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Abstract The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance (p = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.

The dorsal premotor cortex (PMd) plays an essential role in visually guided goal-directed motor behavior. Although there are several planning processes for achieving goal-directed behavior, the separate neural processes are largely unknown. Here, we created a new visuo-goal task to investigate the step-by-step planning processes for visuomotor and visuo-goal behavior in humans. Using functional magnetic resonance imaging, we found activation in different portions of the bilateral PMd during each processing step. In particular, the activated area for rule-based visuomotor and visuo-goal mapping was located at the ventrorostral portion of the bilateral PMd, that for action plan specification was at the dorsocaudal portion of the left PMd, that for transformation was at the rostral portion of the left PMd, and that for action preparation was at the caudal portion of the bilateral PMd. Thus, the left PMd was involved throughout all of the processes, but the right PMd was involved only in rule-based visuomotor and visuo-goal mapping and action preparation. The locations related to each process were generally spatially separated from each other, but they overlapped partially. These findings revealed that there are functional subregions in the bilateral PMd in humans and these subregions form a functional gradient to achieve goal-directed behavior.

Abstract Objectives Dermatomyositis (DM) is an autoimmune disease that presents with a wide variety of clinical manifestations. Patients with DM or clinically amyopathic dermatomyositis (CADM) with antimelanoma differentiation‐associated protein 5 (anti‐MDA5) antibodies are frequently associated with interstitial pneumonia, especially rapidly progressive interstitial lung disease. Progranulin (PGRN) is an autocrine growth factor involved in inflammation. Elevated serum PGRN levels have been reported in the patients with systemic lupus erythematosus and rheumatoid arthritis. However, they have not been precisely studied in DM/CADM. We assessed PGRN levels as a potential biomarker for DM/CADM with anti‐MDA5 antibodies. Methods Twenty‐four DM/CADM patients with anti‐MDA5 antibodies, 12 patients without anti‐MDA5 antibodies, and eight healthy volunteers were enrolled. We measured serum PGRN levels and compared them between the anti‐MDA5 antibody‐positive and antibody‐negative groups. They were also measured before and after the start of treatment in anti‐MDA5 antibody‐positive patients. We examined the correlations between serum PGRN levels and laboratory data such as serum KL‐6 and ferritin levels. Results Patients with DM/CADM, especially those with anti‐MDA5 antibodies, had significantly higher serum PGRN levels than healthy individuals. They decreased after the start of treatment. Serum PGRN levels were positively correlated with serum KL‐6 and ferritin levels, and anti‐MDA5 antibody titers. Conclusions This is the first study to show that PGRN levels were significantly elevated in the sera of DM/CADM patients, particularly in those with anti‐MDA5 antibodies. PGRN may be a useful biomarker of disease activity. However, further studies are required to reveal the mechanisms of PGRN in DM/CADM more precisely.

Abstract Professional boxers train to reduce their body mass before a match to refine their body movements. To test the hypothesis that the well-defined movements of boxers are represented within the motor loop (cortico-striatal circuit), we first elucidated the brain structure and functional connectivity specific to boxers and then investigated plasticity in relation to boxing matches. We recruited 21 male boxers 1 month before a match (Time1) and compared them to 22 age-, sex-, and body mass index (BMI)-matched controls. Boxers were longitudinally followed up within 1 week prior to the match (Time2) and 1 month after the match (Time3). The BMIs of boxers significantly decreased at Time2 compared with those at Time1 and Time3. Compared to controls, boxers presented significantly higher gray matter volume in the left putamen, a critical region representing motor skill training. Boxers presented significantly higher functional connectivity than controls between the left primary motor cortex (M1) and left putamen, which is an essential region for establishing well-defined movements. Boxers also showed significantly higher structural connectivity in the same region within the motor loop from Time1 to Time2 than during other periods, which may represent the refined movements of their body induced by training for the match.

How coherent neural oscillations are involved in task execution is a fundamental question in neuroscience. Although several electrophysiological studies have tackled this issue, the brain-wide task modulation of neural coherence remains uncharacterized. Here, with a fast fMRI technique, we studied shifts of brain-wide neural coherence across different task states in the ultraslow frequency range (0.01–0.7 Hz). First, we examined whether the shifts of the brain-wide neural coherence occur in a frequency-dependent manner. We quantified the shift of a region's average neural coherence by the inter-state variance of the mean coherence between the region and the rest of the brain. A clustering analysis based on the variance's spatial correlation between frequency components revealed four frequency bands (0.01–0.15 Hz, 0.15–0.37 Hz, 0.37–0.53 Hz, and 0.53–0.7 Hz) showing band-specific shifts of the brain-wide neural coherence. Next, we investigated the similarity of the inter-state variance's spectra between all pairs of regions. We found that regions showing similar spectra correspond to those forming functional modules of the brain network. Then, we investigated the relationship between identified frequency bands and modules’ inter-state variances. We found that modules showing the highest variance are those made up of parieto-occipital regions at 0.01–0.15 Hz, while it is replaced with another consisting of frontal regions above 0.15 Hz. Furthermore, these modules showed specific shifting patterns of the mean coherence across states at 0.01–0.15 Hz and above 0.15 Hz, suggesting that identified frequency bands differentially contribute to neural interactions during task execution. Our results highlight that usage of the fast fMRI enables brain-wide investigation of neural coherence up to 0.7 Hz, which opens a promising track for assessment of the large-scale neural interactions in the ultraslow frequency range.

Hideo Yuki,1,* Takao Kamai,1,* Keiichi Kubota,2 Hideyuki Abe,1 Daisaku Nishihara,1 Tomoya Mizuno,1 Akinori Masuda,1 Hironori Betsunoh,1 Masahiro Yashi,1 Yoshitatsu Fukabori,1 Ken-Ichiro Yoshida1 1Department of Urology, 2Department of Gastroenterological Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan *These authors contributed equally to this manuscript Background: Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen. Methods: We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy. Results: Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not. Conclusion: Axitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1). Keywords: renal cell carcinoma, sarcomatoid differentiation, axitinib, tyrosine kinase inhibitors, phosphorylated Akt

Romantic relationship, a widespread feature of human society, is one of the most influential factors in daily life. Although stimuli related to romantic love or being in a romantic relationship commonly result in enhancement of activation or functional connectivity of the reward system, including the striatum, the structure underlying romantic relationship-related regions remain unclear. Because individual experiences can alter gray matter within the adult human brain, we hypothesized that romantic relationship is associated with structural differences in the striatum related to the positive subjective experience of being in a romantic relationship. Because intimate romantic relationships contribute to perceived subjective happiness, this subjective enhancement of happiness might be accompanied by the experience of positive events related to being in a romantic relationship. To test this hypothesis and elucidate the structure involved, we compared subjective happiness, an indirect measure of the existence of positive experiences caused by being in a romantic relationship, of participants with or without romantic partners (N = 68). Furthermore, we also conducted a voxel-based morphometry (VBM) study of the effects of being in a romantic relationship (N = 113). Being in a romantic relationship was associated with greater subjective happiness and reduced gray matter density within the right dorsal striatum. These results suggest that being in a romantic relationship enhances perceived subjective happiness via positive experiences. Furthermore, the observed reduction in gray matter density in the right dorsal striatum may reflect an increase in saliency of social reward within a romantic relationship. Thus, being in a romantic relationship is associated with positive experiences and a reduction of gray matter density in the right dorsal striatum, representing a modulation of social reward.

Abstract Selpercatinib is the first targeted therapy for rearranged during transfection (RET) fusion‐positive unresectable non‐small‐cell lung cancer (NSCLC). The main adverse effects of selpercatinib include hypertension, liver dysfunction, diarrhea, and QT prolongation on electrocardiograms. However, instances of drug‐induced interstitial lung disease (DI‐ILD) are infrequently reported. We describe the first case of a patient with RET fusion‐positive NSCLC treated with selpercatinib who developed DI‐ILD, confirmed pathologically. The patient, a 72‐year‐old woman, initiated selpercatinib treatment following the postoperative recurrence of lung adenocarcinoma. After 15 months of treatment, computed tomography scans revealed multiple infiltrates and ground‐glass opacities in both lungs. A thoracoscopic lung biopsy identified organizing pneumonia, attributed to DI‐ILD caused by selpercatinib. Although she was asymptomatic, the patient's selpercatinib treatment was discontinued, leading to a gradual improvement in the lung infiltrates. Despite the lack of detailed reports, DI‐ILD with selpercatinib represents a potentially serious adverse event and should be approached with caution.

Abstract Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task’s rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

Abstract Background There are few reports of kidney disease caused by cryofibrinogen (CF). There are still many unknowns regarding its diagnosis, treatment, and prognosis. Case presentation A woman in her 70s experienced gross hematuria without any triggers; no urinary abnormalities had been previously detected. At the same time, the urine protein level was 5 g; therefore, a renal biopsy was performed. Light microscopy revealed a membranoproliferative glomerulonephritis-like pattern. And the electron microscopic findings were extremely characteristic and specific. Development of ischemic lesions was observed in the lower legs. A skin biopsy performed at the sites of toe necrosis showed fibrinoid necrotizing vasculitis and thrombi in the blood vessels. Eventually, the patient was diagnosed with cryofibrinogenemia (CF-emia) by mass spectrometry. The effect of steroids was limited. Subsequently, the patient’s renal function rapidly deteriorated, and toe necrosis progressed. The patient died after initiation of hemodialysis. Conclusion Although CF-emia is an unknown disease and has been infrequently reported, no reported cases exhibited rapid worsening of toe necrosis and renal function during the same period. Therefore, this case can be said to be the first case of fulminant cryofibrinogenemia. Due to the development of nephropathy, which is likely to be a factor for poor prognosis, establishment of therapeutic strategies is urgently required.

We measured the adhesion force between a sphere and a plane in water using a surface force apparatus that can measure the adhesion force with ultra-high accuracy. In particular, we focused on the relationship between the withdrawal speed and the adhesion force as one of the dynamic characteristics of the surface force. PDMS (Polydimethylsiloxane) was used as a spherical probe, and PEEK (Poly Ether Ether Ketone) and Si were used as plane samples. The results revealed that the adhesion forces depended on the withdrawal speed in water. This dependence was found to be qualitatively the same as that observed in a vacuum, indicating the influence of the viscoelasticity of PDMS on the adhesion forces. Furthermore, a comparison of the adhesion forces in air and water showed that they are dependent on the combination of materials. We deduced that the wettability of the material affected the adhesion forces. Specifically, the low affinity of the two surfaces to water resulted in hydrophobic attraction, while a hydration repulsion acts when one surface becomes hydrophilic.

Abstract A three-dimensional convolutional neural network model was developed to classify the severity of chronic kidney disease (CKD) using magnetic resonance imaging (MRI) Dixon-based T1-weighted in-phase (IP)/opposed-phase (OP)/water-only (WO) imaging. Seventy-three patients with severe renal dysfunction (estimated glomerular filtration rate [eGFR]

Abstract Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates.

Abstract Background Perioperative management of patients on dialysis is critical for controlling bleeding and thrombotic risk, in addition to infection control. Postoperative anticoagulation is often difficult to control, and different institutions have different policies. Therefore, in this study, we aimed to investigate factors associated with postoperative bleeding events and whether warfarin (WF) therapy affects the incidence of postoperative bleeding events, total mortality, and stroke. Methods Patients who were admitted to the cardiovascular surgery department and underwent valve replacement or plasty were included, and those who underwent mechanical valve introduction were excluded. Thirty-nine patients were included in the study. The primary endpoint was to identify factors associated with the composite endpoint of postoperative bleeding events, and the secondary endpoint was to determine the effect size of WF therapy on postoperative bleeding events, all-cause mortality, and stroke and the strength of association between the crossed endpoints. The strength of the association between the crossed items was examined. Results Low body weight (p = 0.038) was identified as a factor associated with the primary endpoint of postoperative bleeding events. The secondary endpoint of whether or not patients received WF therapy was largely unrelated to bleeding events, all-cause mortality, and postoperative stroke up to 90 days after surgery. Conclusions Preliminary studies suggest that low body weight is a risk factor for postoperative bleeding events in patients on dialysis, although further exploration of other factors will be necessary with the accumulation of similar cases.

Abstract Background Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. Case presentation: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. Conclusions Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.

Abstract Objective Livestock droppings cause some environmental problems, but they have the potential to be used as effective biomass resources. The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), is suitable for efficiently processing such resources. By using BSF larvae for the disposal of livestock droppings, we can obtain two valuable products: protein resources and organic fertilizer. However, there is insufficient research on the digestive enzymes suitable for processing this waste. Here, we aimed to construct an efficient BSF processing system using livestock droppings, and we explored the digestive enzymes involved in this process. Results First, we investigated the characteristics of transcripts expressed in the midgut of BSF larvae and found that immune response-related genes were expressed in the midgut. Then, we investigated digestive enzymes and identified a novel serine protease, HiBrachyurin, whose mRNA was highly expressed in the posterior midgut when BSF larvae fed on horse droppings. Despite the low protein content of horse droppings, larvae that fed on horse droppings accumulated more protein than those in the other groups. Therefore, HiBrachyurin may contribute to digestibility in the early stage of protein degradation in BSF larvae fed on horse droppings.

Abstract Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO)3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions.

Abstract Background The efficacy of neuraxial analgesia varies with spinal canal pathology. Notably, a secondary epidural catheter has been shown to increase neuraxial labor analgesia in women with spinal lesions. Therefore, we present a case in which catheter withdrawal played a critical role in achieving effective labor analgesia in a woman with epidural adhesions after lumbar discectomy who had inadequate analgesia with two epidural catheters. Case presentation We encountered a patient with L5 lumbar epidural adhesions who reported pain even after receiving two epidural catheters. The catheters were placed in the L1/2 and L5/S intervertebral spaces. Analgesic effects were exerted when the L5/S catheter was withdrawn by 1 cm, suggesting that the catheter tip was initially placed inside the adhesion. Conclusions Careful consideration of catheter placement and adjustments by withdrawing the catheter are crucial in managing labor analgesia in patients with known epidural adhesions.

Abstract Prognostic stratification is an urgent concern for patients with colorectal cancer (CRC). The desmoplastic reaction (DR) is speculated to mirror the tumor microenvironment. DR types are considered independent prognostic indicators in CRC, but have not been incorporated in previous prognostic nomograms. We aimed to assess the prognostic significance of a novel approach incorporating histopathological indicators reflecting tumor glandular differentiation and microenvironment. We evaluated 329 consecutive patients with CRC who underwent surgical resection at Kansai Medical University. Histological glandular differentiation was scored as 2 (0 point), 3 (1 point), or 4 (2 points). Tumor buddings (TBs) were classified as TB1 (0 point), TB2 (1 point), or TB3 (2 points). pT1 or 2 was considered as 0 point, pT3 or 4 + DR non-immature type as 1 point, and pT3 or 4 + DR immature type as 2 points. Lymph node metastasis was classified as pN0 (0 point), pN1 (1 point), or pN2 (2 points). The preoperative carcinoembryonic antigen levels were categorized as

Abstract Background A left thoracotomy approach is anatomically appropriate for childhood aortic coarctation; however, the pediatric femoral arteriovenous diameters are too small for cardiopulmonary bypass cannulation. We aimed to determine the safety of a partial cardiopulmonary bypass through the main pulmonary artery and the descending aorta in pediatric aortic coarctation repair. Methods We retrospectively reviewed 10 patients who underwent coarctation repair under partial main pulmonary artery-to-descending aorta cardiopulmonary bypass with a left thoracotomy as the CPB group. During the same period, 16 cases of simple coarctation of the aorta repair, with end-to-end anastomosis through a left thoracotomy without partial CPB assistance, were included as the non-CPB group to evaluate the impact of partial CPB. Results The median age and weight at surgery of the CPB group were 3.1 years (range, 9 days to 17.9 years) and 14.0 (range, 2.8–40.7) kg, respectively. Indications for the partial cardiopulmonary bypass with overlap were as follows: age > 1 year (n = 7), mild aortic coarctation (n = 3), and predicted ischemic time > 30 min (n = 5). Coarctation repair using autologous tissue was performed in seven cases and graft replacement in three. The mean partial cardiopulmonary bypass time, descending aortic clamp time, and cardiopulmonary bypass flow rate were 73 ± 37 min, 57 ± 27 min, and 1.6 ± 0.2 L/min/m2, respectively. Urine output during descending aortic clamping was observed in most cases in the CPB group (mean: 9.1 ± 7.9 mL/kg/h), and the total intraoperative urine output was 3.2 ± 2.7 mL/kg/h and 1.2 ± 1.5 mL/kg/h in the CPB and non-CPB group, respectively (p = 0.020). The median ventilation time was 1 day (range, 0–15), and the intensive care unit stay duration was 4 days (range, 1–16) with no surgical deaths. No major complications, including paraplegia or recurrent coarctation, occurred postoperatively during a median observation period of 8.1 (range, 3.4–17.5) years in the CPB group. In contrast, reoperation with recurrent coarctation was observed in 2 cases in the non-CPB group (p = 0.37). Conclusions Partial cardiopulmonary bypass through the main pulmonary artery and descending aorta via a left thoracotomy is a safe and useful option for aortic coarctation repair in children.

Abstract Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9–43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93–11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01–0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13–11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68–15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Abstract This retrospective observational study aimed to investigate the difference in 4-year outcomes of ranibizumab or aflibercept therapy for macular neovascularization (MNV) with high myopia between pathologic myopia (PM) and non-PM. This study was conducted at Kyoto University Hospital and included consecutive treatment-naïve eyes with active myopic MNV, in which a single intravitreal ranibizumab or aflibercept injection was administered, followed by a pro re nata (PRN) regimen for 4 years. Based on the META-PM study classification, eyes were assigned to the non-PM and PM groups. This study analyzed 118 eyes of 118 patients (non-PM group, 19 eyes; PM group, 99 eyes). Baseline, 1-year, and 2-year best-corrected visual acuity (BCVA) were significantly better in the non-PM group (P = 0.02, 0.01, and 0.02, respectively); however, the 3-year and 4-year BCVA were not. The 4-year BCVA course was similar in both groups. However, the total number of injections over 4 years was significantly higher in the non-PM than in the PM group (4.6 ± 2.6 vs. 2.9 ± 2.6, P = 0.001). Four-year BCVA significantly correlated only with baseline BCVA in both non-PM (P = 0.047, β = 0.46) and PM groups (P

Abstract Background Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. Methods ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. Results ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen’s kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. Conclusions A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.

Summary: Background & Aims: Intermittent nasogastric (ING)/intermittent orogastric (IOG) tube feeding is an intermittent tube feeding (ITF) method in which a catheter is sporadically placed through the mouth or nose into the stomach to administer nutrients with syringes. This method proves advantageous in rehabilitation wards, as it allows for bed release and training. However, detailed reports on this method are limited, and its safety remains controversial. This study aimed to investigate the incidence of complications and risk factors associated with ING/IOG tube feeding. Methods: This longitudinal cohort study included 135 patients who received ING/IOG tube feeding for all meals and were discharged from our hospital between October 2018 and September 2022. The incidence and prevalence of complications (diarrhea, vomiting, and pneumonia) during the first 28 days after admission were retrospectively investigated. Multiple logistic regression analysis was performed to analyze factors associated with complications. The explanatory variables selected were age, functional independence measure (FIM) motor scores, low body mass index (BMI) (

Abstract Background Although proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) are useful in peptic ulcer prevention, their efficacy in preventing other gastrointestinal bleeding remains unclear. This study aimed to identify the status of gastrointestinal bleeding in the modern era when PPIs are widely used. Methods This study included patients who underwent percutaneous coronary intervention (PCI) between 2018 and 2019 at two high-volume centers. Patients were categorized based on whether they experienced gastrointestinal bleeding within 2 years of PCI into groups A (patients who experienced gastrointestinal bleeding within 2 years after PCI) and B (patients who did not experience gastrointestinal bleeding). Results Groups A and B included 21 (4.1%) and 494 (95.9%) patients, respectively (a total of 515 patients). Age at the initial PCI (77.8±2.4 and 72.0±0.5 years in groups A and B, respectively; p = 0.02), weight (53.8±3.2 and 61.8±0.7 kg in groups A and B, respectively; p = 0.01), and concomitant warfarin use (14.3% and 2.0% in groups A and B, respectively; p = 0.0005) were significantly different between the groups. The high bleeding risk rate (90.5% and 47.6% in groups A and B, respectively; p = 0.0001) was significantly different between the groups. A total of 95.9% of patients were taking PPIs or PCAB without significant differences between the groups. However, only one patient, who was taking steroids, had a gastric ulcer during PCAB treatment. Conclusions Acid-related upper gastrointestinal bleeding is largely controlled by PPIs in post-PCI patients. Furthermore, the risk factors for non-acid-related bleeding include older age, lower weight, and concomitant warfarin use.

Abstract Mycobacteroides (Mycobacterium) abscessus, which causes a variety of infectious diseases in humans, is becoming detected more frequently in clinical specimens as cases are spreading worldwide. Taxonomically, M. abscessus is composed of three subspecies of M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense, with different susceptibilities to macrolides. In order to identify rapidly these three subspecies, we determined useful biomarker proteins, including ribosomal protein L29, L30, and hemophore-related protein, for distinguishing the subspecies of M. abscessus using the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) profiles. Thirty-three clinical strains of M. abscessus were correctly identified at the subspecies-level by the three biomarker protein peaks. This study ultimately demonstrates the potential of routine MALDI-MS-based laboratory methods for early identification and treatment for M. abscessus infections.

Abstract Aspiration pneumonia is the leading cause of death in patients with Parkinson’s disease. The incidence of silent aspiration is high in such patients owing to decreased pharyngeal and laryngeal sensation; thus, interventions for this condition may help prevent pneumonia. In this single-arm, open-label study, we used a cervical percutaneous interferential current stimulation device to activate pharyngeal and laryngeal sensory nerves. We evaluated its effectiveness in patients with Hoehn–Yahr stages 2–4 Parkinson’s disease. The primary endpoint was the proportion of patients with a normal cough reflex after consuming 1% citric acid at the end of the intervention compared with baseline measurements. In total, 25 patients received neck percutaneous interferential current stimulation for 20 min twice weekly for 8 weeks. Afterward, the proportion of patients with a normal cough reflex after 1% citric acid consumption increased significantly (p = 0.001), whereas other indicators, such as tongue pressure, peak expiratory flow, and penetration or aspiration during videofluoroscopic examination, remained unchanged. A longer duration of illness, higher Unified Parkinson’s Disease Rating Scale total scores, and higher levodopa equivalent daily doses were significantly associated with improved cough test outcomes. Hence, cervical percutaneous interferential current stimulation significantly improved cough reflexes and may improve silent aspiration. Trial Registration: Japan Registry of Clinical Trials, jRCTs062220013, first registered 09/05/2022.

Abstract This study performed three-dimensional (3D) magnetic resonance imaging (MRI)-based statistical shape analysis (SSA) by comparing patellofemoral instability (PFI) and normal femur models, and developed a machine learning (ML)-based prediction model. Twenty (19 patients) and 31 MRI scans (30 patients) of femurs with PFI and normal femurs, respectively, were used. Bone and cartilage segmentation of the distal femurs was performed and subsequently converted into 3D reconstructed models. The pointwise distance map showed anterior elevation of the trochlea, particularly at the central floor of the proximal trochlea, in the PFI models compared with the normal models. Principal component analysis examined shape variations in the PFI group, and several principal components exhibited shape variations in the trochlear floor and intercondylar width. Multivariate analysis showed that these shape components were significantly correlated with the PFI/non-PFI distinction after adjusting for age and sex. Our ML-based prediction model for PFI achieved a strong predictive performance with an accuracy of 0.909 ± 0.015, and an area under the curve of 0.939 ± 0.009 when using a support vector machine with a linear kernel. This study demonstrated that 3D MRI-based SSA can realistically visualize statistical results on surface models and may facilitate the understanding of complex shape features.

Abstract Background Several models have been used to predict outbreaks during the COVID-19 pandemic, with limited success. We developed a simple mathematical model to accurately predict future epidemic waves. Methods We used data from the Ministry of Health, Labour and Welfare of Japan for newly confirmed COVID-19 cases. COVID-19 case data were summarized as weekly data, and epidemic waves were visualized and identified. The periodicity of COVID-19 in each prefecture of Japan was confirmed using time-series analysis and the autocorrelation coefficient, which was used to investigate the longer-term pattern of COVID-19 cases. Outcomes using the autocorrelation coefficient were visualized via a correlogram to capture the periodicity of the data. An algorithm for a simple prediction model of the seventh COVID-19 wave in Japan comprised three steps. Step 1: machine learning techniques were used to depict the regression lines for each epidemic wave, denoting the “rising trend line”; Step 2: an exponential function with good fit was identified from data of rising straight lines up to the sixth wave, and the timing of the rise of the seventh wave and speed of its spread were calculated; Step 3: a logistic function was created using the values calculated in Step 2 as coefficients to predict the seventh wave. The accuracy of the model in predicting the seventh wave was confirmed using data up to the sixth wave. Results Up to March 31, 2023, the correlation coefficient value was approximately 0.5, indicating significant periodicity. The spread of COVID-19 in Japan was repeated in a cycle of approximately 140 days. Although there was a slight lag in the starting and peak times in our predicted seventh wave compared with the actual epidemic, our developed prediction model had a fairly high degree of accuracy. Conclusion Our newly developed prediction model based on the rising trend line could predict COVID-19 outbreaks up to a few months in advance with high accuracy. The findings of the present study warrant further investigation regarding application to emerging infectious diseases other than COVID-19 in which the epidemic wave has high periodicity.

Abstract Since 2021, a new surge in discrete aurora detections at Mars has been observed by the Emirates Mars Ultraviolet Spectrometer (EMUS) onboard the Emirates Mars Mission (EMM) Hope Orbiter as EMUS started to regularly obtain synoptic auroral images with a high sensitivity. Here we report on a fortuitous conjunction between EMM and Mars Express (MEX) using far ultraviolet (FUV) imaging of discrete aurora by EMM EMUS, in situ measurements of suprathermal electrons by the MEX Analyzer of Space Plasma and Energetic Atoms Electron Spectrometer (ELS), and topside radar sounding of the nightside ionosphere by the MEX Mars Advanced Radar for Subsurface and Ionosphere Sounding (MARSIS). In this event, EMM EMUS imaged a clear discrete aurora signature around moderately strong crustal magnetic fields on the nightside near the dusk terminator, 11 min before which MEX MARSIS measured a prominent local enhancement of the peak electron density in the nightside ionosphere and MEX ELS observed an in situ enhancement of suprathermal electrons at the corresponding location. A remarkable geographic agreement is found between the enhancements of the aurora, ionosphere, and suprathermal electrons, suggesting that the enhanced ionization and auroral emission are caused concurrently by precipitating suprathermal electrons. Subsequent images indicate that the discrete aurora slightly changed its shape in 15 min and mostly disappeared in a few hours. The MEX MARSIS measurements of the auroral ionosphere display overlapping ionospheric and surface echoes indicative of horizontal gradients of the peak electron density. Analysis of the overlapping echoes implies that the auroral ionosphere and electron precipitation could be highly structured with horizontal spatial scales on the order of several tens of km. MEX MARSIS also observed a non-auroral ionospheric enhancement with a wider spatial extent than the local auroral enhancement, suggesting alternative sources of the enhanced nightside ionosphere such as plasma transport. The comparison between the ionospheric structures measured by MEX MARSIS, suprathermal electron flux measured by MEX ELS, and discrete auroral emission imaged by EMM EMUS underscores the complexity of the auroral and non-auroral nightside ionospheres. This motivates further investigations of their sources, transport, and connections to the magnetotail dynamics of Mars.

Studies on the conditions and pollution routes of antibiotic-resistant bacteria (ARB) in rivers can help provide countermeasures against the spread of ARB. This study focused on the pristine uppermost stream of a river, where Escherichia coli (E. coli) and enterococci were detected, although the stream flows through a pristine forest catchment. Antibiotic resistance of E. coli and enterococci isolated from the river water, riverbed sediment, and feces of waterside animals, such as birds and Mustelidae, were investigated throughout the year in the pristine uppermost sites. Antibiotic resistance was present in 1.4% (7/494) of the E. coli strains and 3.0% (24/812) of the enterococcal strains, and was low throughout the year. Although antibiotic resistance of bacteria isolated from feces was not detected in this watershed, the prevalence of multidrug-resistant E. coli was 0.4% (1/246) and 0.6% (1/172) in river water and riverbed sediment samples, respectively were observed. The presence of extended-spectrum β-lactamase (ESBL)-producing E. coli was confirmed in river water samples, and genomic analysis revealed that the samples possessed the CTX-M-15 group. Multidrug-resistant strains and ESBL-producing strains were classified as phylogroups B1 and A, respectively, which are E. coli phenotypes isolated from wild animals. Pulsed-field gel electrophoresis revealed analysis targeting enterococci that strains isolated from river water and bird feces were in the same cluster with 100% similarity. Therefore, bird feces are a source of enterococci in the uppermost stream of the river. Because multidrug-resistant bacteria and ESBL-producing bacteria were present in the pristine uppermost stream of the pristine river, urgent elucidation of the spreading routes of ARB is important.

Abstract Aim Lenvatinib mesylate (LEN) is an oral tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events. This study was aimed at investigating the incidence of LEN‐induced palmar‐planter erythrodysesthesia syndrome (PPES) and its relationship with patient demographics by analyzing clinical laboratory data of LEN‐treated patients with HCC. Methods This was a single‐centre, retrospective study of patients with HCC who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. Results Overall, 75 patients with HCC were enrolled. LEN‐induced PPES was found in 48.0% (36/75 patients). In these patients, alkaline phosphatase (ALP), γ‐Glutamyl transpeptidase (γ‐GTP) and monocytes (MONO) were significantly high (ALP: p = 1.32 × 10−3, γ‐GTP: p = 4.25 × 10−3 and MONO: p = 0.013). The cut off values of ALP, γ‐GTP and MONO for LEN‐induced PPES were estimated at 573 U/L, 89 U/L, and 310 counts/μL, respectively. In the multivariate analysis, γ‐GTP and MONO were independent risk factors for LEN‐induced PPES. Conclusions High γ‐GTP and high MONO were risk factors for LEN‐induced PPES.

Abstract Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium.

BackgroundEndovascular therapy (EVT) for distal medium vessel occlusions requires prioritizing effectiveness and safety. We developed a technique combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter (AC) for M2 occlusions, called the “ONE-SEG technique,” and evaluated its clinical and technical impacts.MethodsThis was a retrospective review of 30 consecutive patients with M2 segment middle cerebral artery occlusion treated using the ONE-SEG technique. This method involves deploying the EMBOTRAP III through a microcatheter in only one segment and guiding the AC to the M2 origin or distal M1. The rates of final-pass expanded thrombolysis in cerebral infarction (eTICI) scores of 2c/3 or 2b/2c/3, safety (symptomatic intracranial hemorrhage [sICH]), and clinical outcomes (modified Rankin Scale [mRS] score 0–2, 0–3 at 90 days, and mortality at 90 days) were evaluated.ResultsOf the 30 cases, 36.7% were female, and the mean age was 75.6 ± 11.0 years. The ONE-SEG technique was used for 17 cases (56.7%, median NIHSS 10 [5–15.5]) with primary M2 occlusion and 13 cases (43.3%, median NIHSS 20 [14–22.5]) with secondary M2 occlusion after proximal thrombus removal. The successful final reperfusion rate (eTICI 2b/2c/3) was 90% overall (27/30 cases). One case (3.3%) developed sICH with secondary M2 occlusion. At 3 months, mRS scores 0–2 were seen in 64.7% of patients with primary M2 occlusion (11/17 cases) and in 23.1% (3/13 cases) with secondary M2 occlusion.ConclusionEVT using the ONE-SEG technique appears to be safe and effective for M2 occlusion.