modifies GßL and mediates mTOR signaling.

The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications; however, underlying mechanisms remain unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GßL (G protein ß-subunit-like protein, also known as mLST8), is modified by SUMO1, 2, and 3 isoforms. Using mutagenesis and mass spectrometry, we identified that GßL is SUMOylated at lysine sites K86, K215, K245, K261, and K305. We found that SUMO depletion reduces mTOR-Raptor (regulatory protein associated with mTOR) and mTOR-Rictor (rapamycin-insensitive companion of mTOR) complex formation and diminishes nutrient-induced mTOR signaling. Reconstitution with WT GßL but not SUMOylation-defective KR mutant GßL promotes mTOR signaling in GßL-depleted cells. Taken together, we report for the very first time that SUMO modifies GßL, influences the assembly of mTOR protein complexes, and regulates mTOR activity.

Evidence for molecular subtyping in pancreatic ductal adenocarcinoma: a systematic review.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) patients exhibit varied responses to multimodal therapy. RNA gene sequencing has unravelled distinct tumour biology subtypes, forming the focus of this review exploring its impact on survival outcomes. METHODS: A systematic search across PubMed, Medline, Embase, and CINAHL databases targeted studies assessing long-term overall and disease-free survival in PDAC patients with molecular subtyping. RESULTS: Fifteen studies including 2731 patients were identified. Molecular subtyping was performed by RNA sequencing and Immunohistochemistry in 14 studies and by Mass Spectrometry in 1 study. Two main tumour subtypes were identified (classical and basal-like or squamous) with basal like associated with poorer outcomes. Further subtypes were identified in individual studies. Superior survival was seen with classical subtype in all other analyses that compared the classical and basal subtypes. High risk stromal subtypes were identified on further analysis of the stroma and were associated with a worse survival independent of the tumour subtype. CONCLUSION: Molecular subtyping of PDAC specimens can identify patients with high-risk tumour biology and poor survival outcomes. Routine subtyping is limited by the cost of RNA sequencing and the volume of raw data generated which has made its translation into routine clinical practice difficult.

Computational analysis of bio-convective eyring-powell nanofluid flow with magneto-hydrodynamic effects over an isothermal cone surface with convective boundary condition.

Non-Newtonian fluids are essential in situations where heat and mass transfer are involved. Heat and mass transfer processes increase efficiency when nanoparticles (0.01≤φ≤0.03) are added to these fluids. The present study implements a computational approach to investigate the behavior of non-Newtonian nanofluids on the surface of an upright cone. Viscous dissipation (0.3≤Ec≤0.9) and magnetohydrodynamics (MHD) (1≤M≤3) are also taken into account. Furthermore, we explore how microorganisms impact the fluid's mass and heat transfer. The physical model's governing equations are transformed into ordinary differential equations (ODEs) using a similarity transformation to make the analysis easier. The ODEs are solved numerically using the Bvp4c solver in MATLAB. The momentum, thermal, concentration, and microbe diffusion profiles are graphically represented in the current research. MHD (1≤M≤3) effects improve the diffusion of microbes, resulting in increased heat and mass transfer rates of 18 % and 19 %, respectively, based on our results. Furthermore, a comparison of our findings with existing literature demonstrates promising agreement.

Midterm Clinical Outcomes of Robotic-Assisted Reverse Hybrid Coronary Revascularization: A Single-Center Experience.

Outcomes of robotic-assisted reverse hybrid coronary revascularization (HCR) remain hindered. We aimed to analyze midterm clinical outcomes of robotic-assisted reverse HCR. All consecutive 285 patients who underwent reverse robotic-assisted HCR between September 2005 and July 2021 were included. Reverse HCR comprises percutaneous coronary intervention with stent implantation in non-left anterior descending (LAD) coronary arteries was performed within 30 days before robotic-assisted left internal thoracic artery (LITA) harvesting and LITA-to-LAD manual anastomosis through a 4-cm left minithoracotomy. Dual antiplatelet therapy was not interrupted in any patient. Preoperatively, mean age was 70.2 years (±11.2). Before surgery, 168 patients received 1 stent, 112 patients 2 stents, and 5 patients 3 stents. Intraoperatively, mean operating room time was 5.9 hours (±1); no case was converted to full sternotomy, whereas 9 patients (3.1%) received intraoperative blood product transfusions. Postoperatively, a small incidence of stroke, 1 (0.3%), reoperation for bleeding, 7 (2.4%), blood product transfusions, 48 (16.8%), and hospital stay (4.8 days) was observed. At 30-day follow-up, 1 patient (0.3%) underwent percutaneous coronary intervention with stent on a surgical LITA-LAD anastomosis owing to graft failure. Mean follow-up was 4.2 years. Reported midterm outcomes included all-cause death in 31 patients (10.9%), major adverse cardiovascular and cerebrovascular events in 102 of 285 (35.9%), nonfatal stroke in 2 of 285 (0.7%), myocardial infarction in 17 of 285 (5.9%), and repeat intervention in 50 of 285 patients (17.5%). This single-center study reports effective and safe clinical outcomes at midterm follow-up of reverse HCR procedures for treating multivessel coronary artery disease.

Risk predictors of race disparity in patients undergoing coronary artery bypass grafting: a propensity-matched analysis.

OBJECTIVES: The aim of this study was to compare long-term prognosis after isolated coronary artery bypass grafting between white and black patients and to investigate risk factors for poorer outcomes among the latest. METHODS: All consecutive 4766 black and white patients undergoing isolated coronary artery bypass grafting between May 2005 and June 2021 at our institution were included. Primary outcomes were long-term incidence of all-cause death and major adverse cardiovascular and cerebrovascular events in black versus white patients. A propensity-matched analysis was used 2 compare groups. RESULTS: After matching, 459 patients were included in each black and white groups while groups were correctly balanced. The mean age was 70.4 vs 70.6 years old (P = 0.7) in black and white groups, respectively. Intraoperatively, mean operating room time and blood product transfusion, were higher in the black group while incidence of extubation in the operating room was higher in the white one. Postoperatively, hospital length of stay was higher in the black cohort. Thirty-day all-cause mortality was not different among groups. The median follow-up time was 4 years. Primary outcome of all-cause death was higher in the black versus the white, respectively. Major adverse cardiovascular and cerebrovascular events incidence was twice higher in the black compared to the white cohort (7.6% vs 3.7%, P = 0.013). Risk predictors for all-cause death and major adverse cardiovascular and cerebrovascular events in blacks were creatinine level, chronic obstructive pulmonary disease, ejection fraction <50% and preoperative atrial fibrillation. CONCLUSIONS: Racial disparities persist in a high-volume centre. Despite no preoperative difference, black minority has a higher incidence of major adverse cardiovascular and cerebrovascular events.

Validation of oxygen saturations measured in the community by emergency medical services as a marker of clinical deterioration in patients with confirmed COVID-19: a retrospective cohort study.

OBJECTIVES: To evaluate oxygen saturation and vital signs measured in the community by emergency medical services (EMS) as clinical markers of COVID-19-positive patient deterioration. DESIGN: A retrospective data analysis. SETTING: Patients were conveyed by EMS to two hospitals in Hampshire, UK, between 1 March 2020 and 31 July 2020. PARTICIPANTS: A total of 1080 patients aged ≥18 years with a COVID-19 diagnosis were conveyed by EMS to the hospital. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was admission to the intensive care unit (ICU) within 30 days of conveyance, with a secondary outcome representing mortality within 30 days of conveyance. Receiver operating characteristic (ROC) analysis was performed to evaluate, in a retrospective fashion, the efficacy of different variables in predicting patient outcomes. RESULTS: Vital signs measured by EMS staff at the first point of contact in the community correlated with patient 30-day ICU admission and mortality. Oxygen saturation was comparably predictive of 30-day ICU admission (area under ROC (AUROC) 0.753; 95% CI 0.668 to 0.826) to the National Early Warning Score 2 (AUROC 0.731; 95% CI 0.655 to 0.800), followed by temperature (AUROC 0.720; 95% CI 0.640 to 0.793) and respiration rate (AUROC 0.672; 95% CI 0.586 to 0.756). CONCLUSIONS: Initial oxygen saturation measurements (on air) for confirmed COVID-19 patients conveyed by EMS correlated with short-term patient outcomes, demonstrating an AUROC of 0.753 (95% CI 0.668 to 0.826) in predicting 30-day ICU admission. We found that the threshold of 93% oxygen saturation is prognostic of adverse events and of value for clinician decision-making with sensitivity (74.2% CI 0.642 to 0.840) and specificity (70.6% CI 0.678 to 0.734).

FANCA c.3624C>T (p.Ser1208=) is a hypomorphic splice variant associated with delayed onset of Fanconi anemia.

ABSTRACT: Fanconi anemia (FA) is a hereditary, DNA repair deficiency disorder caused by pathogenic variants in any 1 of 22 known genes (FANCA-FANCW). Variants in FANCA account for nearly two-thirds of all patients with FA. Clinical presentation of FA can be heterogeneous and include congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. Here, we describe a relatively mild disease manifestation among 6 individuals diagnosed with FA, each compound heterozygous for 1 established pathogenic FANCA variant and 1 FANCA exon 36 variant, c.3624C>T. These individuals had delayed onset of hematological abnormalities, increased survival, reduced incidence of cancer, and improved fertility. Although predicted to encode a synonymous change (p.Ser1208=), the c.3624C>T variant causes a splicing error resulting in a FANCA transcript missing the last 4 base pairs of exon 36. Deep sequencing and quantitative reverse transcription polymerase chain reaction analysis revealed that 6% to 10% of the FANCA transcripts included the canonical splice product, which generated wild-type FANCA protein. Consistently, functional analysis of cell lines from the studied individuals revealed presence of residual FANCD2 ubiquitination and FANCD2 foci formation, better cell survival, and decreased late S/G2 accumulation in response to DNA interstrand cross-linking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T variant is a hypomorphic allele, which contributes to delayed manifestation of FA disease phenotypes in individuals with at least 1 c.3624C>T allele.

Long-term clinical outcomes of robotic-assisted surgical coronary artery revascularisation.

BACKGROUND: Patients who are not candidates for traditional coronary artery bypass grafting (CABG) and amenable only for percutaneous coronary intervention (PCI) with stents can receive the "gold standard" left internal thoracic artery (LITA) to left anterior descending artery (LAD) anastomosis through robotic-assisted CABG and PCI to non-LAD coronary targets. AIMS: We aimed to analyse clinical outcomes of robotic-assisted CABG. METHODS: A total of 2,280 consecutive patients who had undergone robotic-assisted CABG between May 2005 and June 2021 were included in our study. Robotic-assisted LITA harvest was followed by LITA-LAD manual anastomosis through a 4 cm left thoracotomy. Hybrid coronary intervention (HCR) consists of stent implantation in a non-LAD coronary artery performed within 7 days after robotic-assisted LITA-LAD. We performed a propensity-adjusted analysis comparison after dividing all robotic-assisted CABG patients into three time periods: 2005-2010, 615 patients; 2011-2016, 904 patients; and 2017-2021, 761 patients. RESULTS: The mean age increased from 64.5 years in the first time period to 65.8 years in the second time period to 68.1 years in the third (p<0.0001). Operative time was progressively reduced in the three periods (6.4; 6.2; 5.5 hours; p<0.001). The incidence of conversion to sternotomy remained similar for each period (1.8%; 1.7%; 1.5%; p=0.53). Thirty-day mortality in the three periods included 9 (1.4%), 9 (1.0%), and 7 (0.9%) patients, respectively (p=0.91), while 8 (0.3%) patients had PCI with stents in the entire group. The mean follow-up for the entire population was 4.2 years. At follow-up, the rates of all-cause death, major adverse cardiac and cerebrovascular events, non-fatal stroke, and repeat revascularisation with stents were significantly decreased from the first to the last period (pË0.0001). CONCLUSIONS: Robotic-assisted CABG and HCR provide good long-term outcomes in patients who are not candidates for conventional CABG.

Real-world practice patterns and outcomes for RAI-refractory differentiated thyroid cancer.

Background: The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population). Methods: In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated. Results: Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively. Conclusions: Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance. Registration: NCT02303444.