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The Lancet. Digital Health Jul 2024Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used...
A prognostic model for use before elective surgery to estimate the risk of postoperative pulmonary complications (GSU-Pulmonary Score): a development and validation study in three international cohorts.
BACKGROUND
Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used before elective surgery to estimate the risk of postoperative pulmonary complications and to support resource allocation and prioritisation during pandemic recovery.
METHODS
Data from an international, prospective cohort study were used to develop a novel prognostic risk model for pulmonary complications after elective surgery in adult patients (aged ≥18 years) across all operation and disease types. The primary outcome measure was postoperative pulmonary complications at 30 days after surgery, which was a composite of pneumonia, acute respiratory distress syndrome, and unexpected mechanical ventilation. Model development with candidate predictor variables was done in the GlobalSurg-CovidSurg Week dataset (global; October, 2020). Two structured machine learning techniques were explored (XGBoost and the least absolute shrinkage and selection operator [LASSO]), and the model with the best performance (GSU-Pulmonary Score) underwent internal validation using bootstrap resampling. The discrimination and calibration of the score were externally validated in two further prospective cohorts: CovidSurg-Cancer (worldwide; February to August, 2020, during the COVID-19 pandemic) and RECON (UK and Australasia; January to October, 2019, before the COVID-19 pandemic). The model was deployed as an online web application. The GlobalSurg-CovidSurg Week and CovidSurg-Cancer studies were registered with ClinicalTrials.gov, NCT04509986 and NCT04384926.
FINDINGS
Prognostic models were developed from 13 candidate predictor variables in data from 86 231 patients (1158 hospitals in 114 countries). External validation included 30 492 patients from CovidSurg-Cancer (726 hospitals in 75 countries) and 6789 from RECON (150 hospitals in three countries). The overall rates of pulmonary complications were 2·0% in derivation data, and 3·9% (CovidSurg-Cancer) and 4·7% (RECON) in the validation datasets. Penalised regression using LASSO had similar discrimination to XGBoost (area under the receiver operating curve [AUROC] 0·786, 95% CI 0·774-0·798 vs 0·785, 0·772-0·797), was more explainable, and required fewer covariables. The final GSU-Pulmonary Score included ten predictor variables and showed good discrimination and calibration upon internal validation (AUROC 0·773, 95% CI 0·751-0·795; Brier score 0·020, calibration in the large [CITL] 0·034, slope 0·954). The model performance was acceptable on external validation in CovidSurg-Cancer (AUROC 0·746, 95% CI 0·733-0·760; Brier score 0·036, CITL 0·109, slope 1·056), but with some miscalibration in RECON data (AUROC 0·716, 95% CI 0·689-0·744; Brier score 0·045, CITL 1·040, slope 1·009).
INTERPRETATION
This novel prognostic risk score uses simple predictor variables available at the time of a decision for elective surgery that can accurately stratify patients' risk of postoperative pulmonary complications, including during SARS-CoV-2 outbreaks. It could inform surgical consent, resource allocation, and hospital-level prioritisation as elective surgery is upscaled to address global backlogs.
FUNDING
National Institute for Health Research.
Topics: Humans; Elective Surgical Procedures; Postoperative Complications; Female; Prognosis; Middle Aged; Male; Prospective Studies; Aged; COVID-19; Risk Assessment; Adult; Machine Learning; Risk Factors; Lung Diseases; Cohort Studies
PubMed: 38906616
DOI: 10.1016/S2589-7500(24)00065-7 -
Kidney International Reports Jun 2024Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with (Spalt like Transcription Factor 1), is reported to be present in 1:238,000...
INTRODUCTION
Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features.
METHODS
A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in . Data including age, features, and disease progression were collected.
RESULTS
Of 35,044 samples, P or LP variants in were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both TBS diagnoses and the traditional "triad."
CONCLUSION
Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that P/LP variants could be a consequential contributor to monogenic kidney disease.
PubMed: 38899216
DOI: 10.1016/j.ekir.2024.03.030 -
Nature Communications Jun 2024Homology-dependent targeted DNA integration, generally referred to as gene targeting, provides a powerful tool for precise genome modification; however, its fundamental...
Homology-dependent targeted DNA integration, generally referred to as gene targeting, provides a powerful tool for precise genome modification; however, its fundamental mechanisms remain poorly understood in human cells. Here we reveal a noncanonical gene targeting mechanism that does not rely on the homologous recombination (HR) protein Rad51. This mechanism is suppressed by Rad52 inhibition, suggesting the involvement of single-strand annealing (SSA). The SSA-mediated gene targeting becomes prominent when DSB repair by HR or end-joining pathways is defective and does not require isogenic DNA, permitting 5% sequence divergence. Intriguingly, loss of Msh2, loss of BLM, and induction of a target-site DNA break all significantly and synergistically enhance SSA-mediated targeted integration. Most notably, SSA-mediated integration is cell cycle-independent, occurring in the G1 phase as well. Our findings provide unequivocal evidence for Rad51-independent targeted integration and unveil multiple mechanisms to regulate SSA-mediated targeted as well as random integration.
Topics: Humans; Rad51 Recombinase; Rad52 DNA Repair and Recombination Protein; Gene Targeting; Cell Cycle; MutS Homolog 2 Protein; RecQ Helicases; Homologous Recombination; DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; G1 Phase
PubMed: 38890315
DOI: 10.1038/s41467-024-49385-9 -
Nucleic Acids Research Jun 2024Homologous recombination (HR) is a key process for repairing DNA double strand breaks and for promoting genetic diversity. However, HR occurs unevenly across the genome,...
Homologous recombination (HR) is a key process for repairing DNA double strand breaks and for promoting genetic diversity. However, HR occurs unevenly across the genome, and certain genomic features can influence its activity. One such feature is the presence of guanine quadruplexes (G4s), stable secondary structures widely distributed throughout the genome. These G4s play essential roles in gene transcription and genome stability regulation. Especially, elevated G4 levels in cells deficient in the Bloom syndrome helicase (BLM) significantly enhance HR at G4 sites, potentially threatening genome stability. Here, we investigated the role of G4-binding protein Yin Yang-1 (YY1) in modulating HR at G4 sites in human cells. Our results show that YY1's binding to G4 structures suppresses sister chromatid exchange after BLM knockdown, and YY1's chromatin occupancy negatively correlates with the overall HR rate observed across the genome. By limiting RAD51 homolog 1 (RAD51) access, YY1 preferentially binds to essential genomic regions, shielding them from excessive HR. Our findings unveil a novel role of YY1-G4 interaction, revealing novel insights into cellular mechanisms involved in HR regulation.
PubMed: 38869071
DOI: 10.1093/nar/gkae502 -
Ophthalmic Surgery, Lasers & Imaging... Jun 2024
Review
Topics: Humans; Geographic Atrophy; Shaken Baby Syndrome; Infant; Complement Inactivating Agents
PubMed: 38860971
DOI: 10.3928/23258160-20240523-01 -
Cureus May 2024Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition...
Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition to develop cancers. In this report, we discuss the diagnosis and management of a 34-year-old Canadian male BS patient, originally from Honduras, who developed B-cell lymphoma and a subsequent non-small cell lung carcinoma (NSCLC). Given the radiosensitivity of the patient due to his BS diagnosis and the early stage of the low-grade B-cell lymphoma, we relied on surveillance as the clinical approach to his management. The treatment for NSCLC was initiated in stage III of the disease and was palliative in intent. Chemotherapy (12 rounds of paclitaxel, with the dosage gradually increasing from 48 mg to 58 mg and finally to 72 mg) was employed to shrink the left upper lobe (LUL) lung mass. Subsequently, radiotherapy (3000 cGY in 20 fractions) was administered to improve symptoms further. The radiotherapy dose schedule was modified given the patient's BS diagnosis to avoid excessive toxicity. The palliative treatment course was well tolerated by the patient and resulted in symptom relief. However, his cancer progressed over the course of the treatment, ultimately resulting in his death 18 months after the initial diagnosis of NSCLC; no autopsy was performed. We believe this report will spur clinicians to engage in fruitful discussions about tailoring chemotherapy and radiation therapy regimens for treating cancer in BS patients.
PubMed: 38860091
DOI: 10.7759/cureus.60107 -
Biochemical and Biophysical Research... Jun 2024Generation of O-methylguanine (O-meG) by DNA-alkylating agents such as N-methyl N-nitrosourea (MNU) activates the multiprotein mismatch repair (MMR) complex and the...
Generation of O-methylguanine (O-meG) by DNA-alkylating agents such as N-methyl N-nitrosourea (MNU) activates the multiprotein mismatch repair (MMR) complex and the checkpoint response involving ATR/CHK1 and ATM/CHK2 kinases, which may in turn trigger cell cycle arrest and apoptosis. The Bloom syndrome DNA helicase BLM interacts with the MMR complex, suggesting functional relevance to repair and checkpoint responses. We observed a strong interaction of BLM with MMR proteins in HeLa cells upon treatment with MNU as evidenced by co-immunoprecipitation as well as colocalization in the nucleus as revealed by dual immunofluorescence staining. Knockout of BLM sensitized HeLa MR cells to MNU-induced cell cycle disruption and enhanced expression of the apoptosis markers cleaved caspase-9 and PARP1. MNU-treated BLM-deficient cells also exhibited a greater number of 53BP1 foci and greater phosphorylation levels of H2AX at S139 and RPA32 at S8, indicating the accumulation of DNA double-strand breaks. These findings suggest that BLM prevents double-strand DNA breaks during the MMR-dependent DNA damage response and mitigates O-meG-induced apoptosis.
PubMed: 38850810
DOI: 10.1016/j.bbrc.2024.150214 -
Scientific Reports May 2024Prostate cancer (PCa) ranks as the second most prevalent cancer among males globally. However, the exact mechanisms underlying its progression remain inadequately...
Prostate cancer (PCa) ranks as the second most prevalent cancer among males globally. However, the exact mechanisms underlying its progression remain inadequately elucidated. The present study sought to investigate the role and underlying molecular mechanism of hsa_circ_0001671 (circ_0001671) in the pathogenic behavior of PCa cells. Guided by the ceRNA theory, miR-27b-3p was employed to identify circRNAs that could potentially regulate Bloom Syndrome Protein (BLM). A series of experimental approaches including bioinformatics, luciferase assays, Fluorescent In Situ Hybridization (FISH), RNA-pulldown, and RNA Immunoprecipitation (RIP) were utilized to validate the miRNA sponge function of circ_0001671. Divergent primer PCR, RNase R treatments, and Sanger sequencing were conducted for the identification of circ_0001671. Quantitative RT-PCR and Western blot analyses were performed to validate gene expression levels. Both in vitro and in vivo experiments were conducted to assess the functional role of circ_0001671 in PCa cells.It was observed that the expression levels of circ_0001671 and BLM were significantly elevated in PCa tissues and cell lines, whereas miR-27b-3p showed decreased expression. Circ_0001671 was found to promote cellular proliferation, migration, and invasion, while inhibiting apoptosis. In vivo assays confirmed that circ_0001671 facilitated tumor growth. Further mechanistic studies revealed that circ_0001671 acted as a competing endogenous RNA (ceRNA) for BLM by sponging miR-27b-3p. The oncogenic role of circ_0001671 in PCa was shown to be modulated through the miR-27b-3p/BLM axis. In conclusion, circ_0001671 exerts an oncogenic effect in prostate cancer through the regulation of BLM by sponging miR-27b-3p, thus suggesting a novel molecular target for the treatment of PCa.
Topics: Humans; MicroRNAs; Prostatic Neoplasms; Male; RNA, Circular; Gene Expression Regulation, Neoplastic; Cell Proliferation; Cell Line, Tumor; Disease Progression; Animals; Mice; Cell Movement; Mice, Nude; Apoptosis
PubMed: 38806577
DOI: 10.1038/s41598-024-63068-x -
Cell Reports. Medicine Jun 2024Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and...
Little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS2) vaccine breakthrough infections (BTIs) on the magnitude and breadth of the T cell repertoire after exposure to different variants. We studied samples from individuals who experienced symptomatic BTIs during Delta or Omicron waves. In the pre-BTI samples, 30% of the donors exhibited substantial immune memory against non-S (spike) SARS2 antigens, consistent with previous undiagnosed asymptomatic SARS2 infections. Following symptomatic BTI, we observed (1) enhanced S-specific CD4 and CD8 T cell responses in donors without previous asymptomatic infection, (2) expansion of CD4 and CD8 T cell responses to non-S targets (M, N, and nsps) independent of SARS2 variant, and (3) generation of novel epitopes recognizing variant-specific mutations. These variant-specific T cell responses accounted for 9%-15% of the total epitope repertoire. Overall, BTIs boost vaccine-induced immune responses by increasing the magnitude and by broadening the repertoire of T cell antigens and epitopes recognized.
Topics: Humans; SARS-CoV-2; COVID-19; Epitopes, T-Lymphocyte; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes; COVID-19 Vaccines; Spike Glycoprotein, Coronavirus; Immunologic Memory; Female; Adult; Male; Mutation; Middle Aged; T-Lymphocytes; Breakthrough Infections
PubMed: 38781962
DOI: 10.1016/j.xcrm.2024.101583 -
Cell Reports. Medicine Jun 2024Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and...
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
Topics: SARS-CoV-2; Humans; Antibodies, Viral; COVID-19; Spike Glycoprotein, Coronavirus; Antibodies, Neutralizing; Antibodies, Monoclonal; Cross Reactions; Cryoelectron Microscopy; Neutralization Tests
PubMed: 38761799
DOI: 10.1016/j.xcrm.2024.101577