Immunogenicity and Cross-Protection Efficacy of a Genotype F-Derived Attenuated Virus Vaccine Candidate against Mumps Virus in Mice.

Mumps virus (MuV) causes an acute contagious human disease characterized by swelling of the parotid glands. Despite the near elimination of mumps in many countries, the disease has recurred, even in vaccinated populations, especially adolescents. Immunization effectivity of the genotype A vaccine strain Jeryl Lynn (JL) is declining as genotype A is no longer predominant; therefore, a new vaccine strain and booster vaccine are required. We generated a cell culture-adapted MuV genotype F called F30 and evaluated its immunogenicity and cross-protective activity against diverse genotypes. F30 genome nucleotide sequence determination revealed changes in the NP, L, SH, and HN genes, leading to five amino acid changes compared to a minimally passaged stock (F10). F30 showed delayed growth, smaller plaque size in Vero cells, and lower neurotoxicity in neonatal mice than F10. Furthermore, F30 was immunogenic to other genotypes, including the JL vaccine strain, with higher efficacy than that of JL for homologous and heterologous immunization. Further, F30 exhibited cross-protective immunity against MuV genotypes F and G in Ifnar-/- mice after a third immunization with F30 following two doses of JL. Our data suggest that the live-attenuated virus F30 could be an effective booster vaccine to control breakthrough infections and mumps epidemics.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Current Status of SNOMED CT National Extensions and Terminology Managements.

We reviewed and surveyed 15 SNOMEDCT national member countries for SNOMED CT national extensions and terminology managements. We found that national extensions were used for adding new contents, developing reference sets, translating, and mapping with other classification system; and terminology management varies in composition and content due to healthcare environment of each member country, eHealth strategy, and infrastructure of national release centers.

Effect of Anterioposterior Weight-Shift Training with Visual Biofeedback in Patients with Step Length Asymmetry after Subacute Stroke.

Step length asymmetry is a characteristic feature of gait in post-stroke patients. A novel anterioposterior weight-shift training method with visual biofeedback (AP training) was developed to improve the forward progression of the trunk. This study aimed to investigate the effect of AP training on gait asymmetries, patterns, and gait-related function in subacute stroke patients. Forty-six subacute stroke patients were randomly assigned to the AP training group or the control group. The AP training group received conventional gait training and AP training five times per week for 4 weeks. The control group received the same intensity of conventional gait training with patient education for self-anterior weight shifting. Plantar pressure analysis, gait analysis, energy consumption, and gait-related behavioral parameters were assessed before and after training. The AP training group showed significant improvement in step length asymmetry, forefoot contact area and pressure, Berg balance scale score, and Fugl-Meyer assessment scale of lower extremity score compared to the control group (p < 0.05). However, there was no significant between-group difference with respect to energy cost and kinetic and kinematic gait parameters. In conclusion, AP training may help improve the asymmetric step length in stroke patients, and also improve anterior weight shifting, balance, and motor function in subacute stroke survivors.

Unsupervised Domain Adaptation for Mitigating Sensor Variability and Interspecies Heterogeneity in Animal Activity Recognition.

Animal activity recognition (AAR) using wearable sensor data has gained significant attention due to its applications in monitoring and understanding animal behavior. However, two major challenges hinder the development of robust AAR models: domain variability and the difficulty of obtaining labeled datasets. To address this issue, this study intensively investigates the impact of unsupervised domain adaptation (UDA) for AAR. We compared three distinct types of UDA techniques: minimizing divergence-based, adversarial-based, and reconstruction-based approaches. By leveraging UDA, AAR classifiers enable the model to learn domain-invariant features, allowing classifiers trained on the source domain to perform well on the target domain without labels. We evaluated the effectiveness of UDA techniques using dog movement sensor data and additional data from horses. The application of UDA across sensor positions (neck and back), sizes (middle-sized and large-sized), and gender (female and male) within the dog data, as well as across species (dog and horses), exhibits significant improvements in the classification performance and reduced the domain discrepancy. The results highlight the potential of UDA to mitigate the domain shift and enhance AAR in various settings and for different animal species, providing valuable insights for practical applications in real-world scenarios where labeled data is scarce.

High Platelet Reactivity Combined with CYP2C19 Genotype in Predicting Outcomes in East Asian Patients Undergoing Percutaneous Coronary Intervention.

Loss-of-function (LoF) alleles of cytochrome P450 2C19 (CYP2C19), which are prevalent in East Asians, are linked to high platelet reactivity (HPR) phenotype and poor prognosis. We aimed to investigate the incremental predictive value of HPR combined with CYP2C19 genotype in predicting outcomes after drug-eluting stent (DES) implantation. The patients treated with platelet function and genotype-related long-term prognosis in drug-eluting stent (PTRG-DES) consortium enrolled a total of 13,160 Korean patients treated with DES who had platelet function test (PFT) or CYP2C19 genotype, of which, 6,717 patients with PFT and genotype together were categorized. HPR was defined as VerifyNow ≥ 252 P2Y12 reaction unit. The primary outcome was the incidence of major adverse cardiac and cerebrovascular event (MACCE) 5 years after treatment. The patients with both HPR and CYP2C19 LoF/LoF had the highest MACCE rates (6.2%) and increased MACCE risk (adjusted hazard ratio: 1.89, 95% confidence interval: 1.20-2.91, P = 0.006) compared with those without both HPR and CYP2C19 LoF/LoF. There was no effect of interaction between HPR and CYP2C19 genotype on the primary outcome (P = 0.424). Adding combined HPR and CYP2C19 genotype to the conventional model had an incremental influence in predicting MACCE and stent thrombosis. Compared to the model including HPR or CYP2C19 genotype alone, a combination model significantly improved the risk stratification for stent thrombosis but not MACCE. In DES-treated East Asian patients, the combined evaluation of PFT results and CYP2C19 genotyping might improve risk prediction of ischemic events during clopidogrel treatment.

Evaluation of Silk Fibroin/Gellan Gum Hydrogels with Controlled Molecular Weight through Silk Fibroin Hydrolysis for Tissue Engineering Application.

Hydrogel is a versatile material that can be manipulated to achieve the desired physicochemical properties, such as stiffness, pore size, and viscoelasticity. Traditionally, these properties have been controlled through parameters such as concentration and pH adjustments. In this study, we focused on exploring the potential of hydrolyzed silk fibroin (HSF) as a molecular weight-modulating agent to control the physicochemical properties of double-composite hydrogels. We developed a synergistic dual-crosslinked hydrogel by combining ionically crosslinked silk fibroin with gellan gum (GG). The hydrolysis of silk fibroin not only enhanced its hydrophilicity but also enabled adjustments in its mechanical properties, including the pore size, initial modulus elasticity, and relaxation time. Moreover, biocompatibility assessments based on cell viability tests confirmed the potential of these hydrogels as biocompatible materials. By highlighting the significance of developing an HSF/GG dual-crosslinked hydrogel, this study contributes to the advancement of novel double-composite hydrogels with remarkable biocompatibility. Overall, our findings demonstrate the capability of controlling the mechanical properties of hydrogels through molecular weight modulation via hydrolysis and highlight the development of a biocompatible HSF/GG dual-crosslinked hydrogel with potential biomedical applications.

Treatment Strategies of Improving Quality of Care in Patients With Heart Failure.

Heart failure (HF) is a global health problem closely related to morbidity and mortality. As the burden of HF increases, it is necessary to manage and treat this condition well. However, there are differences between real-world practice and guidelines for the optimal treatment for HF. Patient-related, healthcare provider-related, and health system-related factors contribute to poor adherence to optimal care. This review article aims to examine HF treatment patterns and treatment adherence in real-world practice, identify clinical gaps to suggest ways to improve the quality of care for HF and clinical outcomes for patients with HF. Although it is important to optimize treatment based on evidence-based guidelines to the greatest extent, it is known that there is still poor treatment adherence, and many patients do not receive guideline-directed medical therapy, especially at the early stages. To improve medication adherence, qualitative evaluation through performance measurement, as well as education of patients, caregivers and medical staff through a multidisciplinary approach are important.

Factors influencing left ventricular thrombus resolution and its significance on clinical outcomes.

AIMS: A left ventricular thrombus (LVT) is not uncommon in patients with impaired LV systolic function. However, the treatment strategy for LVT has not yet been fully established. We aimed to identify the factors influencing LVT resolution and the significance of LVT resolution on clinical outcomes. METHODS: We retrospectively investigated patients diagnosed with LVT with left ventricular ejection fraction (LVEF) < 50% on transthoracic echocardiography from January 2010 to July 2021 in a single tertiary centre. LVT resolution was monitored through serial follow-up transthoracic echocardiography. The primary clinical outcome was a composite of all-cause death, stroke, transient ischaemic attack, and arterial thromboembolic events. LVT recurrence was also evaluated in patients with LVT resolution. RESULTS: There were 212 patients diagnosed with LVT (mean age, 60.5 ± 14.0 years; male, 82.5%). The mean LVEF was 33.1 ± 10.9%, and 71.7% of patients were diagnosed with ischaemic cardiomyopathy. Most patients were treated with vitamin K antagonists (86.7%), and 28 patients (13.2%) were treated with direct oral anticoagulants or low molecular weight heparin. LVT resolution was observed in 179 patients (84.4%). LVEF improvement failure within 6 months was a significant factor hindering LVT resolution (hazard ratio, HR: 0.52, 95% confidence interval, CI: 0.31-0.85, P = 0.010). During a median 4.0 years of follow-up (interquartile range, IQR: 1.9 to 7.3 years), 32 patients (15.1%) experienced primary outcomes (18 all-cause deaths, 15 strokes, and 3 arterial thromboembolisms) and 20 patients (11.2%) experienced LVT recurrence after LVT resolution. LVT resolution was independently associated with a lower risk for primary outcomes (HR: 0.45, 95% CI: 0.21-0.98, P = 0.045). In the patients with resolved LVT, discontinuation or duration of anticoagulation after resolution were not significant predictors for LVT recurrence, but LVEF improvement failure at LVT resolution was associated with a significantly higher risk of LVT recurrence (HR: 3.10, 95% CI: 1.23-7.78, P = 0.016). CONCLUSIONS: This study suggests that LVT resolution is an important predictor for favourable clinical outcomes. LVEF improvement failure interfered with LVT resolution and appeared to be a crucial factor for LVT recurrence. After LVT resolution, continuation of anticoagulation did not seem to impact LVT recurrence and the prognosis.

Effects of continuous positive airway pressure therapy on left ventricular performance in patients with severe obstructive sleep apnea.

We investigated myocardial performance concerning obstructive sleep apnea (OSA) severity and the benefits of continuous positive airway pressure (CPAP) therapy. In this randomized sham-controlled trial, 52 patients (mean age, 49 years; 92%, males; mean AHI, 59) with severe OSA were randomly assigned to receive either CPAP or sham treatment for 3 months. The severity of OSA was determined using the apnea/hypopnea index (AHI), oxygen desaturation index (ODI), percentage of sleep time below 90% oxygen saturation (T90), and average O2 saturation during sleep (mean SpO2). We compared the changes in myocardial work after 3 months of CPAP (n = 26) versus the sham group (n = 26) at rest and during an exercise stress test. Unlike AHI or ODI, indices of hypoxemia including T90 and mean SpO2 were significantly correlated with global constructive work, as defined by work of left ventricle (LV) that contributes to LV ejection during systole (T90, ß = 0.393, p = 0.012; mean SpO2, ß = 0.331, p = 0.048), and global wasted work (GWW), as defined by work of LV that does not contribute to LV ejection (T90, ß = 0.363, p = 0.015; mean SpO2, ß = - 0.370, p = 0.019). After 3 months, GWW decreased (80.0 ± 49.2 to 60.8 ± 26.3, p = 0.009) and global work efficiency increased (94.0 ± 4.5 to 95.7 ± 2.0, p = 0.008) in the CPAP group compared to those in the sham group. At the 3-month follow-up exercise stress echocardiography, worsening of GWW during exercise was significantly decreased in the CPAP group compared to that in the sham group (p = 0.045 at 50 W). Hypoxemia indices were closely associated with myocardial performance in patients with severe OSA. CPAP treatment for 3 months improved left ventricular myocardial performance by decreasing wasted work and increasing work efficacy compared to the sham treatment.

Impact of reduced night work on shift workers' sleep using difference-in-difference estimation.

OBJECTIVES: We used a quasi-experimental design to investigate the impact of a change in the shift work system by reducing overnight work on the sleep health of workers. METHODS: A difference-in-difference (DID) analysis was used to investigate changes in sleep time and sleep quality between the experimental group (shift workers, N = 116 in 2007 and N = 118 in 2013) and the control group (regular day workers, N = 256 in 2007 and N = 185 in 2013) before and after a change in the shift system that eliminated overnight work. The sleep outcomes were measured using a questionnaire that inquired about sleep duration, mid-sleep awakenings, and subjective sleep quality. We used a generalized estimating equation model to investigate differences in the prevalence of sleep-related outcomes between baseline and post-intervention. RESULTS: In the DID models, the sleep time per day (+0.5 h), the prevalence of awakening during sleep (-13.9%), and self-reported poor sleep quality (-34.9%) were improved with statistical significance during evening shifts in the experimental group, but there was no significant change during day shifts in the experimental group compared to the control group after the implementation of the new shift system without overnight shift. CONCLUSIONS: Quitting overnight work improved sleep health of shift workers.

Remnant cholesterol, low-density lipoprotein cholesterol, and incident cardiovascular disease among Koreans: a national population-based study.

AIMS: The synergistic association of remnant cholesterol (remnant-C) and low-density lipoprotein cholesterol (LDL-C) levels with incident cardiovascular disease (CVD) in various subgroups of Koreans was investigated. METHODS AND RESULTS: Using the national health insurance data, we included subjects aged between 40 and 70 years without a history of CVD and at least two health screenings between 2009 and 2011. The subjects were divided into four groups by LDL-C and remnant-C levels. The primary outcome was CVD, which occurred between 2014 and 2017. Among 3 686 034 (45.6% women) subjects, 144 004 cardiovascular events occurred. Individuals in both high LDL-C and high remnant-C [hazard ratio (HR) 1.266, 95% confidence interval (CI) 1.243-1.289; 7.9%], high LDL-C only (HR 1.098, 95% CI 1.083-1.113; 21.2%), and high remnant-C only groups (HR 1.102, 95% CI 1.087-1.118; 19.1%) had higher risks of CVD than those in the reference group (LDL-C < 3.4 mmol/L and remnant-C < 0.8 mmol/L; 51.8%). A continuous and linear increase in CVD risk was found in those with higher remnant-C levels after adjustment for several confounders, including LDL-C levels. The association of remnant-C ≥ 0.8 mmol/L with an increased CVD risk was consistent across various strata. CONCLUSIONS: Combined high remnant-C and LDL-C levels confer a higher CVD risk than that individually. Elevated remnant-C values independent of LDL-C levels were associated with a risk of incident CVD. Remnant cholesterol levels in addition to LDL-C levels are important considerations in risk stratification for the primary prevention of CVD.

Since remnant-C has recently emerged as a potential risk factor for CVD, the synergistic association of LDL-C and remnant-C with CVD has been investigated among 3 686 034 Koreans (45.6% women) without preceding CVD using nationwide population-based big data. Remnant cholesterol remained proportional to the risk of incident CVD after adjusting for multiple variables, including LDL-C levels.Low-density lipoprotein cholesterol and remnant-C synergistically contributed to incident CVD.

Complete genome sequence and genome characterization of a novel potyvirus from Lamprocapnos spectabilis.

The genome of a new potyvirus from a Lamprocapnos spectabilis plant in South Korea was sequenced by high-throughput sequencing and confirmed by Sanger sequencing. The new potyvirus was tentatively named "lamprocapnos virus A" (LaVA); its complete genome contains 9,745 nucleotides, excluding the 3'-terminal poly(A) tail. The LaVA genome structure is similar to that of members of the genus Potyvirus and contains an open reading frame encoding a large putative polyprotein of 3,120 amino acids (aa) with conserved motifs. The complete genome shared 48%-56% nucleotide sequence identity and the polyprotein shared 41%-52% aa sequence identity with those of other potyviruses. These values are below the standard thresholds for potyvirus species demarcation. Phylogenetic analysis based on polyprotein sequences showed that LaVA belongs to the genus Potyvirus. To our knowledge, this is the first report of the complete genome sequence and genome characterization of a potyvirus infecting Lamprocapnos spectabilis.

Evaluating GPCR modeling and docking strategies in the era of deep learning-based protein structure prediction.

While deep learning (DL) has brought a revolution in the protein structure prediction field, still an important question remains how the revolution can be transferred to advances in structure-based drug discovery. Because the lessons from the recent GPCR dock challenge were inconclusive primarily due to the size of the dataset, in this work we further elaborated on 70 diverse GPCR complexes bound to either small molecules or peptides to investigate the best-practice modeling and docking strategies for GPCR drug discovery. From our quantitative analysis, it is shown that substantial improvements in docking and virtual screening have been possible by the advance in DL-based protein structure predictions with respect to the expected results from the combination of best pre-DL tools. The success rate of docking on DL-based model structures approaches that of cross-docking on experimental structures, showing over 30% improvement from the best pre-DL protocols. This amount of performance could be achieved only when two modeling points were considered properly: 1) correct functional-state modeling of receptors and 2) receptor-flexible docking. Best-practice modeling strategies and the model confidence estimation metric suggested in this work may serve as a guideline for future computer-aided GPCR drug discovery scenarios.

Left atrial strain and clinical outcome in patients with significant mitral regurgitation after surgical mitral valve repair.

Background: This study aimed to investigate the prognostic value of left atrial (LA) strain in patients with significant mitral regurgitation (MR) after surgical mitral valve (MV) repair. Methods: A total of 169 patients (age 55 ± 15 years, 88 men) with moderate or severe MR on echocardiogram at least 6 months after surgical MV repair for primary MR were studied. Two-dimensional, Doppler, and speckle tracking echocardiography including MR quantitative measures, chamber size, and LA strain were comprehensively analyzed. The primary outcome was a composite of cardiovascular death, heart failure hospitalization, and MV reoperation. Results: During a median of 44.4 months [interquartile range (IQR): 18.7-70.3 months] of follow-up, 44 patients (26%) experienced clinical events; these patients had greater MR volume, elevated mean diastolic pressure gradient and pulmonary artery systolic pressure, and enlarged chamber size compared with patients who did not experience events. Patients with events showed significantly lower LA strain [13.3% (IQR: 9.3-23.8%) vs. 24.0% (IQR: 13.1-31.4%), p = 0.003] and higher MR volume/LA strain [3.09 ml/% (IQR: 2.06-5.80 ml/%) vs. 1.57 ml/% (IQR: 1.04-2.72 ml/%), p < 0.001] than those without events. MR volume/LA strain was a good predictor of clinical outcomes (cut-off 1.57 ml/%, area under the curve 0.754, p < 0.001). On multivariable Cox proportional analysis, MR volume/LA strain was independently associated with clinical outcomes (hazard ratio: 1.269, 95% confidence interval: 1.109-1.452, p < 0.001) along with pulmonary artery systolic pressure. Conclusion: A measure of LA mechanical function relative to MR volume is associated with clinical outcomes in patients with significant MR after surgical MV repair.

A Comparative Study on the Influence of Undersampling and Oversampling Techniques for the Classification of Physical Activities Using an Imbalanced Accelerometer Dataset.

Accelerometer data collected from wearable devices have recently been used to monitor physical activities (PAs) in daily life. While the intensity of PAs can be distinguished with a cut-off approach, it is important to discriminate different behaviors with similar accelerometry patterns to estimate energy expenditure. We aim to overcome the data imbalance problem that negatively affects machine learning-based PA classification by extracting well-defined features and applying undersampling and oversampling methods. We extracted various temporal, spectral, and nonlinear features from wrist-, hip-, and ankle-worn accelerometer data. Then, the influences of undersampilng and oversampling were compared using various ML and DL approaches. Among various ML and DL models, ensemble methods including random forest (RF) and adaptive boosting (AdaBoost) exhibited great performance in differentiating sedentary behavior (driving) and three walking types (walking on level ground, ascending stairs, and descending stairs) even in a cross-subject paradigm. The undersampling approach, which has a low computational cost, exhibited classification results unbiased to the majority class. In addition, we found that RF could automatically select relevant features for PA classification depending on the sensor location by examining the importance of each node in multiple decision trees (DTs). This study proposes that ensemble learning using well-defined feature sets combined with the undersampling approach is robust for imbalanced datasets in PA classification. This approach will be useful for PA classification in the free-living situation, where data imbalance problems between classes are common.