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Background and Objectives: Estimating heterogeneous treatment effects (HTEs) in randomized controlled trials (RCTs) has received substantial attention recently. This has led to the development of several statistical and machine learning (ML) algorithms to assess HTEs through identifying individualized treatment effects. However, a comprehensive review of these algorithms is lacking. We thus aimed to catalog and outline currently available statistical and ML methods for identifying HTEs via effect modeling using clinical RCT data and summarize how they have been applied in practice., Study Design and Setting: We performed a scoping review using prespecified search terms in MEDLINE and Embase, aiming to identify studies that assessed HTEs using advanced statistical and ML methods in RCT data published from 2010 to 2022., Results: Among a total of 32 studies identified in the review, 17 studies applied existing algorithms to RCT data, and 15 extended existing algorithms or proposed new algorithms. Applied algorithms included penalized regression, causal forest, Bayesian causal forest, and other metalearner frameworks. Of these methods, causal forest was the most frequently used (7 studies) followed by Bayesian causal forest (4 studies). Most applications were in cardiology (6 studies), followed by psychiatry (4 studies). We provide example R codes in simulated data to illustrate how to implement these algorithms., Conclusion: This review identified and outlined various algorithms currently used to identify HTEs and individualized treatment effects in RCT data. Given the increasing availability of new algorithms, analysts should carefully select them after examining model performance and considering how the models will be used in practice., Competing Interests: Declaration of competing interest All authors have completed the ICMJE uniform disclosure format (available on request from the corresponding author). M.A. received financial supports from Kyoto University related to this work. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several approaches for regulating health and disease by intestinal bacteria, bacteria isolated from food products, and food factors have been investigated; however, the molecular mechanisms underlying the interactions between these bacteria and their hosts are still unknown. Caenorhabditis elegans is a crucial model for exploring various biological phenomena and has been used in studying intestinal bacteria, mainly in the field of antiaging, anti-amyloid β activity in Alzheimer's disease, and its interaction to hosts. The nematode model is expected to be increasingly utilized for elucidating the interactions of beneficial bacteria or food factors with hosts. Herein, we review anti-aging and suppression of amyloid-β expression in a C. elegans model fed lactic acid bacteria, and our developed methods for orally administering food factors and assessing advanced glycation end products as an aging indicator., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Patients with low-to-normal body mass index (BMI; < 25.0 kg/m 2 ) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials., Methods: This cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0-22.4, 22.5-24.9, 25.0-29.9, 30.0-34.9, and 35.0 ≤ kg/m 2 ). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category., Results: Among participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m 2 , 1.9% [n = 5,350]; 20.0-22.4 kg/m 2 , 8.5% [n = 23,818]; and 22.5-24.9 kg/m 2 , 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m 2 , HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0-22.4 kg/m 2 , HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5-24.9 kg/m 2 , HR [95%CI] = 0.92 [0.84 to 1.01])., Conclusions: The protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors., (© 2024. The Author(s).)

Background and Aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC., Approach and Results: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758., Conclusions: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)

An 83-year-old woman presented with disturbance of consciousness and hand tremor. She had taken lithium carbonate 300 mg/day for bipolar disorder and magnesium oxide 660 mg/day for constipation. Blood tests revealed lithium poisoning, hypermagnesemia and acute kidney injury. Computed tomography showed colonic obstruction caused by cancer of the descending colon. In the outpatient section, her blood pressure decreased to 89/54 mmHg, and her heart rate dropped to 40 bpm. We considered that the obstructive ileus induced intravascular dehydration, which led to toxic serum concentrations of lithium and magnesium, triggering the emergence of severe arrythmia induced by sinus dysfunction. The patient was treated with fluid resuscitation and hemodialysis, followed by endoscopic stent replacement for the descending colon cancer obstruction. These treatments improved her general condition and alleviated the lithium poisoning, hypermagnesemia and colonic obstruction. Such a case is considered extremely rare., Competing Interests: We have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Although cardiovascular disease (CVD) is a known risk factor for depression, evidence is lacking regarding whether and to what extent a spouse's CVD is associated with the subsequent mental health of individuals., Objective: To examine the association between CVD onset in spouses and subsequent depression., Design, Setting, and Participants: This cohort study examined 277 142 matched married couples enrolled in the Japan Health Insurance Association health insurance program between April 2015 and March 2022, covering approximately 40% of the working-age population in Japan. Index individuals (primary insured) whose spouses (dependent) experienced incident CVD between April 2016 and March 2022 were 1:1 matched to controls whose spouses did not experience CVD. Matching was based on age, sex, income, or the onset date of the spouses' CVD. Data analysis was conducted from April 2016 to March 2022., Exposure: Spousal onset of CVD between fiscal years 2016 and 2021. The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes were used to identify the composite CVD outcomes (stroke, heart failure, and myocardial infarction)., Main Outcomes and Measures: Multivariate Cox proportional hazards models were used to investigate the association between spouses' new-onset CVD and individuals' depression, adjusting for sociodemographic characteristics and comorbidities of index individuals (diabetes, hypertension, and CVD) and spouses (diabetes, hypertension, and depression). Subgroup analyses were conducted according to sex, age, income levels, and history of CVD., Results: Among 277 142 matched pairs of married couples, 263 610 (95.1%) had a male index individual; the mean (SD) age of index individuals was 58.2 (10.2) years. A new onset of depression was observed in 4876 individuals (1.8%). In multivariable Cox models, there was an association between the spouse's CVD and the individuals' depression (hazard ratio, 1.13 [95% CI, 1.07-1.20]). The subgroup analysis found no evidence of heterogeneity in sex, age, income level, or CVD history. The results were consistent when additionally adjusted for health behaviors (smoking, alcohol consumption, physical activity, and use of antihypertensive drugs) and objectively measured physical health conditions (body mass index, blood pressure, cholesterol levels, glucose levels, and estimated glomerular filtration rate) (hazard ratio, 1.16 [95% CI, 1.06-1.28])., Conclusions and Relevance: In this nationwide cohort study of matched couples, a spouse's onset of CVD was associated with an increased risk of an individual's depression. These findings highlight the importance of preventive care for mental health disorders in individuals whose spouses experience incident CVD.

Lactic acid bacteria (LAB) contribute to human health, and LAB functionality has been studied using Caenorhabditis elegans as an alternative host. However, many studies have focused on the efficacy of a single strain of LAB, and few reports have compared various LAB strains. In this study, we examined the effects of 15 strains of LAB isolated from vegetables, meat, and fermented foods on nematode longevity and healthy lifespan. To reduce the frequency of laborious survival observations, we performed a lifespan assay on agar plates containing 2'-deoxy-5-fluorouridine (FUdR), which inhibits egg hatching and prevents generation mixing. Four beneficial strains showed significant lifespan extension and increased spontaneous nematode mobility, regardless of treatment with or without FUdR and the frequency of survival observation. These results suggested increased longevity and an extended healthy lifespan, confirming the reliability of our method. The four strains are expected to show anti-ageing effects besides longevity and have effects on age-related degenerative diseases. Our labor-saving method can be used as an alternative to conventional methods and enable simultaneous screening of multiple strains. Future research could explore factors contributing to lifespan regulation by comparing and verifying differential strain effects on lifespan., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

The optimal interval between the first and second doses of COVID-19 mRNA vaccines has not been thoroughly evaluated. Employing a target trial emulation approach, we compared the effectiveness of different interdose intervals among >6 million mRNA vaccine recipients in Georgia, USA, from December 2020 to March 2022. We compared three protocols defined by interdose interval: recommended by the Food and Drug Administration (FDA) (17-25 days for Pfizer-BioNTech; 24-32 days for Moderna), late-but-allowable (26-42 days for Pfizer-BioNTech; 33-49 days for Moderna), and late ( ≥ 43 days for Pfizer-BioNTech; ≥50 days for Moderna). In the short-term, the risk of SARS-CoV-2 infection was lowest under the FDA-recommended protocol. Longer-term, the late-but-allowable protocol resulted in the lowest risk (risk ratio on Day 120 after the first dose administration compared to the FDA-recommended protocol: 0.83 [95% confidence interval: 0.82-0.84]). Here, we showed that delaying the second dose by 1-2 weeks may provide stronger long-term protection., (© 2024. The Author(s).)

Farmlands are becoming more important as waterfowl foraging habitats, while natural wetlands are being lost globally. However, it is unclear how waterfowl coexist in agricultural landscapes by resource partitioning. We evaluated the diets of seven sympatric dabbling ducks foraging in rice paddy and lotus fields around Lake Kasumigaura, the second largest lake in Japan, during two wintering seasons (from November to February) by faecal DNA metabarcoding using chloroplast trnL and mitochondrial CO1 region sequences. We examined 420 faecal samples and found different patterns of dietary diversity and composition among the duck species. The pattern also differed between plant and invertebrate food. Dietary niche partitioning was clear in plant food. Large-bodied ducks intensively use crop plants, and other ducks might mediate competition by using terrestrial and aquatic plants that are suitable for their foraging behaviours or microhabitats. Dietary segregation among species was the most apparent in February, when the abundance of foraging ducks was the largest. This study illustrated the complex pattern of dietary niche partitioning of dabbling ducks in agricultural landscapes, which might be difficult to evaluate by conventional approaches. The availability of crop plants, as well as other plant food resources in flooted areas and farmland dikes, may enable ducks to coexist by spatial or behavioural resource partitioning., (© 2022 John Wiley & Sons Ltd.)

The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) expression has been reported in advanced chronic liver diseases as well as cancer tissues. We observed an association between related to HCC incidence and serum AKR1B10 by analyzing patients under treatment with NAs. Serum AKR1B10 levels measured by ELISA were higher in HCC cases under NA treatment compared with non-HCC cases and were associated with lamivudine- and adefovir pivoxil-, but not entecavir- or tenofovir alafenamide-treated cases. The latter drugs did not increase AKR1B10 values even in HCC cases, suggesting that they influence the reduction of AKR1B10 in any cases. This analysis was supported by in-vitro examination, which showed reduced AKR1B10 expression by entecavir and tenofovir via immunofluorescence staining. In conclusion there was a relationship between HBV-related HCC incidence and AKR1B10 under nucleos(t)ide analogues, especially in the use of lamivudine and adefovir pivoxil, but entecavir and tenofovir had suppressive effects of AKR1B10., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To examine differences in the association between educational attainment and mortality by the presence of diabetes and diabetic retinopathy (DR)-a major complication of diabetes., Patients and Methods: We used a nationally representative sample of 54,924 US adults aged 20 years or older with diabetes from the National Health and Nutrition Examination Survey 1999-2018 and its mortality data through 2019. We applied the multivariable Cox proportional hazard models to investigate the associations between educational attainment (low, less than high school; middle, high school; and high, more than high school) and all-cause mortality according to diabetes status: nondiabetes, diabetes without DR, and diabetes with DR. Differences in the survival rate by educational attainment were evaluated using the slope inequality index (SII)., Results: Among the 54,924 participants (mean age, 49.9 years), adults in the low educational group reported an increased risk of all-cause mortality compared with those of the high educational group in any diabetes status (nondiabetes-hazard ratio [HR], 1.69; 95% CI, 1.56-1.82; diabetes without DR-HR, 1.61; 95% CI, 1.37-1.90; diabetes with DR-HR, 1.43; 95% CI, 1.10-1.86). SIIs among the diabetes without DR group and diabetes with DR group were 22.17 and 20.87 per 1000 person-years, respectively, which were 2 times greater than those among the nondiabetes group (SII=9.94)., Conclusion: The differences in the mortality risks owing to the educational attainment increased by the presence of diabetes regardless of the complication of DR. Our findings indicate that prevention of diabetes itself is critical to mitigate health disparities by socioeconomic status such as education status., Competing Interests: All authors state that they have no conflict of interest., (© 2023 The Authors.)

Background: Endoscopic gastroduodenal stent (GDS) placement is widely used as a safe and effective method to rapidly improve gastrointestinal symptoms of malignant gastric outlet obstruction (MGOO). While previous studies reported the utility of chemotherapy after GDS placement for prognosis improvement, they did not fully address the issue of immortal time bias., Objectives: To examine the association between prognosis and clinical course following endoscopic GDS placement, using a time-dependent analysis., Design: Multicenter retrospective cohort study., Methods: This study included 216 MGOO patients who underwent GDS placement between April 2010 and August 2020. Data of patient baseline characteristics, including age, gender, cancer type, performance status (PS), GDS type and length, GDS placement location, gastric outlet obstruction scoring system (GOOSS) score, and history of chemotherapy before GDS were collected. The clinical course following GDS placement was evaluated by GOOSS score, stent dysfunction, cholangitis, and chemotherapy. A Cox proportional hazards model was used to identify prognostic factors after GDS placement. Stent dysfunction, post-stent cholangitis, and post-stent chemotherapy were analyzed as time-dependent covariates., Results: Mean GOOSS scores before and after GDS were 0.7 and 2.4, respectively, with significant improvement after GDS placement ( p  < 0.001). The median survival time after GDS placement was 79 [95% confidence interval (CI): 68-103] days. In multivariate Cox proportional hazards model with time-dependent covariates, PS 0-1 [hazard ratio (HR): 0.55, 95% CI: 0.40-0.75; p  < 0.001], ascites (HR: 1.45, 95% CI: 1.04-2.01; p  = 0.028), metastasis (HR: 1.84, 95% CI: 1.31-2.58; p  < 0.001), post-stent cholangitis (HR: 2.38, 95% CI: 1.37-4.15; p  = 0.002), and post-stent chemotherapy (HR: 0.01, 95% CI: 0.002-0.10; p  < 0.001) significantly affected prognosis after GDS placement., Conclusion: Post-stent cholangitis and tolerability to receive chemotherapy after GDS placement influenced prognosis in MGOO patients., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

We propose a partial point cloud completion approach for scenes that are composed of multiple objects. We focus on pairwise scenes where two objects are in close proximity and are contextually related to each other, such as a chair tucked in a desk, a fruit in a basket, a hat on a hook and a flower in a vase. Different from existing point cloud completion methods, which mainly focus on single objects, we design a network that encodes not only the geometry of the individual shapes, but also the spatial relations between different objects. More specifically, we complete missing parts of the objects in a conditional manner, where the partial or completed point cloud of the other object is used as an additional input to help predict missing parts. Based on the idea of conditional completion, we further propose a two-path network, which is guided by a consistency loss between different sequences of completion. Our method can handle difficult cases where the objects heavily occlude each other. Also, it only requires a small set of training data to reconstruct the interaction area compared to existing completion approaches. We evaluate our method qualitatively and quantitatively via ablation studies and in comparison to the state-of-the-art point cloud completion methods.

In Alzheimer's disease (AD), the amyloid-β (Aβ) protein begins to accumulate in the brain 20 years prior to any dementia symptoms manifestation, in which Aβ aggregates in the brain, causing destruction of nerve cells and resulting in memory impairments. Lifestyle and diet appear to inhibit Aβ production and amyloid deposition. Therefore, identifying factors that prevent Aβ production and administering them before the onset of AD, may be an effective preventive method. Lactic acid bacteria (LAB) exhibit various health effects on the host and are expected to have protective effects on neurological functions via brain-gut correlation. However, the protective effects of LAB against Aβ are not well understood. We investigated whether LAB feeding could ameliorate the toxicity of Aβ peptide accumulation in transgenic Caenorhabditis elegans expressing the human Aβ peptide in neurons or muscle as an AD model. Aβ expressed in muscle caused myopathy and worm paralysis, while Aβ in neurons disturbed chemotactic activity. Among 14 screened strains, Lactococcus laudensis (LL) and Pediococcus parvulus (PP) prevented the AD worms from losing their chemotaxis behavior and becoming paralyzed by the Aβ peptide. Immunostaining and western blotting indicated that Aβ peptide was significantly suppressed in worms fed these two strains, and binding of the Aβ to vitellogenin was particularly inhibited. Conversely, the mRNA level of the Aβ gene did not change between LL- or PP-fed worms and the control. In conclusion, LL and PP alleviate neurotoxicity by inhibiting Aβ accumulation; AD model worms can be used to screen efficient LAB for AD prevention., Competing Interests: Declaration of Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Lactic acid bacteria are beneficial to Caenorhabditis elegans; however, bacteria acting as probiotics in nematodes may not necessarily have probiotic functions in humans. Lactococcus cremoris subsp. cremoris reportedly has probiotic functions in humans. Therefore, we determined whether the strain FC could exert probiotic effects in C. elegans in terms of improving host defenses and extending life span. Live FC successfully extended the life span and enhanced host defense compared to Escherichia coli OP50 (OP50), a standard food source for C. elegans. The FC-fed worms were tolerant to Salmonella enterica subsp. enterica serovar Enteritidis or Staphylococcus aureus infection and had better survival than the OP50-fed control worms. Further, the chemotaxis index, an indicator of perception ability, was more stable and significantly higher in FC-fed worms than in the control worms. The increase in autofluorescence from advanced glycation end products (AGEs) with aging was also ameliorated in FC-fed worms. FC showed beneficial effects in daf-16 and pmk-1 mutants, but not in skn-1 mutants. Since SKN-1 is the C. elegans ortholog of Nrf2, we measured the transcription of heme oxygenase-1 (HO-1), which is regulated by Nrf2, in murine macrophages and found that HO-1 mRNA expression was increased >5 times by inoculation with FC cells. Thus, FC could exert antisenescence effects via the SKN-1/Nrf2 pathway. This study showed for the first time that FC supported perceptive function and suppressed AGEs in nematodes as probiotic bacteria. Therefore, C. elegans can be an alternative model to screen for probiotic bacteria that can be used for antisenescence effects in humans. IMPORTANCE Aging is one of our greatest challenges. The World Health Organization proposed that "active aging" might encourage people to continue to work according to their capacities and preferences as they grow old and would prevent or delay disabilities and chronic diseases that are costly to both individuals and the society, considering that disease prevention is more economical than treatment. Probiotic bacteria, such as lactobacilli, are live microorganisms that exert beneficial effects on human health when ingested in sufficient amounts and can promote longevity. The significance of this study is that it revealed the antisenescence and various beneficial effects of the representative probiotic bacterium Lactococcus cremoris subsp. cremoris strain FC exerted via the SKN-1/Nrf2 pathway in the nematode Caenorhabditis elegans.

We propose IM3D+, a novel approach to reconstructing 3D motion data from a flexible magnetic flux sensor array using deep learning and a structure-aware temporal bilateral filter. Computing the 3D configuration of markers (inductor-capacitor (LC) coils) from flux sensor data is difficult because the existing numerical approaches suffer from system noise, dead angles, the need for initialization, and limitations in the sensor array's layout. We solve these issues with deep neural networks to learn the regression from the simulation flux values to the LC coils' 3D configuration, which can be applied to the actual LC coils at any location and orientation within the capture volume. To cope with the influence of system noise and the dead-angle limitation caused by the characteristics of the hardware and sensing principle, we propose a structure-aware temporal bilateral filter for reconstructing motion sequences. Our method can track various movements, including fingers that manipulate objects, beetles that move inside a vivarium with leaves and soil, and the flow of opaque fluid. Since no power supply is needed for the lightweight wireless markers, our method can robustly track movements for a very long time, making it suitable for various types of observations whose tracking is difficult with existing motion-tracking systems. Furthermore, the flexibility of the flux sensor layout allows users to reconfigure it based on their own applications, thus making our approach suitable for a variety of virtual reality applications.