Search

Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.

Epidemiological studies suggest that poor nutrition during pregnancy predisposes offspring to the development of lifestyle-related noncommunicable diseases and psychiatric disorders later in life. However, the molecular mechanisms underlying this predisposition are not well understood. In our previous study, using rats as model animals, we showed that behavioral impairments are induced by prenatal undernutrition. In this study, we identified solute carrier 22 family member 23 (Slc22a23) as a gene that is irreversibly upregulated in the rat brain by undernutrition during fetal development. Because the substrate of the SLC22A23 transporter has not yet been identified and the biological role of the Slc22a23 gene in vivo is not fully understood, we generated pan-Slc22a23 knockout rats and examined their phenotype in detail. The Slc22a23 knockout rats showed a lean phenotype, an increase in spontaneous locomotion, and improved endurance, indicating that they are not overweight and are even healthier in an ad libitum feeding environment. However, the knockout rats had reduced hippocampal volume, and the behavioral analysis suggested that they may have impaired cognitive function regarding novel objects.

BackgroundEarly arrhythmia recurrences commonly occur after atrial fibrillation (AF) ablation because of irritability and inflammation of left atrium. We hypothesized that short-term use of Saireito would be effective in reducing frequent atrial tachyarrhythmias in the early-phase post-ablation.MethodsOne hundred patients undergoing catheter ablation for symptomatic AF were randomly assigned to either a 30-day use of Saireito or control group. The primary endpoint was total number of episodes of frequent atrial tachyarrhythmias including definite recurrent AF and frequent premature atrial contractions during the 30-day treatment period post-ablation.ResultsThree (6.0%) out of 50 patients treated with Saireito discontinued the drug because of adverse symptoms. The Saireito group was associated with a numerically lower number of episodes of frequent atrial tachyarrhythmias than the control group (3.1 versus 5.2 times, P = 0.17). The mean daily episodes of frequent atrial tachyarrhythmias were significantly fewer in the Saireito group during Day-6 to Day-10 (0.12/day versus 0.27/day, P = 0.03), and during Day-11 to Day-15 (0.08/day versus 0.24/day, P = 0.001). The prevalence of adverse symptoms during the 30-day treatment period was significantly higher in the Saireito group (18.0% versus 2.0%, P = 0.005).ConclusionsThirty-day use of Saireito following AF ablation was associated with a tendency toward reduced number of episodes of frequent atrial tachyarrhythmias during the treatment period, with more pronounced effect in the first two weeks.

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20-30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08-5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41-7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5-7.8] vs 10.4 months [95% CI: 7.9-12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292

Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the pre-Bötzinger complex, which are critical for the generation of inspiratory rhythm, and phrenic and hypoglossal motoneurons. Herein, we assessed the effects of OX2R-selective agonists TAK-925 (danavorexton) and OX-201 on respiratory function. In in vitro electrophysiologic analyses using rat medullary slices, danavorexton and OX-201 showed tendency and significant effect, respectively, in increasing the frequency of inspiratory synaptic currents of inspiratory neurons in the pre-Bötzinger complex. In rat medullary slices, both danavorexton and OX-201 significantly increased the frequency of inspiratory synaptic currents of hypoglossal motoneurons. Danavorexton and OX-201 also showed significant effect and tendency, respectively, in increasing the frequency of burst activity recorded from the cervical (C3-C5) ventral root, which contains axons of phrenic motoneurons, in in vitro electrophysiologic analyses from rat isolated brainstem-spinal cord preparations. Electromyogram recordings revealed that intravenous administration of OX-201 increased burst frequency of the diaphragm and burst amplitude of the genioglossus muscle in isoflurane- and urethane-anesthetized rats, respectively. In whole-body plethysmography analyses, oral administration of OX-201 increased respiratory activity in free-moving mice. Overall, these results suggest that OX2R-selective agonists enhance respiratory function via activation of the diaphragm and genioglossus muscle through stimulation of inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons. OX2R-selective agonists could be promising drugs for various conditions with respiratory dysfunction.

To identify a biomarker for the early diagnosis of enzootic bovine leukosis (EBL) caused by bovine leukemia virus (BLV), we investigated the expression of a microRNA, bta-miR-375, in cattle serum. Using quantitative reverse-transcriptase PCR analysis, we measured bta-miR-375 levels in 27 samples from cattle with EBL (EBL cattle), 45 samples from animals infected with BLV but showing no clinical signs (NS cattle), and 30 samples from cattle uninfected with BLV (BLV negative cattle). In this study, we also compared the kinetics of bta-miR-375 with those of the conventional biomarkers of proviral load (PVL), lactate dehydrogenase (LDH), and thymidine kinase (TK) from the no-clinical-sign phase until EBL onset in three BLV-infected Japanese black (JB) cattle. Bta-miR-375 expression was higher in NS cattle than in BLV negative cattle (P < 0.05) and greater in EBL cattle than in BLV negative and NS cattle (P < 0.0001 for both comparisons). Receiver operating characteristic curves demonstrated that bta-miR-375 levels distinguished EBL cattle from NS cattle with high sensitivity and specificity. In NS cattle, bta-miR-375 expression was increased as early as at 2 months before EBL onset-earlier than the expression of PVL, TK, or LDH isoenzymes 2 and 3. These results suggest that serum miR-375 is a promising biomarker for the early diagnosis of EBL.

The evaluation of the structural integrity of mechanically dynamic organs such as lungs is critical for the diagnosis of numerous pathologies and the development of therapies. This task is classically performed by histology experts in a qualitative or semi-quantitative manner. Automatic digital image processing methods appeared in the last decades, and although immensely powerful, tools are highly specialized and lack the versatility required in various experimental designs. Here, a set of scripts for the image processing software ImageJ/Fiji to easily quantify fibrosis extend and alveolar airspace availability in Sirius Red or Masson's trichrome stained samples is presented. The toolbox consists in thirteen modules: sample detection, particles filtration (automatic and manual), border definition, air ducts identification, air ducts walls definition, parenchyma extraction, MT-staining specific pre-processing, fibrosis detection, fibrosis particles filtration, airspace detection, and visualizations (tissue only or tissue and airspace). While the process is largely automated, critical parameters are accessible to the user for increased adaptability. The modularity of the protocol allows for its adjustment to alternative experimental settings. Fibrosis and airspace can be combined as an evaluation of the structural integrity of the organ. All settings and intermediate states are saved to ensure reproducibility. These new analysis scripts allow for a rapid quantification of fibrosis and airspace in a large variety of experimental settings.

ObjectiveLong-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality.MethodsRetrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome.ResultsOf 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], PConclusionA steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

BackgroundEpiretinal membrane (ERM) causes visual impairment such as reduction in visual acuity and metamorphopsia due to retinal traction. With the improvement of optical coherence tomography (OCT) and microincision vitrectomy surgery (MIVS), the surgery of ERM has significantly advanced. However, there have been no large-scale studies on the following: (1) how to evaluate visual impairment in ERM, (2) the relationship between OCT findings and visual function, (3) when is the optimal timing of surgery, and (4) the relationship between the surgical instruments as well as techniques and prognosis. The purpose of this study was to obtain evidence regarding these ERM surgeries.Methods and designThis is a prospective, multicenter cohort study of ERM surgery in Japan from March 1, 2023, to March 31, 2027 (UMIN000048472, R-3468-2). Patients who underwent ERM surgery during the study period and agreed to participate in this study will be included. The goal is to have a total of 5,000 eyes surgically treated for ERM. The following data will be collected: age, gender, medical history, subjective symptoms, visual function before and 6 and 12 months after surgery, clinical findings, OCT data, surgical technique, instruments used in surgery, and complications.DiscussionThe results of this study will support the surgical decisions and procedures in ERM practices.

ObjectiveIn this study, we aimed to investigate the effects of the concurrent exercise training (CET) associated with the enalapril maleate on blood pressure variability (BPV) and renal profile in an experimental model of arterial hypertension (AH) and postmenopause.MethodsFemale ovariectomized spontaneously hypertensive rats (SHR) were distributed into 4 groups (n = 8/group): sedentary (SO), sedentary + enalapril (SOE), trained (TO) and trained + enalapril (TOE). Both enalapril (3mg/kg) and CET (3 days/week) were conducted during 8 weeks. Blood pressure (BP) was directly recorded for BPV analyses. Renal function, morphology, inflammation and oxidative stress were assessed.ResultsThe SOE, TO e TOE groups presented decreased systolic BP compared with SO. Both trained groups (TO and TOE) presented lower BPV and increased baroreflex sensitivity (TO: 0.76 ± 0.20 and TOE: 1.02 ± 0.40 vs. SO: 0.40 ± 0.07 ms/mmHg) compared with SO group, with additional improvements in TOE group. Creatinine and IL-6 levels were reduced in SOE, TO and TOE compared with SO group, while IL-10 was increased only in TOE group (vs. SO). Enalapril combined with CET promote reduction in lipoperoxidation (TOE: 1.37 ± 0.26 vs. SO: 2.08 ± 0.48 and SOE: 1.84 ± 0.35 μmol/mg protein) and hydrogen peroxide (TOE: 1.89 ± 0.40 vs. SO: 3.70 ± 0.19 and SOE: 2.73 ± 0.70 μM), as well as increase in catalase activity (vs. sedentary groups). The tubulointerstitial injury was lower in interventions groups (SOE, TO and TOE vs. SO), with potentialized benefits in the trained groups.ConclusionsEnalapril combined with CET attenuated BPV and baroreflex dysfunctions, probably impacting on end-organ damage, as demonstrated by attenuation in the AH-induced renal inflammations, oxidative stress and morphofunctional impairments in postmenopausal rats.

Repeating X-ray computed tomography (CT) measurements over a short period of time allows for obtaining a spatiotemporal four-dimensional (4D) volume image. This study presents an interactive method for segmenting a 4DCT image by fitting a template model to a target organ. The template consists of a three-dimensional (3D) mesh model and free-form-deformation (FFD) cage enclosing the mesh. The user deforms the template by placing multiple curve constraints that specify the boundary shape of the template in 3D space. We also present curve constraints shared over all time frames and interpolated along the time axis to facilitate efficient curve specification. Our method formulates the template deformation using the FFD cage modification, allowing the user to switch between our curve-based method and traditional FFD at any time. To illustrate the feasibility of our method, we show segmentation results in which we could accurately segment three organs from a 4DCT image capturing a swallowing motion. To evaluate the usability of our method, we conducted a user study comparing our curve-based method with the cage-based FFD. We found that the participants finished segmentation in approximately 20% interaction time periods on average with our method. [ABSTRACT FROM AUTHOR]

ObjectiveThe purpose of this study was to evaluate the performance of algorithms for identifying cases of severe hypoglycemia in Japanese hospital administrative data.MethodsThis was a multicenter, retrospective, observational study conducted at 3 acute-care hospitals in Japan. The study population included patients aged ≥18 years with diabetes who had an outpatient visit or hospital admission for possible hypoglycemia. Possible cases of severe hypoglycemia were identified using health insurance claims data and Diagnosis Procedure Combination data. Sixty-one algorithms using combinations of diagnostic codes and prescription of high concentration (≥20% mass/volume) injectable glucose were used to define severe hypoglycemia. Independent manual chart reviews by 2 physicians at each hospital were used as the reference standard. Algorithm validity was evaluated using standard performance metrics.ResultsIn total, 336 possible cases of severe hypoglycemia were identified, and 260 were consecutively sampled for validation. The best performing algorithms included 6 algorithms that had sensitivity ≥0.75, and 6 algorithms that had positive predictive values ≥0.75 with sensitivity ≥0.30. The best-performing algorithm with sensitivity ≥0.75 included any diagnoses for possible hypoglycemia or prescription of high-concentration glucose but excluded suspected diagnoses (sensitivity: 0.986 [95% confidence interval 0.959-1.013]; positive predictive value: 0.345 [0.280-0.410]). Restricting the algorithm definition to those with both a diagnosis of possible hypoglycemia and a prescription of high-concentration glucose improved the performance of the algorithm to correctly classify cases as severe hypoglycemia but lowered sensitivity (sensitivity: 0.375 [0.263-0.487]; positive predictive value: 0.771 [0.632-0.911]).ConclusionThe case-identifying algorithms in this study showed moderate positive predictive value and sensitivity for identification of severe hypoglycemia in Japanese healthcare data and can be employed by future pharmacoepidemiological studies using Japanese hospital administrative databases.

Various brain functions that are necessary to maintain life activities materialize through the interaction of countless neurons. Therefore, it is important to analyze functional neuronal network. To elucidate the mechanism of brain function, many studies are being actively conducted on functional neuronal ensemble and hub, including all areas of neuroscience. In addition, recent study suggests that the existence of functional neuronal ensembles and hubs contributes to the efficiency of information processing. For these reasons, there is a demand for methods to infer functional neuronal ensembles from neuronal activity data, and methods based on Bayesian inference have been proposed. However, there is a problem in modeling the activity in Bayesian inference. The features of each neuron's activity have non-stationarity depending on physiological experimental conditions. As a result, the assumption of stationarity in Bayesian inference model impedes inference, which leads to destabilization of inference results and degradation of inference accuracy. In this study, we extend the range of the variable for expressing the neuronal state, and generalize the likelihood of the model for extended variables. By comparing with the previous study, our model can express the neuronal state in larger space. This generalization without restriction of the binary input enables us to perform soft clustering and apply the method to non-stationary neuroactivity data. In addition, for the effectiveness of the method, we apply the developed method to multiple synthetic fluorescence data generated from the electrical potential data in leaky integrated-and-fire model.

Rabbit anti-asialo-GM1 (ASGM1) serum or polyclonal antibodies can eliminate mouse splenic natural killer (NK) cell activity in vitro and in vivo. We developed rabbit monoclonal antibodies (mAbs) against ASGM1 using a single-cell analysis and isolation system. Five mAbs (GA109, GA115, GA116, GA131, and GA134) that were reactive to ASGM1 were isolated from the spleen lymphocytes of rabbits immunized with ASGM1. Enzyme-linked immunosorbent assay and thin-layer chromatography immunostaining results showed that the mAbs strongly reacted with ASGM1. Two mAbs (GA116 and GA134) reacted exclusively with ASGM1, whereas three mAbs (GA109, GA115, and GA131) showed slight or considerable cross-reactivity with GM1. The administration of the mAbs (4-20 μg) to BALB/c mice completely abolished NK cell activity in vivo. The anti-ASGM1 rabbit mAbs obtained in this study may provide a useful and reproducible tool for various future studies, such as depleting NK cell activity to enhance xenograft engraftment in mouse models.

ObjectivesThis study aimed to characterize the content of frequently asked questions about the treatment of rheumatoid arthritis (RA) on the internet in Japan and to evaluate the quality of websites related to the questions.MethodsWe searched terms on the treatment of RA on Google and extracted frequently asked questions generated by the Google "people also ask" function. The website that answered each question was also obtained. We categorized the questions based on the content. The quality of the websites was evaluated using the brief DISCERN, Journal of American Medical Association benchmark criteria, and Clear Communication Index.ResultsOur search yielded 83 questions and the corresponding websites. The most frequently asked questions were regarding the timeline of treatment (n = 17, 23%) and those on the timeline of the clinical course (n = 13, 16%). The median score of brief DISCERN was 11 points, with only 7 (8%) websites having sufficient quality. Websites having sufficient quality based on the Journal of American Medical Association benchmark criteria and Clear Communication Index were absent.ConclusionsThe questions were most frequently related to the timeline of treatment and clinical course. Physicians should provide such information to patients with RA in the counseling and education materials.

BackgroundsThe prognostic implication of weight loss after discharge from acute heart failure (AHF) remains unclear. We sought to investigate the association of weight loss between discharge and 6-month visit with subsequent clinical outcomes in patients with AHF.MethodsWe analyzed 686 patients with AHF in the prospective longitudinal follow-up study derived from the Kyoto Congestive Heart Failure registry, and divided them into 2 groups based on the weight loss at 6-month index visit. We defined the weight loss as ≥ 5% decrease in body weight from discharge to 6-month index visit.ResultsThere were 90 patients (13.1%) with a weight loss at 6-month visit. Patients in the weight loss group compared with those in the no weight loss group had higher body weight at discharge and lower body weight at 6-mont visit. Patients in the weight loss group had a lower systolic blood pressure, higher brain-type natriuretic peptide, lower serum albumin, lower hemoglobin, higher prevalence of heart failure with reduced ejection fraction at 6-month visit, and a lower prescription rate of inhibitors of renin-angiotensin system than those in the no weight loss group. The cumulative 6-month incidence of all-cause death was significantly higher in the weight loss group than in the no weight loss group (14.2% and 4.3%, log-rank PConclusionBody weight loss of ≥5% at 6-month visit after discharge was associated with subsequent all-cause death in patients with AHF.

Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M4N, the M4N concentration in most of the organs in mice reached ~1 μM (the M4N concentration in intestines and fat pads was as high as 20-40 μM) and treatment with the combination of M4N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M4N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M4N suppressed oxygen consumption in cultured LN229 cells, indicating that M4N inhibited oxidative phosphorylation. Treatment with M4N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M4N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M4N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M4N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.

Lymphatic fluid drains from the liver via the periportal lymphatic, hepatic venous lymphatic, and superficial lymphatic systems. We performed a postmortem study to clarify the three-dimensional structure and flow dynamics of the human hepatic venous lymphatic system, as it still remains unclear. Livers were excised whole from three human cadavers, injected with India ink, and sliced into 1-cm sections from which veins were harvested. The distribution of lymphatic vessels was observed in 5 μm sections immunostained for lymphatic and vascular markers (podoplanin and CD31, respectively) using light microscopy. Continuity and density of lymphatic vessel distribution were assessed in en-face whole-mount preparations of veins using stereomicroscopy. The structure of the external hepatic vein wall was assessed with scanning electron microscopy (SEM). The lymphatic dynamics study suggested that lymphatic fluid flows through an extravascular pathway around the central and sublobular veins. A lymphatic vessel network originates in the wall of sublobular veins, with a diameter greater than 110 μm, and the peripheral portions of hepatic veins and continues to the inferior vena cava. The density distribution of lymphatic vessels is smallest in the peripheral portion of the hepatic vein (0.03%) and increases to the proximal portion (0.22%, p = 0.012) and the main trunk (1.01%, p < 0.001), correlating positively with increasing hepatic vein diameter (Rs = 0.67, p < 0.001). We revealed the three-dimensional structure of the human hepatic venous lymphatic system. The results could improve the understanding of lymphatic physiology and liver pathology.

Hyaluronan (HA) is a high-molecular-weight glycosaminoglycan and widely distributed in all connective tissues and organs with diverse biological functions. HA has been increasingly used as dietary supplements targeted to joint and skin health for humans. We here first report isolation of bacteria from human feces that are capable of degrading HA to lower molecular weight HA oligosaccharides (oligo-HAs). The bacteria were successfully isolated via a selective enrichment method, in which the serially diluted feces of healthy Japanese donors were individually incubated in an enrichment medium containing HA, followed by the isolation of candidate strains from streaked HA-containing agar plates and selection of HA-degrading strains by measuring HA using an ELISA. Subsequent genomic and biochemical assays identified the strains as Bacteroides finegoldii, B. caccae, B. thetaiotaomicron, and Fusobacterium mortiferum. Furthermore, our HPLC analysis revealed that the strains degraded HA to oligo-HAs of various lengths. Subsequent quantitative PCR assay targeting the HA degrading bacteria showed that their distribution in the Japanese donors varied. The evidence suggests that dietary HA is degraded by the human gut microbiota with individual variation to oligo-HAs components, which are more absorbable than HA, thereby exerting its beneficial effects.

Deep learning technology has been used in the medical field to produce devices for clinical practice. Deep learning methods in cytology offer the potential to enhance cancer screening while also providing quantitative, objective, and highly reproducible testing. However, constructing high-accuracy deep learning models necessitates a significant amount of manually labeled data, which takes time. To address this issue, we used the Noisy Student Training technique to create a binary classification deep learning model for cervical cytology screening, which reduces the quantity of labeled data necessary. We used 140 whole-slide images from liquid-based cytology specimens, 50 of which were low-grade squamous intraepithelial lesions, 50 were high-grade squamous intraepithelial lesions, and 40 were negative samples. We extracted 56,996 images from the slides and then used them to train and test the model. We trained the EfficientNet using 2,600 manually labeled images to generate additional pseudo labels for the unlabeled data and then self-trained it within a student-teacher framework. Based on the presence or absence of abnormal cells, the created model was used to classify the images as normal or abnormal. The Grad-CAM approach was used to visualize the image components that contributed to the classification. The model achieved an area under the curve of 0.908, accuracy of 0.873, and F1-score of 0.833 with our test data. We also explored the optimal confidence threshold score and optimal augmentation approaches for low-magnification images. Our model efficiently classified normal and abnormal images at low magnification with high reliability, making it a promising screening tool for cervical cytology.

Finding the shortest paths for packets from sources to destinations in packet-switched communication networks is an inevitable problem in building a future high-speed information society. A routing method with memory information has already been proposed to alleviate the congestion of large volumes of packet flow. This routing method shows a high transmission completion rate even for large volumes of packet flows in communication networks with scale-free properties. However, the method exhibits poor performance for networks with local triangular connections and long distances between nodes. To overcome these problems, in this study, we first enhanced the routing performance of the conventional communication network models by using the betweenness centrality of nodes, which is one of the network centralities that measures the number of shortest paths that pass through each node in the networks. Subsequently, we adaptively changed the transmitting paths of packets by using only local information. Numerical simulations indicated that our routing method performs successfully for various topologies of communication networks by avoiding the congested node, and effectively using the memory information.

ObjectivesOne primary concern about receiving care at home is that survival might be shortened because the quality and quantity of treatment provided at home will be inferior to that given in the hospital. Although our previous study demonstrated a longer survival of those with home-based palliative care (PC), it lacked adjustment for some potential confounders including symptoms and treatments during the stay. We aimed to compare the survival times among advanced cancer patients receiving home-based and hospital-based PC with adjusting for symptoms and treatments.MethodWe compared survival time of participants who enrolled two multicenter, prospective cohort studies of advanced cancer patients at 45-home-based PC services between July 2017 and December 2017, and at 23-hospital-based PC services between January 2017 and December 2017. We analyzed with stratification by the estimated survival of Days, Weeks, and Months, which were defined by modified Prognosis in Palliative care Study predictor models-A. We conducted a Cox regression analysis with adjusting for potential confounders including symptoms and treatments during the stay.ResultsA total of 2,998 patients were enrolled in both studies and 2,878 patients were analyzed; 988 patients receiving home-based PC and 1,890 receiving hospital-based PC. The survival time of patients receiving home-based PC was significantly longer than that of patients receiving hospital-based PC for the Days Prognosis (estimated median survival time: 10 days [95% CI 8.1-11.8] vs. 9 days [95% CI 8.3-10.4], p = 0.157), the Weeks prognosis (32 days [95% CI 28.9-35.4] vs. 22 days [95% CI 20.3-22.9], p < 0.001), and the Months Prognosis, (65 days [95% CI 58.2-73.2] vs. 32 days [95% CI 28.9-35.4], p < 0.001).ConclusionIn this cohort of advanced cancer patients with a Weeks or Months prognosis, those receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments.

BackgroundGrowing evidence suggests that intervention for smoking cessation enhances alcohol abstinence in treatment settings for alcohol dependence. However, research in this field is rare in Asians.MethodWe prospectively investigated the association of smoking status with drinking status using 9 surveys mailed during a 12-month period in 198 Japanese alcohol-dependent men (70 never/ex-smokers and 128 smokers) who admitted for the first time and completed a 3-month inpatient program for simultaneous alcohol abstinence and smoking cessation.ResultsNonsmoking during the first month after discharge and at the end of follow-up was reported in 28.9% and 25.0% of the baseline smokers, respectively. Kaplan-Meier estimates showed that a 12-month alcohol abstinence and heavy-drinking-free status were more frequent among never/ex-smokers (45.1% and 59.8%, respectively) and baseline smokers who quit smoking during the first month after discharge (59.0% and 60.8%, respectively), compared with sustained smokers (30.0% and 41.2%, respectively). Among the baseline smokers, the multivariate odds ratio (95% confidence interval) for smoking cessation during the first month were 2.77 (1.01-7.61) for alcohol abstinence during the period and 2.50 (1.00-6.25) for use of varenicline, a smoking cessation agent, during the inpatient program. After adjusting for age, drinking profile, lifestyle, family history of heavy or problem drinking, lifetime episodes of other major psychiatric disorders, and medications at discharge, the multivariate hazard ratios (HRs) for drinking lapse were 0.57 (0.37-0.89) for the never/ex-smoking and 0.41 (0.23-0.75) for new smoking cessation groups, respectively, compared with sustained smoking, while the corresponding HRs for heavy-drinking lapse were 0.55 (0.33-0.90) and 0.47 (0.25-0.88), respectively. The HR for drinking lapse was 0.63 (0.42-0.95) for the nonsmoking group (vs. smoking) during the observation period, while the HR for heavy-drinking lapse was 0.58 (0.37-0.91) for the nonsmoking group (vs. smoking) during the observation period. Other significant variables that worsened drinking outcomes were higher daily alcohol intake prior to hospitalization, family history of heavy or problem drinking and psychiatric medications at discharge.ConclusionNonsmoking was associated with better outcomes on the drinking status of Japanese alcohol-dependent men, and a smoking cessation program may be recommended to be integrated into alcohol abstinence programs.

Mouse spermatogenesis, from spermatogonial stem cell proliferation to sperm formation, can be reproduced in vitro by culturing testis tissue masses of neonatal mice. However, it remains to be determined whether this method is also applicable when testis tissues are further divided into tiny fragments, such as segments of the seminiferous tubule (ST), a minimal anatomical unit for spermatogenesis. In this study, we investigated this issue using the testis of an Acrosin-GFP/Histone H3.3-mCherry (Acr/H3) double-transgenic mouse and monitored the expression of GFP and mCherry as indicators of spermatogenic progression. Initially, we noticed that the cut and isolated stretches of ST shrunk rapidly and conglomerated. We therefore maintained the isolation of STs in two ways: segmental isolation without truncation or embedding in soft agarose. In both cases, GFP expression was observed by fluorescence microscopy. By whole-mount immunochemical staining, meiotic spermatocytes and round and elongating spermatids were identified as Sycp3-, crescent-form GFP-, and mCherry-positive cells, respectively. Although the efficiency was significantly lower than that with tissue mass culture, we clearly showed that spermatogenesis can be induced up to the elongating spermatid stage even when the STs were cut into short segments and cultured in isolation. In addition, we demonstrated that lowered oxygen tension was favorable for spermatogenesis both for meiotic progression and for producing elongating spermatids in isolated STs. Culturing isolated STs rather than tissue masses is advantageous for explicitly assessing the various environmental parameters that influence the progression of spermatogenesis.

Although biomarkers to predict coronavirus disease 2019 (COVID-19) severity have been studied since the early pandemic, no clear guidelines on using them in clinical practice are available. Here, we examined the ability of four biomarkers to predict disease severity using conserved sera from COVID-19 patients who received inpatient care between January 1, 2020 and September 21, 2021 at the National Center for Global Health and Medicine, collected at the appropriate time for prediction. We predicted illness severity in two situations: 1) prediction of future oxygen administration for patients without oxygen support within 8 days of onset (Study 1) and 2) prediction of future mechanical ventilation support (excluding non-invasive positive pressure ventilation) or death of patients within 4 days of the start of oxygen administration (Study 2). Interleukin-6, IFN-λ3, thymus and activation-regulated chemokine, and calprotectin were measured retrospectively. Other laboratory and clinical information were collected from medical records. AUCs were calculated from ROC curves and compared for the predictive ability of the four biomarkers. Study 1 included 18 patients, five of whom had developed oxygen needs. Study 2 included 45 patients, 13 of whom required ventilator management or died. In Study 1, IFN-λ3 showed a good predictive ability with an AUC of 0.92 (95% CI 0.76-1.00). In Study 2, the AUC of each biomarker was 0.70-0.74. The number of biomarkers above the cutoff showed the possibility of good prediction with an AUC of 0.86 (95% CI 0.75-0.97). When two or more biomarkers were positive, sensitivity and specificity were 0.92 and 0.63, respectively. In terms of biomarker testing at times when prognostication may be clinically useful, IFN-λ3 was predictive of oxygenation demand and a combination of the four biomarkers was predictive of mechanical ventilator requirement.

Cortical bone thickness is important for the mechanical function of bone. Ontogeny, aging, sex, body size, hormone levels, diet, behavior, and genetics potentially cause variations in postcranial cortical robusticity. However, the factors associated with cranial cortical robusticity remain poorly understood. Few studies have examined cortical robusticity in both cranial and postcranial bones jointly. In the present study, we used computed tomography (CT) images to measure cortical bone thicknesses in the cranial vault and humeral diaphysis. This study clearly showed that females have a greater cranial vault thickness and greater age-related increase in cranial vault thickness than males. We found an age-related increase in the full thickness of the temporal cranial vault and the width of the humeral diaphysis, as well as an age-related decrease in the cortical thickness of the frontal cranial vault and the cortical thickness of the humeral diaphysis, suggesting that the mechanisms of bone modeling in cranial and long bones are similar. A positive correlation between cortical indices in the cranial vault and humeral diaphysis also suggested that common factors affect cortical robusticity. We also examined the association of polymorphisms in the WNT16 and TNFSF11 genes with bone thickness. However, no significant associations were observed. The present study provides fundamental knowledge about similarities and differences in the mechanisms of bone modeling between cranial and postcranial bones.

The leopard cat (Prionailurus bengalensis), an endangered species in South Korea, is a small feline widely distributed in Asia. Here, we investigated the diet of leopard cats in the inland areas of Korea by examining their fecal contents using vertebrate mitochondrial 12S rRNA gene sequencing and shotgun metagenomic sequencing. Shotgun metagenomic sequencing revealed that the feces were rich in DNA not only of vertebrates but also of arthropods and plants, but care should be taken when using shotgun metagenomic sequencing to identify vertebrates at low taxonomic levels (e.g., genus level), as it was often erroneous. Meanwhile, vertebrate mitochondrial 12S rRNA gene sequencing was found to be accurate in the genus-level identification, as the genera identified were consistent with the Korean fauna. We found that small mammals such as murids were their main prey. By using these two sequencing methods in combination, this study demonstrated that accurate information about the overall dietary content and vertebrate prey of leopard cats could be obtained. We expect that the continued community efforts to expand the genome database of wildlife, including vertebrates, will alleviate the problem of erroneous identification of prey at low taxonomic levels by shotgun metagenomic sequencing in the near future.

In sumo wrestling, a traditional sport in Japan, many wrestlers suffer from injuries through bouts. In 2019, an average of 5.2 out of 42 wrestlers in the top division of professional sumo wrestling were absent in each grand sumo tournament due to injury. As the number of injury occurrences increases, professional sumo wrestling becomes less interesting for sumo fans, requiring systems to prevent future occurrences. Statistical injury prediction is a useful way to communicate the risk of injuries for wrestlers and their coaches. However, the existing statistical methods of injury prediction are not always accurate because they do not consider the long-term effects of injuries. Here, we propose a statistical model of injury occurrences for sumo wrestlers. The proposed model provides the estimated probability of the next potential injury occurrence for a wrestler. In addition, it can support making a risk-based injury prevention scenario for wrestlers. While a previous study modeled injury occurrences by using the Poisson process, we model it by using the Hawkes process to consider the long-term effect of injuries. The proposed model can also be applied to injury prediction for athletes of other sports.

BackgroundSerrated polyps have recently been reported in patients with ulcerative colitis (UC); however, their prevalence and detailed characteristics remain unclear.MethodsThe prevalence and clinicopathological and biological characteristics of serrated polyps in patients with UC were retrospectively examined in a single tertiary inflammatory bowel disease center in Japan from 2000 to 2020.ResultsAmong 2035 patients with UC who underwent total colonoscopy, 252 neoplasms, including 36 serrated polyps (26 in colitis-affected segments, 10 in colitis-unaffected segments), were identified in 187 patients with UC. The proportion of serrated polyps was 1.8% (36/2035). Serrated polyps in colitis-affected segments were common with extensive colitis (88%), history of persistent active colitis (58%), and long UC duration (12.1 years). Serrated polyps in colitis-affected segments were more common in men (88%). Of the 26 serrated polyps in colitis-affected segments, 15, 6, and 5 were categorized as sessile serrated lesion-like dysplasia, traditional serrated adenoma-like dysplasia, and serrated dysplasia not otherwise specified, respectively. Sessile serrated lesion-like dysplasia was common in the proximal colon (67%) and with BRAF mutation (62%), whereas traditional serrated adenoma-like dysplasia and serrated dysplasia not otherwise specified were common in the distal colon (100% and 80%, respectively) and with KRAS mutations (100% and 75%, respectively).ConclusionsSerrated polyps comprised 14% of the neoplasias in patients with UC. Serrated polyps in colitis-affected segments were common in men with extensive and longstanding colitis, suggesting chronic inflammation in the development of serrated polyps in patients with UC.

BackgroundAlthough anticoagulants are indicated for many elderly patients with non-valvular atrial fibrillation (NVAF), some patients do not receive anticoagulant therapy, whose characteristics and outcomes are diverse.Methods and resultsIn this sub-analysis of the All Nippon AF In the Elderly (ANAFIE) Registry, the phenotypes of patients who were not receiving anticoagulants at baseline were evaluated by cluster analysis using Ward's linkage hierarchical algorithm. Of 32,275 enrolled patients, 2445 (7.6%) were not receiving anticoagulants. Two clusters were identified: (1) elderly paroxysmal AF (PAF) patients with a high proportion of catheter ablation history (57%) and (2) very elderly patients with a high prevalence of previous major bleeding (43%). Respective mean ages were 80.9 and 84.2 years, mean CHA2DS2-VASc scores were 3.8 and 4.9, PAF prevalences were 100.0% and 31.4%, proportions of patients with catheter ablation history were 21.0% and 7.9%, and proportions of patients with a history of major bleeding were 4.0% and 10.8%. Annual incidence rates were 2.72% and 8.81% for all-cause death, 1.66% and 5.85% for major adverse cardiovascular or neurological events, 1.08% and 3.30% for stroke or systemic embolism, and 0.69% and 1.19% for major bleeding, respectively.ConclusionsIn this cohort of elderly NVAF patients from the ANAFIE Registry who were not receiving anticoagulants, over half had PAF with a high proportion of catheter ablation history and a low incidence of adverse outcomes; for them, non-prescription of anticoagulants may be partially understandable, but they should be carefully monitored regarding AF burden or atrial cardiomyopathy and be adequately anticoagulated when adverse findings are detected. The remaining were very elderly patients with a high prevalence of previous major bleeding and a high incidence of adverse outcomes; for them, non-prescription of anticoagulants is inappropriate because of the high thromboembolic risk.Trial registrationRegistration: http://www.umin.ac.jp/; Unique identifier: UMIN000024006.

BackgroundThe impact of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) on the prognosis of biliary tract cancer (BTC) is not completely understood. Therefore, in our study, we investigated the effects of the various immune cells infiltration in tumor microenvironment (TME).MethodsA total of 130 patients with BTC who underwent surgical treatment at our institution were enrolled in this study. We retrospectively evaluated TILs and TAMs with immunohistochemical staining.ResultsWith CD8-high, CD4-high, FOXP3-high, and CD68-low in TME as one factor, we calculated Immunoscore according to the number of factors. The high Immunoscore group showed significantly superior overall survival (OS) and recurrence-free survival (RFS) than the low Immunoscore group (median OS, 60.8 vs. 26.4 months, p = 0.001; median RFS not reached vs. 17.2 months, p < 0.001). Also, high Immunoscore was an independent good prognostic factor for OS and RFS (hazards ratio 2.05 and 2.41 and p = 0.01 and p = 0.001, respectively).ConclusionsHigh Immunoscore group had significantly superior OS and RFS and was an independent good prognostic factor for OS and RFS.

Magnetic resonance (MR) imaging is a powerful imaging modality for obtaining anatomical information with high spatial and temporal resolution. In the drug delivery system (DDS) framework, nanoparticles such as liposomes are potential candidates for MR imaging. We validated that RGD peptides are possible targeting molecules for pancreatic cancer with αvβ3 integrin expression. This study aimed to evaluate RGD-modified liposomes loaded with ferrioxamine B for pancreatic cancer imaging. We synthesized four types of RGD-modified liposomes encapsulated with ferrioxamine B (SH-, H-, M-, and L-RGD-liposomes). The binding affinity of RGD-modified liposomes was evaluated in a competitive inhibition study using 125I-echistatin. To investigate the pharmacokinetics of RGD-modified liposomes, a biodistribution study using RGD-liposomes labeled with 111In was carried out in a human pancreatic cancer PANC-1 xenograft mouse model. Finally, MR was performed using ferrioxamine-B-loaded liposomes. RGD-liposomes inhibited the binding of 125I-echistatin to RGD. The biodistribution study revealed that 111In-RGD-liposomes accumulated significantly in the liver and spleen. Among the 111In-RGD-liposomes, 111In-H-RGD-liposomes showed the highest tumor-to-normal tissue ratio. In the MR study, H-RGD-liposomes loaded with ferrioxamine B showed higher tumor-to-muscle signal ratios than RKG-liposomes loaded with ferrioxamine B (control). We successfully synthesized RGD-liposomes that can target αvβ3 integrin. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that poor nutrition during pregnancy predisposes offspring to the development of lifestyle-related noncommunicable diseases and psychiatric disorders later in life. However, the molecular mechanisms underlying this predisposition are not well understood. In our previous study, using rats as model animals, we showed that behavioral impairments are induced by prenatal undernutrition. In this study, we identified solute carrier 22 family member 23 (Slc22a23) as a gene that is irreversibly upregulated in the rat brain by undernutrition during fetal development. Because the substrate of the SLC22A23 transporter has not yet been identified and the biological role of the Slc22a23 gene in vivo is not fully understood, we generated pan-Slc22a23 knockout rats and examined their phenotype in detail. The Slc22a23 knockout rats showed a lean phenotype, an increase in spontaneous locomotion, and improved endurance, indicating that they are not overweight and are even healthier in an ad libitum feeding environment. However, the knockout rats had reduced hippocampal volume, and the behavioral analysis suggested that they may have impaired cognitive function regarding novel objects. [ABSTRACT FROM AUTHOR]

Microbial volatile organic compounds (VOCs) emitted from fungi are known as their secondary metabolites from environmental sources. However, their physiological roles remain to be unclear. Even though the roles are still unknown, VOCs are deliberately released to convey information to both homologous and non-homologous organisms. We investigated the effects of single VOCs (hexanal, benzaldehyde, heptanal, 2-ethyl-1-hexanol, 3-octanone, 2-undecanone, 3-octanol, 2-Phenylethanol, 2-phenyl-2-propanol, phenylbenzaldehyde, 2-pentadecanone, β-trans-bergamotene, β-bisabolene, 2-methyl-5 -(1-methylethyl)pyrazine) on the fungal growth. In parallel, application of the co-culturing system in a growth chamber allowed free gas and VOCs exchange between emitter colonies of Fusarium solani and Aspergillus fumigatus, or between colonies of different growth stages of the same species. Distinct self-inhibition occurred by the emitters of fungal growing colonies against receiver ones on the stage of conidial germination or against the younger colonies at an earlier stage in both fungi. Similarly, the phenomenon of allelopathy appeared to work between growing colonies of F. solani and the germinating conidia or young colonies of A. fumigatus or vice versa. Solid phase microextraction—gas chromatography/mass spectrometry revealed VOCs compounds of each fungi. In F. solani, hexanal and benzaldehyde appeared to be significant inhibitors for colony growth. Benzaldehyde inhibited filamentous growth but not conidial germination. In A. fumigatus, heptanal seemed to be an equivalent effector. The inhibitory effect of benzaldehyde was more distinct on the A. fumigatus conidial germination than its filamentous growth. [ABSTRACT FROM AUTHOR]

Background: Early arrhythmia recurrences commonly occur after atrial fibrillation (AF) ablation because of irritability and inflammation of left atrium. We hypothesized that short-term use of Saireito would be effective in reducing frequent atrial tachyarrhythmias in the early-phase post-ablation. Methods: One hundred patients undergoing catheter ablation for symptomatic AF were randomly assigned to either a 30-day use of Saireito or control group. The primary endpoint was total number of episodes of frequent atrial tachyarrhythmias including definite recurrent AF and frequent premature atrial contractions during the 30-day treatment period post-ablation. Results: Three (6.0%) out of 50 patients treated with Saireito discontinued the drug because of adverse symptoms. The Saireito group was associated with a numerically lower number of episodes of frequent atrial tachyarrhythmias than the control group (3.1 versus 5.2 times, P = 0.17). The mean daily episodes of frequent atrial tachyarrhythmias were significantly fewer in the Saireito group during Day-6 to Day-10 (0.12/day versus 0.27/day, P = 0.03), and during Day-11 to Day-15 (0.08/day versus 0.24/day, P = 0.001). The prevalence of adverse symptoms during the 30-day treatment period was significantly higher in the Saireito group (18.0% versus 2.0%, P = 0.005). Conclusions: Thirty-day use of Saireito following AF ablation was associated with a tendency toward reduced number of episodes of frequent atrial tachyarrhythmias during the treatment period, with more pronounced effect in the first two weeks. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20–30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08–5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41–7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5–7.8] vs 10.4 months [95% CI: 7.9–12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292<300 characters). [ABSTRACT FROM AUTHOR]

Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Background Catheter ablation for asymptomatic atrial fibrillation (AF) remains controversial. The aim of the present study was to explore the prognostic impact of catheter ablation in asymptomatic AF patients. Methods We performed a post-hoc analysis of 537 risk-matched pairs of AF patients receiving first-time catheter ablation or conservative management. The primary outcome measure was a composite of cardiovascular death, heart failure (HF) hospitalization, ischemic stroke, or major bleeding. The study patients were divided into asymptomatic and symptomatic patients, and were further divided according to the presence or absence of previous AF-related complications (ischemic stroke or HF hospitalization). Results Most baseline characteristics were well balanced between the catheter ablation versus conservative management groups. The median follow-up period was 5.3 years. Catheter ablation as compared to conservative management was associated with significantly lower incidence of the primary outcome measure in the asymptomatic AF patients (14.7% versus 25.4% at 8-year, log-rank P = 0.008). However, the advantage of catheter ablation was significant only in the high-risk subset of patients with the previous AF-related complications (19.2% versus 55.6% at 8-year, log-rank P = 0.006), but not in those without (13.9% and 17.3%, P = 0.08). On the other hand, among the symptomatic AF patients, catheter ablation was associated with significantly lower incidence of the primary outcome measure regardless of the previous AF-related complications. Conclusions In the post-hoc analysis of the matched AF cohort, catheter ablation as compared with conservative management was associated with better long-term clinical outcomes among asymptomatic AF patients only when the previous AF-related complications were present.