Lissencephaly caused by a de novo mutation in tubulin TUBA1A: a case report and literature review.

Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.

Eukaryotic translation initiation factor EIF4G1 p.Ser637Cys mutation in a family with Parkinson's disease with antecedent essential tremor.

Essential tremor (ET) and Parkinson's disease (PD) are common chronic movement disorders that can cause a substantial degree of disability. However, the etiology underlying these two conditions remains poorly understood. In the present study, Whole-exome sequencing of peripheral blood samples from the proband and Sanger sequencing of the other 18 family members, and pedigree analysis of four generations of 29 individuals with both ET and PD in a nonconsanguineous Chinese family were performed. Specifically, family members who had available medical information, including historical documentation and physical examination records, were included. A novel c.1909A>T (p.Ser637Cys) missense mutation was identified in the eukaryotic translation initiation factor 4γ1 (EIF4G1) gene as the candidate likely responsible for both conditions. In total, 9 family members exhibited tremor of the bilateral upper limbs and/or head starting from ages of ≥40 years, 3 of whom began showing evidence of PD in their 70s. Eukaryotic initiation factor 4 (eIF4)G1, a component of the translation initiation complex eIF4F, serves as a scaffold protein that interacts with many initiation factors and then binds to the 40S ribosomal subunit. The EIF4G1 (p.Ser637Cys) might inhibit the recruitment of the mRNA to the ribosome. In conclusion, the results from the present study suggested that EIF4G1 may be responsible for the hereditary PD with 'antecedent ET' reported in the family assessed.

The effect of robotic surgery on low anterior resection syndrome in patients with lower rectal cancer: a propensity score-matched analysis.

BACKGROUND: Many patients experience anorectal dysfunction after rectal surgery, which is known as low anterior resection syndrome (LARS). Robotic systems have many technical advantages that may be suitable for functional preservation after low rectal resection. Thus, the study aimed to explore whether robotic surgery can reduce the incidence and severity of LARS. METHODS: Patients undergoing minimally invasive sphincter-sparing surgery for low rectal cancer were enrolled between January 2015 and December 2020. The patients were divided into robotic or laparoscopic groups. The LARS survey was conducted at 6, 12 and 18 months postoperatively. Major LARS scores were analysed as the primary endpoint. In order to reduce confounding factors, one-to-two propensity score matches were used. RESULTS: In total, 342 patients were enrolled in the study. At 18 months postoperatively, the incidence of LARS was 68.7% (235/342); minor LARS was identified in 112/342 patients (32.7%), and major LARS in 123/342 (36.0%). After matching, the robotic group included 74 patients, and the laparoscopic group included 148 patients. The incidence of major LARS in the robotic group was significantly lower than that in the laparoscopic group at 6, 12, and 18 months after surgery. In multivariate logistic regression analysis, tumour location, laparoscopic surgery, intersphincteric resection, neoadjuvant therapy, and anastomotic leakage were independent risk factors for major LARS after minimally invasive sphincter-sparing surgery for low rectal cancer. Furthermore, a major LARS prediction model was constructed. Results of model evaluation showed that the nomogram had good prediction accuracy and efficiency. CONCLUSIONS: Patients with low rectal cancer may benefit from robotic surgery to reduce the incidence and severity of LARS. Our nomogram could aid surgeons in setting an individualized treatment program for low rectal cancer patients.

Clinical features and risk factors of plastic bronchitis caused by Mycoplasma pneumoniae pneumonia in children.

BACKGROUND: We analyzed the clinical characteristics of children with plastic bronchitis (PB) caused by Mycoplasma pneumoniae (MP) and explored its risk factors. METHODS: We prospectively analyzed clinical data of children with MP pneumonia (MPP) treated with fiberoptic bronchoscopy (FB). Patients were classified into a PB and non-PB group. General information, clinical manifestations, laboratory tests, results of computed tomography scan, and FB findings were compared between groups. We conducted statistical analysis of risk factors for developing PB. RESULTS: Of 1169 children who had MPP and were treated with FB, 133 and 1036 were in the PB and non-PB groups, respectively. There were no significant differences in sex, age, and incident season between groups (P > 0.05). The number of children in the PB group decreased during the COVID-19 pandemic. Compared with children in the non-PB group, those in the PB group had longer duration of hospitalization, increased levels of neutrophil (N), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH), alanine transaminase (ALT) and aspartate transaminase (AST); lower levels of lymphocyte (L) and platelet (PLT); and higher incidence of lack of appetite, decreased breath sounds, single lobar infiltrate, pleural effusion, pericardial effusion, mucosal erosion and/or necrosis, and bronchial embolization. L levels and pleural effusion were identified as risk factors in multivariate logistic regression. CONCLUSIONS: Children with PB caused by MPP had a strong and local inflammatory response. L levels and pleural effusion were independent risk factors of PB with MPP in children. Our findings will help clinicians identify potential PB in pediatric patients for early and effective intervention.

Coupling relationships between urban block spatial morphology and microclimate in severe cold regions.

This study investigates the relationship between urban block spatial morphology and microclimate in severe cold regions, using Shenyang, China as a case study. We employed computational fluid dynamics theory-based numerical simulation software and a controlled variable approach to analyze the microclimate effects of four key aspects: street conforming line ratio, street interface density, street aspect ratio, and building roof forms. The primary findings are as follows: Decreasing conforming line ratios initially increase average wind speed and temperature. Lower interface densities reduce average wind speed but raise temperature. Higher aspect ratios correspond to increased wind speed and decreased temperature. Additionally, upward sloping roofs correlate with higher average wind speed and temperature. This research provides a perspective for evaluating urban microclimates, considering human perception of urban block space. It also suggests spatial layout design strategies for different types of streets in severe cold regions, considering the climate environment.

[Research progress in vaccines of SARS-CoV-2].

Since the outbreak of corona virus disease 2019 (COVID-19), viral strains have mutated and evolved. Vaccine research is the most direct and effective way to control COVID-19. According to different production mechanisms, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines included inactivated virus vaccine, live attenuated vaccine, mRNA vaccine, DNA vaccine, viral vector vaccine, virus-like particle vaccine and protein subunit vaccine. Among them, viral protein subunit vaccine has a wide application prospect due to its high safety and effectiveness. Viral nucleocapsid protein has high immunogenicity and low variability which could be a new direction for vaccine production. We summarized the current development of vaccine research by reviewing the current progress, vaccine safety and vaccine immune efficiency. It is hoped that the proposed possible development strategies could provide a reference for epidemic prevention work in future.

Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7: A case report.

BACKGROUND: Spinocerebellar ataxia recessive type 7 (SCAR7) is a rare clinical manifestation beginning in childhood or adolescence. SCAR7 is caused by tripeptidyl peptidase 1 (TPP1) gene mutations, and presents with cerebellar ataxia, pyramidal signs, neurocognitive impairment, deep paresthesia, and cerebellar atrophy. CASE SUMMARY: Here, we describe a 25-year-old female patient in China who presented with increasing difficulty walking, falling easily, shaking limbs, instability holding items, slurred speech, coughing when drinking, palpitations, and frequent hunger and overeating. Magnetic resonance imaging showed cerebellar atrophy. Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene: c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg. Considering the patient's clinical presentation and genetic test results, we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency, which may lead to SCAR7. CONCLUSION: We report the first case of SCAR7 from China. We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7, expanding the range of known disease-causing mutations for SCAR7.

The clinical predictive value of geriatric nutritional risk index in elderly rectal cancer patients received surgical treatment after neoadjuvant therapy.

Objective: The assessment of nutritional status has been recognized as crucial in the treatment of geriatric cancer patients. The objective of this study is to determine the clinical predictive value of the geriatric nutritional risk index (GNRI) in predicting the short-term and long-term prognosis of elderly rectal cancer (RC) patients who undergo surgical treatment after neoadjuvant therapy. Methods: Between January 2014 and December 2020, the clinical materials of 639 RC patients aged ≥70 years who underwent surgical treatment after neoadjuvant therapy were retrospectively analysed. Propensity score matching was performed to adjust for baseline potential confounders. Logistic regression analysis and competing risk analysis were conducted to evaluate the correlation between the GNRI and the risk of postoperative major complications and cumulative incidence of cancer-specific survival (CSS). Nomograms were then constructed for postoperative major complications and CSS. Additionally, 203 elderly RC patients were enrolled between January 2021 and December 2022 as an external validation cohort. Results: Multivariate logistic regression analysis showed that GNRI [odds ratio = 1.903, 95% confidence intervals (CI): 1.120-3.233, p = 0.017] was an independent risk factor for postoperative major complications. In competing risk analysis, the GNRI was also identified as an independent prognostic factor for CSS (subdistribution hazard ratio = 3.90, 95% CI: 2.46-6.19, p < 0.001). The postoperative major complication nomogram showed excellent performance internally and externally in the area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analysis (DCA). When compared with other models, the competing risk prognosis nomogram incorporating the GNRI achieved the highest outcomes in terms of the C-index, AUC, calibration plots, and DCA. Conclusion: The GNRI is a simple and effective tool for predicting the risk of postoperative major complications and the long-term prognosis of elderly RC patients who undergo surgical treatment after neoadjuvant therapy.

Aging characteristics of degradable and non-biodegradable microplastics and their adsorption mechanism for sulfonamides.

As emerging pollutants, microplastics (MPs) and antibiotics (ATs) became a research hotspot in recent years. To evaluate the carrier effect of degradable and non-biodegradable MPs in the aquatic environment, the adsorption behaviors of polyamide (PA) and polylactic acid (PLA) towards two sulfonamide antibiotics (SAs) were investigated. Both chemical and photo-aging were used to handle the virgin MPs. Compared with PA, PLA was aged more drastically, showing the obvious grooves, notches and folds. However, due to the higher temperature during chemical aging, the tiny KPLA (PLA aged by K2S2O8) particles were agglomerated and the specific surface area was reduced to nearly 95 %. For PA, the oxidation of chemical aging was stronger than photo-aging. After aging, the hydrophilicity and polarity of MPs increased. In the adsorption experiments, the adsorption capacity of PA towards SAs was 1.7 times higher than that of PLA. Aging process enabled the adsorption capacity of PLA increased 1.22-3.18 times. Overall, the adsorption capacity of sulfamethoxazole (SMX) by both MPs was superior to sulfamerazine (SMR). These results would help to understand the carrier effects and potential ecological risks of MPs towards co-existing contaminants.

Anti-biofilm effect of salivary histatin 5 on Porphyromonas gingivalis.

This study aimed to investigate the effects of salivary histatin 5 (Hst5) on Porphyromonas gingivalis (P. gingivalis) biofilms in vitro and in vivo and the possible mechanisms. In in vitro experiments, P. gingivalis biomass was determined by crystal violet staining. Polymerase chain reaction, scanning electron microscopy, and confocal laser scanning microscopy were used to determine the Hst5 concentration. A search for potential targets was performed using transcriptomic and proteomic analyses. In vivo experimental periodontitis was established in rats to evaluate the effects of Hst5 on periodontal tissues. Experimental results showed that 25 µg/mL Hst5 effectively inhibited biofilm formation, and increased concentrations of Hst5 increased the inhibitive effect. Hst5 might bind to the outer membrane protein RagAB. A combination of transcriptomic and proteomic analyses revealed that Hst5 could regulate membrane function and metabolic processes in P. gingivalis, in which RpoD and FeoB proteins were involved. In the rat periodontitis model, alveolar bone resorption and inflammation levels in periodontal tissues were reduced by 100 µg/mL Hst5. This study showed that 25 µg/mL Hst5 inhibited P. gingivalis biofilm formation in vitro by changing membrane function and metabolic process, and RpoD and FeoB proteins might play important roles in this process. Moreover, 100 µg/mL Hst5 inhibited periodontal inflammation and alveolar bone loss in rat periodontitis via its antibacterial and anti-inflammatory effects. KEY POINTS: • Anti-biofilm activity of histatin 5 on Porphyromonas gingivalis was investigated. • Histatin 5 inhibited Porphyromonas gingivalis biofilm formation. • Histatin 5 showed inhibitory effects on the occurrence of rat periodontitis.

Tensile Overload Injures Human Alveolar Epithelial Cells through YAP/F-Actin/MAPK Signaling.

BACKGROUND: Explosion shockwaves can generate overloaded mechanical forces and induce lung injuries. However, the mechanism of lung injuries caused by tensile overload is still unclear. METHODS: Flow cytometry was used to detect the apoptosis of human alveolar epithelial cells (BEAS-2B) induced by tensile overload, and cell proliferation was detected using 5-ethynyl-2'-deoxyuridine (EdU). Immunofluorescence and Western blot analysis were used to identify the tensile overload on the actin cytoskeleton, proteins related to the mitogen-activated protein kinase (MAPK) signal pathway, and the Yes-associated protein (YAP). RESULTS: Tensile overload reduced BEAS-2B cell proliferation and increased apoptosis. In terms of the mechanism, we found that tensile overload led to the depolymerization of the actin cytoskeleton, the activation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase 1/2 (ERK1/2), and the upregulation of YAP expression. Jasplakinolide (Jasp) treatment promoted the polymerization of the actin cytoskeleton and reduced the phosphorylation of tension-overload-activated JNK and ERK1/2 and the apoptosis of BEAS-2B cells. Moreover, the inhibition of the JNK and ERK1/2 signaling pathways, as well as the expression of YAP, also reduced apoptosis caused by tensile overload. CONCLUSION: Our study establishes the role of the YAP/F-actin/MAPK axis in tensile-induced BEAS-2B cell injury and proposes new strategies for the treatment and repair of future lung injuries.

Association between periodontal disease and oral squamous cell carcinoma: a systematic review and meta-analysis.

To investigate the relation between periodontal disease (PD) and oral squamous cell carcinoma (OSCC) we systematically searched records published up to August 2022. Odds ratios (OR) and relative risk (RR) with 95% confidence intervals (95% CI) were estimated to evaluate this relation, then sensitivity analysis was performed accordingly. Begg's test and Egger's test were used to detect publication bias. Out of 970 papers from several databases, 13 studies were included. Summary estimates showed that PD was positively associated with the prevalence of OSCC (OR = 3.28, 95% CI: 1.87 to 5.74), especially for severe PD (OR = 4.23, 95% CI: 2.92 to 6.13). No evident publication bias was revealed. No increased OSCC risk among patients with PD was shown according to the combined results (RR = 1.50, 95% CI: 0.93 to 2.42). Patients with OSCC exhibited significant differences in alveolar bone loss, clinical attachment loss, and bleeding on probing, when compared with controls. The systematic review and meta-analysis suggested that there was a positive association between PD and prevalence of OSCC. However, according to the current evidence, a causal relation is unclear.

Targeting tumor energy metabolism via simultaneous inhibition of mitochondrial respiration and glycolysis using biodegradable hydroxyapatite nanorods.

Tumor cells obtain energy supply from the unique metabolic pathways of mitochondrial respiration and glycolysis, which can be used interchangeably to produce adenosine triphosphate (ATP) for survival. To simultaneously block the two metabolic pathways and sharply cut off ATP supply, a multifunctional "nanoenabled energy interrupter" (called as HNHA-GC) was prepared by attaching glucose oxidase (GOx), hyaluronic acid (HA), and 10-hydroxycamptothecin (CPT) on the surface of degradable hydroxyapatite (NHA) nanorods. After targeted delivery of HNHA-GC to the tumor site by HA, the tumor-selective acid degradation of HNHA-GC as well as the subsequent deliveries of Ca2+, drug CPT, and GOx take place. The released Ca2+ and CPT induce mitochondrial dysfunction by Ca2+ overload and chemotherapy respectively, while the GOx-triggered glucose oxidation inhibits glycolysis by starvation therapy (exogenous effect). The generated H2O2 and released CPT increase the intracellular reactive oxygen (ROS) level. Moreover, the generated H+ and enhanced ROS promote Ca2+ overload by accelerating the degradation of HNHA-GC and preventing intracellular Ca2+ efflux, respectively (endogenous effect). As a result, the HNHA-GC displays a promising therapeutic modality for simultaneously cutting off mitochondrial and glycolytic ATP production through a combination of Ca2+ overload, chemotherapy, and starvation therapy.

Association between prior appendectomy and the risk and course of Crohn's disease: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The appendix has an important immune function in both health and disease, and appendectomy may influence microbial ecology and immune function. This meta-analysis aims to assess the association between appendectomy and the risk and course of Crohn's disease (CD). METHODS: PubMed, EMBASE, and the Cochrane Library were used to identify all studies published until June 2022. Data from studies evaluating the association between appendectomy and CD were reviewed. RESULTS: A total of 28 studies were included in the final analysis, comprising 22 case-control and 6 cohort studies. A positive relationship between prior appendectomy and the risk of developing CD was observed in both case-control studies (odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.22-2.08) and cohort studies (relative risk [RR]: 2.28, 95% CI: 1.66-3.14). The elevated risk of CD persisted 5 years post-appendectomy (RR = 1.24, 95% CI: 1.12-1.36). The risk of developing CD was similarly elevated regardless of the presence (RR = 1.64, 95% CI: 1.17-2.31) or absence (RR = 2.77, 95% CI: 1.84-4.16) of appendicitis in patients. Moreover, significant differences were found in the proportion of terminal ileum lesions (OR = 1.63; 95% CI: 1.38-1.93) and colon lesions (OR = 0.70; 95% CI: 0.5-0.84) between CD patients with appendectomy and those without appendectomy. CONCLUSIONS: The risk of developing CD following an appendectomy is significant and persists 5 years postoperatively. Moreover, the elevated risk of CD may mainly occur in the terminal ileum.

Seizure Outcome After Surgery for Refractory Epilepsy Diagnosed by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/MRI): A Systematic Review and Meta-Analysis.

OBJECTIVE: When magnetic resonance imaging (MRI) fails to detect an underlying epileptogenic lesion, the odds of a good outcome after epilepsy surgery are significantly lower (20%-65% compared with 60%-90% if a lesion is detected). We investigated the possible effects of introducing hybrid 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI into the decision algorithm for patients with lesioned and nonlesioned drug-resistant epilepsy. METHODS: Three databases were searched from January 1990 to October 2022. We registered the protocol with International Platform of Registered Systematic Review and Meta-analysis Protocols. Studies in which 18F-FDG PET/MRI was conducted with ≥12 months of postsurgical follow-up in patients with refractory epilepsy. Random-effects meta-analysis was used to calculate the proportion of patients with good outcomes. Metaregression was used to investigate sources of heterogeneity. RESULTS: We identified 8105 studies, of which 23 (1292 patients in total) were included. The overall good postoperative outcome rate was 71% (95% confidence interval 63.6-74.9). Good outcome was associated with the location of the refractory epileptic lesion (temporal lobe or extratemporal; risk ratio 1.27 [95% confidence interval 1.01-1.52], P = 0.009); Length of postoperative follow-up ≥40 months included in the same study accounted for 0.6% of the observed heterogeneity. CONCLUSIONS: Seventy-one percent of patients with refractory epilepsy and 18F-FDG PET/MRI epileptogenic lesion features had a good outcome of epilepsy after surgery. Our findings can be incorporated into routine preoperative consultations and emphasize the importance of the complete resection of the temporal lobe epileptogenic zone for 18F-FDG PET/MRI detection when safe and feasible.

A novel missense mutation in SPAST causes hereditary spastic paraplegia in male members of a family: A case report.

Hereditary spastic paraplegia (HSP) comprises a group of hereditary and neurodegenerative diseases that are characterized by axonal degeneration or demyelination of bilateral corticospinal tracts in the spinal cord; affected patients exhibit progressive spasticity and weakness in the lower limbs. The most common manifestation of HSP is spastic paraplegia type 4 (SPG4), which is caused by mutations in the spastin (SPAST) gene. The present study reports the clinical characteristics of affected individuals and sequencing analysis of a mutation that caused SPG4 in a family. All affected family members exhibited spasticity and weakness of the lower limbs and, notably, only male members of the family were affected. Whole­exome sequencing revealed that all affected individuals had a novel c.1785C>A (p. Ser595Arg) missense mutation in SPAST. Bioinformatics analysis revealed changes in both secondary and tertiary structures of the mutated protein. The novel missense mutation in SPAST supported the diagnosis of SPG4 in this family and expands the spectrum of pathogenic mutations that cause SPG4. Analysis of SPAST sequences revealed that most pathogenic mutations occurred in the AAA domain of the protein, which may have a close relationship with SPG4 pathogenesis.

Comparison of robotic versus laparoscopic lateral lymph node dissection for advanced lower rectal cancer: a retrospective study at two institutions.

BACKGROUND: Lateral lymph node dissection (LLND) represents a technically challenging procedure. This study aimed to evaluate the perioperative, genitourinary functional and mid-term oncological outcomes of laparoscopic lateral lymph node dissection (LLLND) and robotic lateral lymph node dissection (RLLND) for advanced lower rectal cancer (ALRC). METHODS: Between January 2015 and April 2021, consecutive patients who underwent RLLND and LLLND at two high-volume centres were enrolled. The perioperative outcomes, genitourinary function recovery and mid-term oncological outcomes of the patients were compared. A subgroup analysis of patients who underwent neoadjuvant chemoradiotherapy (nCRT) was performed. RESULTS: A total of 205 patients were included in the analysis, with 95 in the RLLND group and 110 in the LLLND group. The patients in the RLLND group had a longer operative time, less blood loss, and more harvested internal iliac lymph nodes than did those in the LLLND group. In postoperative complication, urinary retention was less frequent in the RLLND group than in the LLLND group. Additionally, the RLLND group had better genitourinary function recovery. Similar results were also observed from the nCRT subgroup analysis. Moreover, there was no significant difference in mid-term oncological outcomes between the two groups. Further subgroup analysis indicated that the patients who underwent nCRT + LLLND/RLLND had better local control than those who underwent only LLLND/RLLND. CONCLUSIONS: RLLND is safe and feasible for ALRC and is associated with more harvested internal iliac lymph nodes and better genitourinary function recovery. NCRT combined with minimally invasive LLND could constitute an improved strategy for ALRC.

Genetically determined serum bilirubin level and the risk of heart failure: A mendelian randomization study.

Background: The association between serum bilirubin level and heart failure (HF) was controversial in previous observational studies and the causal effects of bilirubin on HF have not been investigated. Here, we conducted a Mendelian randomization (MR) study to investigate the associations between genetically determined bilirubin level and HF. Methods: Summary data on the association of single nucleotide polymorphisms (SNPs) with serum bilirubin levels were obtained from genome-wide association study (GWAS) for individuals of European descent and East Asian descent separately. Statistical data for gene-HF associations were extracted from three databases: the HERMES Consortium (47,309 cases and 930,014 controls), FinnGen study (30,098 cases and 229,612 controls) for European population and Biobank Japan (2,820 HF cases and 192,383 controls) for East Asian population. We applied a two-sample Mendelian randomization framework to investigate the causal association between serum bilirubin and HF. Results: Findings from our MR analyses showed that genetically determined serum bilirubin levels were not causally associated with HF risk in either European or East Asian population (odds ratio [OR] = 1.01 and 95% confidence interval [CI] = .97-1.05 for HERMES Consortium; OR = 1.01 and 95% CI = .98-1.04 for FinnGen Study; OR = .82, 95% CI: .61-1.10 for Biobank Japan). These results remained unchanged using different Mendelian randomization methods and in sensitivity analyses. Conclusion: Our study did not find any evidence to support a causal association between serum bilirubin and HF.

Altered gut microbiome composition by appendectomy contributes to colorectal cancer.

Appendectomy impacts the homeostasis of gut microbiome in patients. We aimed to study the role of appendectomy in colorectal cancer (CRC) risk through causing gut microbial dysbiosis. Population-based longitudinal study (cohort 1, n = 129,155) showed a 73.0% increase in CRC risk among appendectomy cases throughout 20 years follow-up (Adjusted sub-distribution hazard ratio (SHR) 1.73, 95% CI 1.49-2.01, P < 0.001). Shotgun metagenomic sequencing was performed on fecal samples from cohort 2 (n = 314). Gut microbial dysbiosis in appendectomy subjects was observed with significant enrichment of 7 CRC-promoting bacteria (Bacteroides vulgatus, Bacteroides fragilis, Veillonella dispar, Prevotella ruminicola, Prevotella fucsa, Prevotella dentalis, Prevotella denticola) and depletion of 5 beneficial commensals (Blautia sp YL58, Enterococcus hirae, Lachnospiraceae bacterium Choco86, Collinsella aerofaciens, Blautia sp SC05B48). Microbial network analysis showed increased correlation strengths among enriched bacteria and their enriched oncogenic pathways in appendectomy subjects compared to controls. Of which, B. fragilis was the centrality in the network of the enriched bacteria. We further confirmed that appendectomy promoted colorectal tumorigenesis in mice by causing gut microbial dysbiosis and impaired intestinal barrier function. Collectively, this study revealed appendectomy-induced microbial dysbiosis characterized by enriched CRC-promoting bacteria and depleted beneficial commensals, signifying that the gut microbiome may play a crucial role in CRC development induced by appendectomy.