Artificial intelligence based real-time prediction of imminent heart failure hospitalisation in patients undergoing non-invasive telemedicine.

Background: Remote patient management may improve prognosis in heart failure. Daily review of transmitted data for early recognition of patients at risk requires substantial resources that represent a major barrier to wide implementation. An automated analysis of incoming data for detection of risk for imminent events would allow focusing on patients requiring prompt medical intervention. Methods: We analysed data of the Telemedical Interventional Management in Heart Failure II (TIM-HF2) randomized trial that were collected during quarterly in-patient visits and daily transmissions from non-invasive monitoring devices. By application of machine learning, we developed and internally validated a risk score for heart failure hospitalisation within seven days following data transmission as estimate of short-term patient risk for adverse heart failure events. Score performance was assessed by the area under the receiver-operating characteristic (ROCAUC) and compared with a conventional algorithm, a heuristic rule set originally applied in the randomized trial. Results: The machine learning model significantly outperformed the conventional algorithm (ROCAUC 0.855 vs. 0.727, p < 0.001). On average, the machine learning risk score increased continuously in the three weeks preceding heart failure hospitalisations, indicating potential for early detection of risk. In a simulated one-year scenario, daily review of only the one third of patients with the highest machine learning risk score would have led to detection of 95% of HF hospitalisations occurring within the following seven days. Conclusions: A machine learning model allowed automated analysis of incoming remote monitoring data and reliable identification of patients at risk of heart failure hospitalisation requiring immediate medical intervention. This approach may significantly reduce the need for manual data review.

Comparative analysis of recurrence predictors and outcomes for atrial tachyarrhythmia following atrial fibrillation ablation: high-power short-duration vs. conventional pulmonary vein isolation.

Atrial fibrillation (AF) is a common cardiac arrhythmia, with structural and electrical remodeling being significant risk factors for recurrence post-catheter ablation. The advent of high-power short-duration pulmonary vein isolation (HPSD-PVI) presents a novel approach, potentially enhancing procedural success rates through the creation of transmural lesions without overheating. This study investigates the predictors of atrial tachyarrhythmia (ATA) recurrence and compares outcomes between HPSD-PVI and conventional PVI techniques. A total of 1005 patients undergoing radiofrequency catheter ablation (RFA) for AF were retrospectively analyzed in this study. The cohort was divided based on the ablation strategy: conventional PVI from February 2013 to September 2018, and HPSD-PVI from October 2018 onwards. The primary objective was to compare the predictors of ATA recurrence and the outcome between the two groups. Among 969 patients analyzed after exclusions, independent predictors of recurrence differed between groups; higher CHADS2/CHA2DS2-VASc scores and lower left ventricular ejection fraction (LVEF) were significant in the HPSD-PVI group, while non-paroxysmal AF, larger left atrial volume index (LAVI), and longer AF history were predictors in the conventional PVI group. The HPSD-PVI group showed a trend toward lower ATA recurrence rates compared to the conventional PVI group in the propensity-score-matched (PSM) cohort (log-rank test, p = 0.06). Higher CHADS2/CHA2DS2-VASc scores and lower LVEF were also independent predictors of ATA recurrence in the PSM cohort.

Fertilizer-driven FO and MD integrated process for shale gas produced water treatment: Draw solution evaluation and PAC enhancement.

It is a great challenge for effective treatment of shale gas produced water (SGPW), a typical industrial wastewater with complex composition. Single forward osmosis (FO) or membrane distillation (MD) process has been widely used for desalination of SGPW, with membrane fouling not well addressed. Fertilizer draw solution (DS) with high osmotic pressure is less likely to cause FO fouling and can be used for irrigation. An integrated process using fertilizer-driven FO (FDFO) and MD process was proposed for the first time for SGPW treatment, and characteristics of fertilizer DS and powdered activated carbon (PAC) enhancement were assessed. The DS using KCl and (NH4)2SO4 had high MD fluxes (36.8-38.8 L/(m2·h)) and low permeate conductivity (below 50 µS/cm), increasing the contact angle of the MD membrane by 113 % than that without FO, while the DS using MgCl2 and NH4H2PO4 produced a lower reverse salt flux (0.9-3.2 g/(m2·h)). When diluted DS was treated using PAC, the MD permeate conductivity was further reduced to 35 µS/cm without ammonia, and the membrane hydrophobicity was maintained to 71-83 % of the original. The mechanism of the FDFO-MD integrated process for mitigating MD fouling and improving permeate quality was analyzed, providing guidance for efficient SGPW treatment.

The impact of transanal drainage tube on the incidence of anastomotic leakage and small bowel obstruction in radical surgery (Dixon) for rectal cancer: a retrospective cohort study.

Background: Anastomotic leakage (AL) and small bowel obstruction (SBO) are common complications after rectal cancer radical surgery (Dixon). Although the commonly used defunctioning stoma (DS) can reduce the incidence and harm of AL, it increases the probability of other adverse consequences, including SBO. Therefore, a safe and effective method for preventing the complications related to the radical surgery of rectal cancer is urgently needed. Previous studies have found that transanal drainage tube (TDT) can have a positive impact on the incidence of these two complications by draining gas and feces from the intestinal lumen, without causing other serious consequences. Therefore, this article further explores the clinical benefits that TDT can bring by analyzing the clinical data of postoperative patients with rectal cancer. Methods: This study included 221 patients who underwent radical surgery (Dixon) for rectal cancer in Hubei Cancer Hospital from September 2020 to February 2023, determine whether it meets the inclusion criteria of this study based on preoperative examination, intraoperative exploration results, and treatment methods. DS was used in 70 patients and TDT in 88 patients during the surgery; meanwhile, no protective anastomotic measures were applied in 63 patients. Seventy patients subjected to DS were categorized as group 1, 88 patients subjected to TDT as group 2, and 63 patients with no protective measures for anastomosis as group 3. Through postoperative clinical manifestations, imaging examinations, and laboratory tests, a total of 18 cases of AL and 30 cases of SBO were identified in the three groups. The effectiveness of TDT and that of other surgical procedures in preventing complications, accelerating postoperative recovery, and reducing surgical costs were compared through univariate and multivariate analyses. Results: The clinical features of the three groups have baseline comparability. No statistically difference was noted in baseline characteristics between three groups (all P>0.05). The incidence of AL and SBO in group 1 are 7.1% and 27.1%, in group 2 are 3.4% and 4.5%, and in group 3 are 15.9% and 11.1%. Compared to patients in no protective anastomotic measures with TDT and DS, TDT has a lower incidence of postoperative AL (P<0.05) and SBO (P>0.05), and faster postoperative recovery (P<0.05). The cost of inpatient surgery is not significantly different (P>0.05). Although DS can reduce the incidence of AL to a certain extent (P>0.05), it significantly increased the incidence of SBO (P<0.05), delayed postoperative defecation time (P<0.05) and caused higher cost (P<0.001). Compared to DS, the incidence of AL in TDT is not significantly different (P>0.05), but the incidence of SBO is noticeably lower (P<0.001), with faster postoperative recovery and less cost (P<0.05). Conclusions: TDT is a safer, more effective, and more economical surgery for preventing postoperative complications.

CHA2DS2-VASc predicts readmission, outcomes and resource utilization in patients undergoing coronary artery bypass grafting: A 7-year National Readmission Database study.

BACKGROUND: CHA2DS2-VASc score is used to assess thromboembolic risk in patients with atrial fibrillation (AF)/atrial flutter (AFL), however its utilization to predict outcomes and readmission at following discharge in patients undergoing coronary artery bypass grafting (CABG) regardless of AF/AFL presence is understudied. We sought to assess its utility in predicting outcomes, length of hospital stay (LOS), and healthcare-associated costs (HAC) in these patients. METHOD: The National Readmission Database (NRD) was queried from 2010 to 2017 for patients with/without AF/AFL undergoing CABG using the International Classification of Diseases, Ninth and Tenth editions (ICD-9-&-10). Multiple regression analysis and multivariate analysis using Cox-Hazard analysis were used to evaluate outcomes up to 90-day readmission from discharge, LOS, and HAC against CHA2DS2-VASc score (cut-off-score:6) were abstracted from the database. RESULTS: Of the 420,458 patients that underwent CABG, 76,859 (18.3 %) were re-admitted to hospital within 90-days from discharge. Statistically significant increase in 90-day all-cause readmissions were demonstrated with increasing CHA2DS2-VASc score [No AF/AFL vs AF/AFL: score-0 (2.4 % vs1.4 %), score-6 (3.1 % vs 4.5 %, p-value<0.0001]. Similar trends were seen in re-admissions for TIA/Stroke and heart failure. The survival rate for all events were lower with incremental increase in CHA2DS2-VASc score (score-0 = 100 %; score-6 = 73 %, p-value<0.0001). Greater LOS and HAC was associated with increasing higher CHA2DS2-VASc score (standardized-beta[ß]; no AF/AFL vs AF/AFL: LOS = score-1: 0.08 vs 0.06, score-6: 0.12 vs 0.13. HAC = score-1: 0.02 vs 0.009, score-6: 0.02 vs 0.01, p-value <0.001). CONCLUSION: CHA2DS2-VASc score is an easy-to-use tool that predicts poorer outcomes, higher readmission, longer LOS, higher HAC, not just in patients with AF/AFL undergoing CABG, but also in those without AF/AFL.

Association between Dental Fear and Children's Oral Health-Related Quality of Life.

OBJECTIVES: This study aimed to examine the association between both parental dental fear and children's dental fear and its impact on the Oral Health-Related Quality of Life (OHRQoL) of Saudi children in the Eastern Province of Saudi Arabia. METHODS: Data on 93 individuals aged 7-12 years were collected using clinical examination and Arabic-validated questionnaires: the Child Oral Health Impact Profile-Short Form (COHIP-SF19), and the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS). Negative binomial regression analysis was performed to study the association between children's fear and parental dental fear as well as the OHRQoL, while adjusting for certain confounders. RESULTS: Overall, our multivariate analyses showed that children with high dental fear (CFSS-DS ≥ 38, p = 0.027) and a higher percentage of dental caries (p = 0.013) had a significantly lower OHRQoL after adjusting for clinical and socio-demographic factors. Further, parental fear of dentists was significantly associated with children's fear of dentists (p < 0.001). CONCLUSIONS: Our findings demonstrate that children's fear and dental caries are both associated with poorer OHRQoL. Further, parental dental fear about dentists was associated with children's fear of dentists.

Booster vaccination using bivalent DS-5670a/b is safe and immunogenic against SARS-CoV-2 variants in children aged 5-11 years: a phase 2/3, randomized, active-controlled study.

Background: DS-5670 is a messenger ribonucleic acid (mRNA) vaccine platform targeting the receptor-binding domain (RBD) of the spike protein derived from severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Booster vaccination against coronavirus disease 2019 (COVID-19) with monovalent DS-5670a (incorporating mRNA encoding the RBD from the original SARS-CoV-2 strain) or bivalent DS-5670a/b (original and omicron BA.4-5 RBD antigens) is effective and safe in adults. Data from a phase 2/3 active-controlled, non-inferiority, pediatric study evaluating a third booster dose of DS-5670a/b are reported here. Methods: Children aged 5-11 years who had completed the two-dose primary vaccination series with monovalent BNT162b2 (original strain) at least 3 months prior to enrolment were randomly assigned to receive DS-5670a/b (20 µg of mRNA) or bivalent BNT1 62b2 (original/omicron BA.4-5; 10 µg of mRNA) on Day 1. The primary efficacy endpoint was blood neutralization geometric mean titer (GMT) against SARS-CoV-2 (omicron variant BA.5.2.1) and immune response rate (≥ 4-fold increase in post-vaccination circulating anti-SARS-CoV-2 neutralizing activity) on Day 29. Results: Among evaluable participants (DS-5670a/b, n = 74; bivalent BNT162b2, n = 75), the adjusted GMT ratio of DS-5670a/b to bivalent BNT162b2 on Day 29 was 1.636 (95% CI, 1.221, 2.190). Immune response rates were ≥ 89% with both study vaccines; adjusted difference 2.6% (95% CI, -7.8, 13.8). The prespecified non-inferiority margins were exceeded, and the study met the primary endpoint. DS-5670a/b also demonstrated broad neutralization activity across recent omicron sublineages and no cases of COVID-19 between Days 8-29 post-administration were reported. There were no novel safety concerns in the pediatric population at data cut-off. Conclusions: Bivalent DS-5670a/b was non-inferior to bivalent BNT162b2 in terms of immunogenicity, and had a manageable safety profile, when administered as a heterologous booster in children aged 5-11 years. Clinical trial registration: https://jrct.niph.go.jp/, identifier jRCT2031220665.

KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies.

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.

[Feasibility of Adapting Various Tumor-to-normal Bone Ratio Images on an Automatic Quantification Package for Phantom-based Image Quality Assessment in Bone SPECT].

We investigated the impact of the tumor-to-normal bone ratio (TNR) on the concordance rate between a detectability score classified by software (DSsoft) using an automatic quantification package for bone SPECT (Hone Graph) and a detectability score classified by visual assessment (DSvisual), and considered the feasibility of applying this software to various TNR images. 99mTc solution was filled into a SIM2 bone phantom to achieve TNRs of 4, 6, and 8, performed by dynamic SPECT acquisitions performed for 12 minutes; reconstructions were performed using ordered subset expectation maximization at timepoints ranging from 4 to 12 minutes. This yielded a total of 384 lesions (96 SPECT images). We investigated the weighted kappa (κw) coefficient between DSsoft and DSvisual at various TNRs and evaluated the change in analysis accuracy before and after applying newly created analysis parameters. DSs were defined on a 4-point scale (4: excellent, 3: adequate, 2: average, 1: poor), and visual evaluations were conducted by three board-certified nuclear medicine technologists. The κw coefficients between DSsoft and DSvisual were 0.75, 0.97, and 0.93 for TNRs 4, 6, and 8, respectively, with each κw coefficient being significant (p<0.01). In the TNR 4 image group, κw coefficients significantly increased with the implementation of new parameters proposed in this study. We concluded that the software's automatic analysis would be closer to a visual assessment within the TNR range of 4-8 and that applying new parameters derived from this study to images with TNR 4 further improves the software's automatic analysis accuracy of DSsoft. We suggest that software will be a useful tool for optimizing bone SPECT imaging techniques.

Accelerated CEST imaging through deep learning quantification from reduced frequency offsets.

PURPOSE: To shorten CEST acquisition time by leveraging Z-spectrum undersampling combined with deep learning for CEST map construction from undersampled Z-spectra. METHODS: Fisher information gain analysis identified optimal frequency offsets (termed "Fisher offsets") for the multi-pool fitting model, maximizing information gain for the amplitude and the FWHM parameters. These offsets guided initial subsampling levels. A U-NET, trained on undersampled brain CEST images from 18 volunteers, produced CEST maps at 3 T with varied undersampling levels. Feasibility was first tested using retrospective undersampling at three levels, followed by prospective in vivo undersampling (15 of 53 offsets), reducing scan time significantly. Additionally, glioblastoma grade IV pathology was simulated to evaluate network performance in patient-like cases. RESULTS: Traditional multi-pool models failed to quantify CEST maps from undersampled images (structural similarity index [SSIM] <0.2, peak SNR <20, Pearson r <0.1). Conversely, U-NET fitting successfully addressed undersampled data challenges. The study suggests CEST scan time reduction is feasible by undersampling 15, 25, or 35 of 53 Z-spectrum offsets. Prospective undersampling cut scan time by 3.5 times, with a maximum mean squared error of 4.4e-4, r = 0.82, and SSIM = 0.84, compared to the ground truth. The network also reliably predicted CEST values for simulated glioblastoma pathology. CONCLUSION: The U-NET architecture effectively quantifies CEST maps from undersampled Z-spectra at various undersampling levels.

A Sonochemical and Mechanochemical One-Pot Multicomponent/Click Coupling Strategy for the Sustainable Synthesis of Bis-heterocyclic Drug Scaffolds.

Bis-heterocycles were synthesized via a consecutive one-pot process by a Groebke-Blackburn-Bienaymé reaction (GBB-3CR) followed by Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) assisted by alternative sustainable energies (ASE) such as ultrasound irradiation (USI) and mechanical. These efficient and convergent strategies allowed the in situ generation of complex azides functionalized with imidazo[1,2-a]pyridines (IMPs), which was used as a synthetic platform. The target molecules contain two privileged scaffolds in medicinal chemistry: IMPs and the heterocyclic bioisostere of trans-amide bond, the 1,4-disubstituted 1H-1,2,3-triazoles (1,4-DS-1,2,3-Ts).

R2-CHA2DS2-VASc Score for Cardiovascular Event Prediction After Bioprosthetic Valve Replacement　- Subanalysis From the BPV-AF Registry.

Background: There are few studies evaluating the prognostic prediction method in atrial fibrillation (AF) patients after bioprosthetic valve (BPV) replacement. The R2-CHA2DS2-VASc score is increasingly used for the prediction of cardiovascular (CV) events in patients with AF, device implantation, and acute coronary syndrome. We aimed to evaluate the predictive value of the R2-CHA2DS2-VASc score for future CV events in AF patients after BPV replacement. Methods and Results: The BPV-AF, an observational, multicenter, prospective registry, enrolled AF patients who underwent BPV replacement. The primary outcome measure was a composite of stroke, systemic embolism, CV events including heart failure requiring hospitalization, and cardiac death. A total of 766 patients was included in the analysis. The mean R2-CHA2DS2-VASc score was 5.7±1.8. Low (scores 0-1), moderate (scores 2-4), and high (scores 5-11) R2-CHA2DS2-VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively. The median follow-up period was 491 (interquartile range 393-561) days. Kaplan-Meier analysis showed a higher incidence of the composite CV events in the high R2-CHA2DS2-VASc score group (log rank test; P<0.001). Multivariate Cox proportional hazards regression analysis revealed that the R2-CHA2DS2-VASc score as a continuous variable was an independent predictor of composite CV outcomes (hazard ratio 1.36; 95% confidence interval 1.18-1.55; P<0.001). Conclusions: The R2-CHA2DS2-VASc score is useful for CV risk stratification in AF patients after BPV replacement.

Comparing CHA2DS2-VA and CHA2DS2-VASc scores for stroke risk stratification in patients with atrial fibrillation: a temporal trends analysis from the retrospective Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) cohort.

Background: Contemporary data have shown a decrease in the ischaemic stroke risk associated with female sex in patients with atrial fibrillation (AF). We evaluated temporal trends in the predictive value of a non-sex CHA2DS2-VASc risk score (ie. CHA2DS2-VA). Methods: The FinACAF study covers all patients with incident AF between 2007 and 2018 in Finland from all levels of care. The CHA2DS2-VA score was compared with the CHA2DS2-VASc using continuous and category-based net reclassification indices (NRIs), integrated discrimination improvement (IDI), c-statistics and decision curve analyses. Findings: We identified 144,879 anticoagulant naïve patients with new-onset AF between 2007 and 2018 (49.9% women; mean age 72.1 years), of whom 3936 (2.7%) experienced ischaemic stroke during one-year follow-up. Based on both continuous and category-based NRIs, the CHA2DS2-VA score was inferior to the CHA2DS2-VASc in the early years (-0.333 (95% CI -0.411 to -0.261) and -0.118 (95% CI -0.137 to -0.099), respectively). However, the differences attenuated over time, and by the end of the study period, the continuous NRI became non-significant (-0.093 (95% CI -0.165 to 0.032)), whereas the category-based NRI reversed in favor of the CHA2DS2-VA (0.070 (95% CI 0.048-0.087)). The IDI was non-significant in early years (0.0009 (95% CI -0.0024 to 0.0037)), but over time became statistically significant in favor of the CHA2DS2-VA score (0.0022 (95% CI 0.0001-0.0044)). The Cox models fitted with the CHA2DS2-VA and the CHA2DS2-VASc scores exhibited comparable discriminative capability in the beginning of the study (p-value 0.63), but over time marginal differences in favor of the CHA2DS2-VA score emerged (p-value 0.0002). Interpretation: In 2007-2008 (when females had higher AF-related stroke risks than males), the CHA2DS2-VASc score outperformed the CHA2DS2-VA score, but the initial differences between the scores attenuated over time. By the end of the study period in 2017-2018 (with limited/no sex differences in AF-related stroke), there was marginal superiority for the CHA2DS2-VA score. Funding: This work was supported by the Aarne Koskelo Foundation, The Finnish Foundation for Cardiovascular Research, The Finnish State Research funding, and Helsinki and Uusimaa Hospital District research fund.

Comparative genomic analysis identifies potential adaptive variation in Mycoplasma ovipneumoniae.

Mycoplasma ovipneumoniae is associated with respiratory disease in wild and domestic Caprinae globally, with wide variation in disease outcomes within and between host species. To gain insight into phylogenetic structure and mechanisms of pathogenicity for this bacterial species, we compared M. ovipneumoniae genomes for 99 samples from 6 countries (Australia, Bosnia and Herzegovina, Brazil, China, France and USA) and 4 host species (domestic sheep, domestic goats, bighorn sheep and caribou). Core genome sequences of M. ovipneumoniae assemblies from domestic sheep and goats fell into two well-supported phylogenetic clades that are divergent enough to be considered different bacterial species, consistent with each of these two clades having an evolutionary origin in separate host species. Genome assemblies from bighorn sheep and caribou also fell within these two clades, indicating multiple spillover events, most commonly from domestic sheep. Pangenome analysis indicated a high percentage (91.4 %) of accessory genes (i.e. genes found only in a subset of assemblies) compared to core genes (i.e. genes found in all assemblies), potentially indicating a propensity for this pathogen to adapt to within-host conditions. In addition, many genes related to carbon metabolism, which is a virulence factor for Mycoplasmas, showed evidence for homologous recombination, a potential signature of adaptation. The presence or absence of annotated genes was very similar between sheep and goat clades, with only two annotated genes significantly clade-associated. However, three M. ovipneumoniae genome assemblies from asymptomatic caribou in Alaska formed a highly divergent subclade within the sheep clade that lacked 23 annotated genes compared to other assemblies, and many of these genes had functions related to carbon metabolism. Overall, our results suggest that adaptation of M. ovipneumoniae has involved evolution of carbon metabolism pathways and virulence mechanisms related to those pathways. The genes involved in these pathways, along with other genes identified as potentially involved in virulence in this study, are potential targets for future investigation into a possible genomic basis for the high variation observed in disease outcomes within and between wild and domestic host species.

Novel antibody-drug conjugates based on DXd-ADC technology.

In recent years, antibody-drug conjugate (ADC) technology, which uses monoclonal antibodies (mAbs) to specifically deliver effective cytotoxic payloads to tumor cells, has become a promising method of tumor targeted therapy. ADCs are a powerful class of biopharmaceuticals that link antibodies targeting specific antigens and small molecule drugs with potent cytotoxicity via a linker, thus enabling selective destruction of cancer cells while minimizing systemic toxicity. DXd is a topoisomerase I inhibitor that induces DNA damage leading to cell cycle arrest, making it an option for ADC payloads. The DXd-ADC technology, developed by Daiichi Sankyo, is a cutting-edge platform that produces a new generation of ADCs with improved therapeutic metrics and has shown significant therapeutic potential in various types of cancer. This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents.

Induction of Cell Death by Bifidobacterium infantis DS1685 in Colorectal and Breast Cancers via SMAD4/TGF-Beta Activation.

Therapeutic advancements in treatments for cancer, a leading cause of mortality worldwide, have lagged behind the increasing incidence of this disease. There is a growing interest in multifaceted approaches for cancer treatment, such as chemotherapy, targeted therapy, and immunotherapy, but due to their low efficacy and severe side effects, there is a need for the development of new cancer therapies. Recently, the human microbiome, which is comprised of various microorganisms, has emerged as an important research field due to its potential impact on cancer treatment. Among these microorganisms, Bifidobacterium infantis has been shown to significantly improve the efficacy of various anticancer drugs. However, research on the role of B. infantis in cancer treatment remains insufficient. Thus, in this study, we explored the anticancer effect of treatment with B. infantis DS1685 supernatant (BI sup) in colorectal and breast cancer cell lines. Treatment with BI sup induced SMAD4 expression to suppress cell growth in colon and breast cancer cells. Furthermore, a decrease in tumor cohesion was observed through the disruption of the regulation of EMT-related genes by BI sup in 3D spheroid models. Based on these findings, we anticipate that BI sup could play an adjunctive role in cancer therapy, and future cotreatment of BI sup with various anticancer drugs may lead to synergistic effects in cancer treatment.

Anticoagulation in Patients With Device-Detected Atrial Fibrillation With and Without a Prior Stroke or Transient Ischemic Attack: The NOAH-AFNET 6 Trial.

BACKGROUND: Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device-detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device-detected AF but with no ECG-documented AF is unclear. METHODS AND RESULTS: This prespecified analysis of the NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device-detected AF with and without a prior stroke or TIA in the randomized, double-blind, double-dummy NOAH-AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device-detected AF randomized in the NOAH-AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time-to-event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient-year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient-year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient-year]; no anticoagulation: 6 out of 131 [2.3% per patient-year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients). CONCLUSIONS: Anticoagulation appears to have ambiguous effects in patients with device-detected AF and a prior stroke or TIA in this hypothesis-generating analysis of the NOAH-AFNET 6 in the absence of ECG-documented AF, partially due to a low rate of stroke without anticoagulation.

Complete genome constellation of a dominant Bovine rotavirus genotype circulating in Bangladesh reveals NSP4 intragenic recombination with human strains.

Rotavirus A is a leading cause of non-bacterial gastroenteritis in humans and domesticated animals. Despite the vast diversity of bovine Rotavirus A strains documented in South Asian countries, there are very few whole genomes available for phylogenetic study. A cross-sectional study identified a high prevalence of the G6P[11] genotype of bovine Rotavirus A circulating in the commercial cattle population in Bangladesh. Next-generation sequencing and downstream phylogenetic analysis unveiled all 11 complete gene segments of this strain (BD_ROTA_CVASU), classifying it under the genomic constellation G6P[11]-I2-R2-C2-M2-A13-N2-T6-E2-H3, which belongs to a classical DS-1-like genomic backbone. We found strong evidence of intragenic recombination between human and bovine strains in the Non-structural protein 4 (NSP4) gene, which encodes a multifunctional enterotoxin. Our analyses highlight frequent zoonotic transmissions of rotaviruses in diverse human-animal interfaces, which might have contributed to the evolution and pathogenesis of this dominant genotype circulating in the commercial cattle population in Bangladesh.

Novel insight into neurofilament light chain and rhythm outcomes after catheter ablation of new-onset atrial fibrillation: A prospective cohort study.

BACKGROUND: Atrial fibrillation (AF) is an age-related disorder closely linked to autonomic nervous system dysfunction. Neurofilament light chain (NFL) protein is a biomarker for neurodegenerative diseases. OBJECTIVE: The purpose of this study was to evaluate the predictive value of NFL in forecasting AF recurrence after ablation. METHODS: Patients newly diagnosed with AF who underwent catheter ablation were included. Serum NFL levels were measured using enzyme-linked immunosorbent assay. The primary outcome was AF recurrence during follow-up. RESULTS: A total of 215 consecutive patients were enrolled, with average follow-up period of 10.69 months. During this period, 29 patients experienced AF recurrence. Multivariate Cox regression analysis revealed that high NFL levels (≥300 pg/mL) were an independent predictor of recurrence risk (adjusted hazard ratio [HR] 3.756; 95% confidence interval [CI] 1.392-10.136). The associations between NFL levels and AF recurrence were consistent across subgroups defined by age (>65 years), gender, hypertension, and paroxysmal AF. Restricted cubic spline analysis showed a consistent linear relationship across the entire range of NFL levels. Furthermore, incorporating NFL into the CHA2DS2-VASc score model significantly improved the prediction of recurrent AF risk, as demonstrated by time-dependent area under the curve and decision curve analysis. Notable enhancements were also observed in terms of net reclassification improvement (HR 0.464; 95% CI 0.226-0.675; P <.05) and integrated discrimination improvement (HR 0.087; 95% CI 0.017-0.183; P = .08). CONCLUSION: NFL may serve as an effective biomarker for risk stratification and therapeutic decision-making in patients with new-onset AF who have undergone catheter ablation.

Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.

In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1WT), the LMS-causing Pro269Ser mutant (PSS1P269S), and PSS1WT in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.