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Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.

Introduction We report a case of rectal perforation following SpaceOAR placement utilized with iodine‐125 low‐dose‐rate brachytherapy for prostate cancer. Case presentation A 65‐year‐old patient with localized prostate cancer underwent SpaceOAR placement following LDR‐BT. No significant issues occurred with the SpaceOAR procedure, and no abnormalities were found on the next day's T2‐weighted magnetic resonance imaging. Two weeks later, a colonoscopy was performed due to mucus stools revealing rectal perforation attributed to SpaceOAR. By maintaining Macrogol 4000 and a low residue diet, the perforation healed within 6 months. Conclusion Rectal ulcers and perforations are the most common severe adverse events from SpaceOAR placement. Effective management strategies are crucial since complications can't be entirely avoided, even with skilled surgeons.

Aneurysmal subarachnoid hemorrhage (aSAH) is a critical condition with high in-hospital mortality rates. Delayed cerebral ischemia (DCI), a secondary complication associated with aSAH, can also contribute to morbidity and mortality. Although draining the hematoma from the subarachnoid space has been considered effective in preventing DCI, the placement of a drainage system could increase the risk of bacterial meningitis and ventriculitis. This study aimed to examine the association between meningitis following aSAH and the occurrence of DCI, focusing on the role of cerebral vasospasm. Patients who underwent endovascular coiling or surgical clipping for aSAH from April 2001 to March 2022 were included in this study, while those who did not undergo postoperative drainage were excluded. The patient's clinical characteristics, treatment modalities, and outcomes were then analyzed, after which logistic regression was used to assess the odds ratios (OR) for DCI. A total of 810 patients with aSAH were included in this study. Meningitis following aSAH was identified as an independent factor associated with DCI (odds ratio 5.0 [95% confidence intervals (CI) 2.3-11]). Other significant factors were female sex (odds ratio 1.5 [95% CI 0.89-2.5]) and surgical clipping (odds ratio 2.1 [95% CI 1.3-3.4]). This study demonstrated a significant association between meningitis following aSAH and the development of DCI, suggesting that the inflammatory environment associated with meningitis may contribute to cerebral vasospasm. Early recognition and treatment of meningitis in patients with aSAH could reduce the risk of DCI and improve patient outcomes.

ABSTRACT Bartonella henselae, a Gram-negative facultative intracellular bacterium, is the etiological agent of cat-scratch disease and also causes bacillary angiomatosis in immunocompromised individuals. Although the ability to promote vascular endothelial cell proliferation differs among Bartonella species, variations among strains within B. henselae remain unclear. Bartonella angiogenic factor A (BafA) and Bartonella adhesin A (BadA) have been identified as autotransporters of B. henselae that are involved in endothelial cell proliferation. Although strain-specific differences in the expression of BadA and the VirB/D4 type IV secretion system have been reported, BafA expression among B. henselae strains has yet to be examined. Therefore, the present study investigated the proliferation-promoting ability of 13 B. henselae strains from several sources in human umbilical vein endothelial cells (HUVECs). We identified BafA variants 1 and 2 based on the deduced amino acid sequences of its passenger domain. The recombinant proteins of both variants exhibited similar proliferation activity against HUVECs. However, BafA variant 2 strains showed cytotoxicity at a high bacterial inoculum in a direct coculture with HUVECs, which was attenuated in an indirect coculture. These strains, in contrast to BafA variant 1 strains, highly expressed BadA and exhibited bacterial aggregation. Based on a core genome SNP analysis of 50 B. henselae strains, the BafA variant types corresponded to clades 1–4. These results indicate that vasoproliferative traits differ among B. henselae clades based on the variant types. Therefore, this study provides a new conceptual framework in which the clades of B. henselae may predict their pathogenicity in humans.IMPORTANCEBartonella species including Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis cause vasoproliferative lesions. Their proliferation-promoting ability in vascular endothelial cells differs among Bartonella species; however, it is unclear whether these differences exist among B. henselae strains. We herein showed that B. henselae strains exhibited variable proliferation-promoting ability and cytotoxicity in vascular endothelial cells, which corresponded to the bafA gene variants possessed by the strains. The expression levels of Bartonella angiogenic factor A (BafA) and Bartonella adhesin A, as well as the degree of proliferation-promoting ability and cytotoxicity in endothelial cells, varied among the strains. A core genome SNP analysis of strains using whole genome sequencing data divided B. henselae strains into four clades, with each clade corresponding to BafA variants 1–4. These results suggest the differential vasoproliferative potency of B. henselae, with potential implications in clinical management, including risk stratification and predictions of the clinical course.

Tablets are the most typical dosage forms of pharmaceutical inventions. Sustained-release (SR) tablet formulations are designed to release the drug gradually in the bloodstream and often require less frequent dosing. Current strategies to optimize sustained-release tablet dissolution time still rely on the traditional approach, which is time-consuming and expensive. In the present context, we have demonstrated alternate machine learning and deep learning models through the TPOT AutoML platform. Six machine learning (ML) models were compared to improve the methodology for dissolution time prediction, particularly the decision tree regressor (DTR), gradient boost regressor (GBR), random forest regressor (RFR), extra tree regressor (ETR), XGBoost regressor (XGBR), and deep learning (DL). The obtained results indicated that machine learning methods are convincing in speculating the dissolution time, especially the random forest regressor, but upon hypertuning of the deep neural network, the deep learning model with a 10-fold cross-validation scheme demonstrated superior predictive performance with an NRMSE of 8% and an R2 of 0.92. The major essentials affecting the dissolution time of SR tablets were explained using the SHAP method.

Objective: Pulmonary complications, which are occasionally severe, are common adverse events following the administration of clazosentan. This study aimed to identify factors associated with severe pulmonary adverse events due to clazosentan after aneurysmal subarachnoid hemorrhage (aSAH). Methods: We conducted a retrospective study of 59 patients transported to our hospital and diagnosed with aSAH between April 2022 and May 2023. Results: The analysis included 33 patients who were treated with clazosentan. Pulmonary complications occurred in 20 patients (61 %) and clazosentan administration was discontinued due to severe pulmonary complications in 7 patients (21 %). The cardiothoracic ratio on admission was significantly higher (57 % vs. 49 %, p = 0.0081) and clazosentan was initiated earlier after aSAH onset (42 vs. 66 h, p = 0.047) in patients who discontinued clazosentan compared with patients who completed administration of clazosentan. The median duration of clazosentan administration was 3.2 days in the discontinuation group. No significant associations were found between the time of clazosentan initiation and the incidence of angiographic vasospasm, delayed cerebral ischemia, or 90-day modified Rankin scale. Conclusions: The risk of severe pulmonary complications is higher in patients with high cardiothoracic ratios on admission, and delaying clazosentan initiation may prevent pulmonary complications even in high-risk cases.

Abstract Background Ehlers–Danlos syndrome (EDS) is a genetic disorder that causes fragility of the systemic connective tissues. Of the 13 subtypes, vascular EDS (vEDS) is associated with abnormalities in collagen production, resulting in arterial rupture and intestinal perforation. Herein, we report the case of a man with confirmed vEDS who survived a ruptured dissected splenic artery aneurysm triggered by perforation of the sigmoid colon. Case presentation A 48-year-old man presented to our hospital with sudden severe lower abdominal pain. The patient was genetically diagnosed with vEDS at the age of 43 years. Abdominal computed tomography (CT) showed fluid and free air surrounding the sigmoid colon. These findings suggested sigmoid colon perforation, and emergency surgery was needed. Hartmann’s procedure was performed. The resected specimen showed a 2-cm-sized depression around the perforation. Histopathological findings showed an abscess and exudate in the serosa of the perforation and thinning of the intrinsic muscular layer in the depressed area. The patient was doing well postoperatively; however, on the ninth postoperative day, sudden upper abdominal pain developed. CT revealed an intra-abdominal hemorrhage due to rupture of a dissecting splenic artery aneurysm. The aneurysm was not observed on preoperative CT and was distant from the surgical site. Urgent transcatheter arterial embolization was performed. Although embolization of the splenic artery was attempted during the procedure, the arterial dissection spread to the common hepatic artery. Moreover, the proper hepatic and gastroduodenal arteries were poorly visualized, probably due to vasospasm. Although complications associated with extensive embolization were a concern, embolization of the splenic and common hepatic arteries was necessary to save the patient’s life. After embolization, angiography showed that the left hepatic blood flow was maintained from the inferior phrenic artery, and the right hepatic inflow was maintained from the superior mesenteric artery via the peribiliary vascular plexus in the hilar area. The patient recovered well and was discharged on the 19th postoperative day. Conclusions vEDS can cause arterial rupture after intestinal surgery. Therefore, careful post-operative management is necessary. Moreover, cooperation with interventional radiologists is important for prompt treatment of vascular complications.

Key Clinical Message A 46‐year‐old male developed respiratory distress due to asthma‐chronic obstructive pulmonary disease overlap and experienced severe tremor caused by beta2 agonist inhalant. We present our successful experience with tizanidine administration.

Objective The objective was to analyse the associations of intensive care unit (ICU) and high care unit (HCU) organisational structure on in-hospital mortality among patients with sepsis in Japan’s acute care hospitals.Design Multicentre cross-sectional study.Settings Patients with sepsis aged ≥18 years who received critical care in acute care hospitals throughout Japan between April 2018 and March 2019 were identified using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB).Interventions None.Participants 10 968 patients with sepsis were identified. ICUs were categorised into three groups: type 1 ICUs (fulfilling stringent staffing criteria such as experienced intensivists and high nurse-to-patient ratios), type 2 ICUs (less stringent criteria) and HCUs (least stringent criteria).Primary outcome measure The study’s primary outcome measure was in-hospital mortality. Cox proportional hazards regression analysis was performed to examine the impact of ICU/HCU groups on in-hospital mortality.Results We analysed 2411 patients (178 hospitals) in the type 1 ICU group, 3653 patients (422 hospitals) in the type 2 ICU group and 4904 patients (521 hospitals) in the HCU group. When compared with the type 1 ICU group, the adjusted HRs for in-hospital mortality were 1.12 (95% CI 1.04 to 1.21) for the type 2 ICU group and 1.17 (95% CI 1.08 to 1.26) for the HCU group.Conclusion ICUs that fulfil more stringent staffing criteria were associated with lower in-hospital mortality among patients with sepsis than HCUs. Differences in organisational structure may have an association with outcomes in patients with sepsis, and this was observed by the NDB.

Abstract Aim This study aimed to evaluate the prognostic impact of total neoadjuvant therapy (TNT) for borderline resectable pancreatic cancer with arterial involvement (BR‐A) pancreatic cancer. Methods We analyzed 81 patients initially diagnosed as BR‐A who received initial treatments between 2007 and 2021. Among them, 18 patients who received upfront surgery were classified as the UFS group, while 30 patients who were treated with neoadjuvant chemoradiotherapy were classified as the NACRT group. Furthermore, 33 patients who planned to receive a combination treatment of over 6 months of systemic chemotherapies followed by chemoradiotherapy before surgery were classified as the TNT group. Results There were no significant differences in the patients’ backgrounds between the three groups at the time of initial treatment. The resection rates of the UFS, NACRT, and TNT groups were 89%, 77%, and 67%, respectively. NACRT had no impact on the prognosis compared to upfront surgery. In sharp contrast, the TNT group had a significantly better prognosis compared to the other groups, especially after pancreatic resection. Multivariate analysis demonstrated that TNT and resection were independent prognostic factors for the patients of BR‐A. Conclusion TNT can be a promising therapeutic strategy for patients with BR‐A.

Abstract White adipose tissue (WAT) is critical for whole-body energy metabolism, and its dysfunction leads to various metabolic disorders. In recent years, many studies have suggested that impaired mitochondria may contribute to obesity-related decline in adipose tissue function, but the detailed mechanisms remain unclear. To investigate these mechanisms, we carried out a comprehensive analysis of WAT from mice with diet-induced obesity. We discovered the transcription factor Parkin interactive substrate (PARIS or ZNF746), which suppresses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, to be accumulated in adipose progenitor cells from obese mice. Furthermore, we demonstrated that 3T3-L1 preadipocytes with overexpression of PARIS protein exhibited decreased mitochondrial biogenesis and impaired adipogenesis. Our results suggest that the accumulation of PARIS protein may be a novel component in the pathogenesis of obesity-related dysfunction in WAT.

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal lung disease characterized by tissue scarring and declining lung function. The MUC5B promoter polymorphism rs35705950, a significant genetic predisposition for IPF, paradoxically associates with better survival and slower disease progression than other IPF genotypes. This study investigates the potential paradoxical protective effects of this MUC5B variant in lung fibrosis. For this purpose, we developed a transgenic mouse model overexpressing the human MUC5B rs35705950 variant in the proximal large airways. Lung fibrosis was induced through subcutaneous injection of bleomycin. Results demonstrated significantly reduced lung fibrosis severity in transgenic mice compared to wild-type mice, assessed by trichrome staining, Ashcroft scoring, and hydroxyproline levels. Additionally, transgenic mice showed significantly lower levels of inflammatory cells and cytokines (TNFα, IL-6, IFNγ) and growth factors (PDGF, CTGF, IL-13) in the bronchoalveolar lavage fluid and lung tissues. There was also a significant decrease in mRNA expressions of fibrosis-related markers (periostin, fibronectin, Col1a1). In summary, this study reveals that mucin overexpression related to the MUC5B rs35705950 variant in the large airways significantly attenuates lung fibrosis and inflammatory responses in transgenic mice. These findings suggest that the rs35705950 variant modulates inflammatory and fibrotic responses in the proximal airways, which may contribute to the slower disease progression observed in IPF patients carrying this variant. Our study offers a possible explanation for the paradoxical beneficial effects of the MUC5B variant despite its role as a significant predisposing factor for IPF.

Abstract The high overpotential of oxygen reduction reaction (ORR) prevents the wide commercialization of fuel cells and metal‐air batteries. To accelerate the reaction rate, porous electrocatalysts draw attention to obtain a higher specific surface area. However, the effect of micropores on ORR kinetics has not been understood because of the non‐uniform pore sizes, length, and tortuosity of practical electrocatalysts. In this study, we evaluate ORR activity in a micropore using platinum model electrodes with arrays of cylindrical pores with a uniform pore diameter of 1.8 nm. The model electrodes having pore lengths of 45, 100, and 380 nm are fabricated, and their ORR performances are examined by electrochemical measurements and numerical simulations in 0.1 mol dm−3 KOH aqueous solution. The intrinsic ORR activity of the micropore is successfully obtained with the electrode having a pore length of 45 nm, where oxygen transport resistance in the micropore has little effect on ORR. It is found that the intrinsic ORR activity of the micropore is higher than that of a planar Pt surface. X‐ray photoelectron spectroscopy and CO stripping voltammetry indicate a downshift of the d‐band center, which can be the origin of the high intrinsic ORR activity.

Abstract Background Pancreatic lipomas (PLs) arising from the adipose tissue in the pancreatic parenchyma are rare among pancreatic tumors. Coexisting pancreatic ductal adenocarcinoma (PDAC) and PLs have not been previously reported. Herein, we report a case of PDAC arising from the pancreatic parenchyma with chronic pancreatitis compressed by a large PL. Case presentation The patient was a 69-year-old male. He had been diagnosed with a PL using computed tomography (CT) 12 years previously. The tumor had been slowly growing and was followed up carefully because of the possibility of well-differentiated liposarcoma. During follow-up, laboratory data revealed liver damage and slightly elevated levels of inflammatory markers. Contrast-enhanced CT revealed the previously diagnosed 12 cm pancreatic head tumor and an irregular isodensity mass at the upper margin of the tumor that invaded and obstructed the distal common bile duct. Magnetic resonance cholangiopancreatography demonstrated no specific findings in the main pancreatic duct. Based on these imaging findings, the patient underwent endoscopic retrograde biliary drainage and bile duct brushing cytology, which revealed indeterminate findings. The differential diagnosis of the tumor at that time was as follows: (1) pancreatic liposarcoma (focal change from well-differentiated to dedifferentiated, not lipoma), (2) distal cholangiocarcinoma, and (3) pancreatic cancer. After the cholangitis improved, a pancreatoduodenectomy was performed. Histologically, hematoxylin–eosin staining revealed moderately differentiated PDAC compressed by proliferating adipose tissue. The adipose lesion showed homogeneous adipose tissue with no evidence of sarcoma, which led to a diagnosis of lipoma. Additionally, extensive fibrosis of the pancreatic parenchyma and atrophy of the acinar cells around the lipoma was suggestive of chronic pancreatitis. The pathological diagnosis was PDAC (pT2N0M0 pStage Ib) with chronic pancreatitis and PL. The postoperative course was uneventful, and the patient was discharged on the 15th day after surgery. The patient received adjuvant chemotherapy and has remained recurrence-free for more than 6 months. Conclusions PL may be associated with the development of PDAC in the surrounding inflammatory microenvironment of chronic pancreatitis. In cases of growing lipomas, careful radiologic surveillance may be needed not only for the possibility of liposarcoma but also for the coincidental occurrence of PDAC.

Abstract Japan has implemented a cluster-based approach for coronavirus disease 2019 (COVID-19) from the pandemic’s beginning based on the transmission heterogeneity (overdispersion) of severe acute respiratory coronavirus 2 (SARS-CoV-2). However, studies analyzing overdispersion of transmission among new variants of concerns (VOCs), especially for Omicron, were limited. Thus, we aimed to clarify how the transmission heterogeneity has changed with the emergence of VOCs (Alpha, Delta, and Omicron) using detailed contact tracing data in Yamagata Prefecture, Japan. We estimated the time-varying dispersion parameter ( $${k}_{t}$$ k t ) by fitting a negative binomial distribution for each transmission generation. Our results showed that even after the emergence of VOCs, there was transmission heterogeneity of SARS-CoV-2, with changes in $${k}_{t}$$ k t during each wave. Continuous monitoring of transmission dynamics is vital for implementing appropriate measures. However, a feasible and sustainable epidemiological analysis system should be established to make this possible.

Acidic amino acid peptides have a high affinity for bone. Previously, we demonstrated that radiogallium complex-conjugated oligo-acidic amino acids possess promising properties as bone-seeking radiopharmaceuticals. Here, to elucidate the effect of stereoisomers of Glu in Glu-containing peptides [(Glu)14] on their accumulation in the kidney, the biodistributions of [67Ga]Ga-N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid-conjugated (l-Glu)14 ([67Ga]Ga-HBED-CC-(l-Glu)14), [67Ga]Ga-HBED-CC-(d-Glu)14, [67Ga]Ga-HBED-CC-(dl-Glu)14, and [67Ga]Ga-HBED-CC-(d-Glu-l-Glu)7 were compared. Although the accumulation of these compounds in the bone was comparable, their kidney accumulation and retention were strikingly different, with [67Ga]Ga-HBED-CC-(d-Glu-l-Glu)7 exhibiting the lowest level of kidney accumulation among these compounds. Repeated d- and l-peptides may be a useful method for reducing renal accumulation in some cases.

We synthesized a new silyl porphyrin derivative conjugated with 6-deoxy-6-sulfo-α-d-glucopyranose (SGlc). Conjugation with SGlc improved A549 cellular uptake without significant changes in the photophysical and photochemical properties and subcellular localization. This improved cellular uptake led to enhanced photodynamic activity. Furthermore, conjugation with SGlc suppressed dark toxicity. These advantages were not observed for a conjugate with a glucose molecule. These results indicated that the conjugation with SGlc is a promising strategy for enhancing photodynamic efficacy.

ABSTRACTAbove-ground biomass (AGB) is an important indicator of crop productivity. Destructive measurements of AGB incur huge costs, and most non-destructive estimations cannot be applied to diverse cultivars having different canopy architectures. This insufficient access to AGB data has potentially limited improvements in crop productivity. Recently, a deep learning technique called convolutional neural network (CNN) has been applied to estimate crop AGB due to its high capacity for digital image recognition. However, the versatility of the CNN-based AGB estimation for diverse cultivars is still unclear. We established and evaluated a CNN-based estimation method for rice AGB using digital images with 59 diverse cultivars which were mostly in World Rice Core Collection. Across two years at two locations, we took 12,183 images of 59 cultivars with commercial digital cameras and manually obtained their corresponding AGB. The CNN model was established by using 28 cultivars and showed high accuracy (R2 = 0.95) to the test dataset. We further evaluated the performance of the CNN model by using 31 cultivars, which were not in the model establishment. The CNN model successfully estimated AGB when the observed AGB was lesser than 924 g m−2 (R2 = 0.87), whereas it underestimated AGB when the observed AGB was greater than 924 g m−2 (R2 = 0.02). This underestimation might be improved by adding training data with a greater AGB in further study. The present study indicates that this CNN-based estimation method is highly versatile and could be a practical tool for monitoring crop AGB in diverse cultivars.

Background: Information regarding the outcomes of transcatheter aortic valve replacement (TAVR) in men is limited. This study aimed to investigate short- to mid-term outcomes and prognostic predictors in this population. Method and Results: The data of 519 men were analyzed from 1,693 consecutive patients with symptomatic severe aortic stenosis who underwent TAVR at six hospitals between April 2010 and July 2020. The primary endpoint was all-cause mortality at 30 days after TAVR. The mean age and Society of Thoracic Surgeons (STS) score were 83.7 ± 5.9 years and 6.3 ± 4.7%, respectively. Overall, 23.5% of patients consumed alcohol with a frequency of > 1 drinks/week, and 12.1% consumed alcohol with a frequency of > 8 drinks/week, while 66.1% were former smokers and 4.2% were current smokers. Mortality at 30 days was 0.8%. During the median follow-up period of 448 days, the estimated survival rates at 1 year post-TAVR was 90.7 ± 1.4%. In multivariate analysis, the serum albumin level [hazard ratio (HR): 2.20, 95% confidence interval (CI):1.36–3.62, p = 0.001], atrial fibrillation (HR: 1.79, 95% CI: 1.13–2.82, p = 0.012), and STS score (HR: 1.33, 95% CI: 1.06–1.67, p = 0.015) were independently associated with all-cause mortality following TAVR. Adjusted hazard ratios of current smoking, heavy drinking, and presence of cancer were 1.05 (95% CI: 0.36–2.98),1.37 (95% CI: 0.75–2.48), and 1.13 (95% CI: 0.75–2.48), respectively. Conclusion: Our study demonstrated that serum albumin levels, atrial fibrillation, and STS score were independently associated with all-cause mortality following TAVR in men.

The mechanical performance of a printed object in 3D concrete printing is influenced by the interfacial bonding strength between the deposited filaments. Hence, the physical properties of the layer interface and the influential factors have been studied. This study aims to clarify the mechanism of aggregate distribution heterogeneity as well as the influence of printing material extrusion speed on the heterogeneity inside the filament. A laboratory-scale material extruder is developed and used in this study. The aggregate distribution is evaluated in a quantitative manner with the cross-sectional image obtained by X-ray computed tomography. The images were taken in the deposited filament and the material extrusion nozzle for printing. Results show that large aggregate moves from the outside of the printing nozzle toward the center with increasing extrusion speed from 1.8 to 7.1 mm/s. As extrusion speed increases, it is inferred that a lubrication layer forms on the inner surface of the nozzle, causing the transition of material extrusion behavior from laminate flow to plug flow. Thus, the aggregate distribution appears differently inside the filament. This finding indicates that the magnitude of friction against the nozzle wall alters the die swell during discharge as well as the aggregate distribution before and after extrusion.

The expression in Ecscherichia coli, purification, and characterization of both wild type and His6-tagged MAH are reported. The MAH data are similar to those of fatty acid amide hydrolase and support the suggestion that there are two distinct subgroups within the amidase signature family.

Research has been conducted on mandelate metabolic pathway enzymes which allow Pseudomonas putida ATCC 12633 to utilize mandalate enantiomers as a carbon source. The authors report the isolation and expression of open reading frame genes coding for mandalate dehydrogenase, mandalate racemase and benzylformate decarboxylase in Escherichia coli, and reveal that the purified gene products have been characterized as mandelamide hydrolase and NAD(P) (super)+ -dependent benzaldehyde dehydrogenase.

Abstract Background Clinicians, researchers, and patients alike would greatly benefit from more accessible and inexpensive biomarkers for neural β-amyloid (Aβ). We aimed to assess the performance of fully automated plasma Aβ immunoassays, which correlate significantly with immunoprecipitation mass spectrometry assays, in predicting brain Aβ status as determined by visual read assessment of amyloid positron emission tomography (PET). Methods The plasma Aβ42/Aβ40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies (discovery and validation studies). The discovery and validation sample sets were retrospectively and randomly selected from participants with early Alzheimer’s disease (AD) identified during screening for the elenbecestat Phase 3 program. Results We included 197 participants in the discovery study (mean [SD] age 71.1 [8.5] years; 112 females) and 200 in the validation study (age 70.8 [7.9] years; 99 females). The plasma Aβ42/Aβ40 ratio predicted amyloid PET visual read status with areas under the receiver operating characteristic curves of 0.941 (95% confidence interval [CI] 0.910–0.973) and 0.868 (95% CI 0.816–0.920) in the discovery and validation studies, respectively. In the discovery study, a cutoff value of 0.102 was determined based on maximizing the Youden Index, and the sensitivity and specificity were calculated to be 96.0% (95% CI 90.1–98.9%) and 83.5% (95% CI 74.6–90.3%), respectively. Using the same cutoff value, the sensitivity and specificity in the validation study were calculated to be 88.0% (95% CI 80.0–93.6%) and 72.0% (95% CI 62.1–80.5%), respectively. Conclusions The plasma Aβ42/Aβ40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice.

Abstract The prevalence of and mortality from non-tuberculous mycobacteria (NTM) infections have been steadily increasing worldwide. Most NTM infections are caused by Mycobacterium avium-intracellulare complex (MAC). MAC can escape from killing by neutrophils, which are professional phagocytes. However, the involvement of neutrophils in the pathogenesis of MAC infection is poorly understood. The present study assessed the roles of neutrophil extracellular trap (NET) formation in neutrophil defense mechanisms against infection with MAC strains, including M. avium isolated from patients with severe or mild lung tissue destruction. Although all MAC induced NET formation, non-pathogenic mycobacteria (M. gordonae and M. smegmatis) slightly but not significantly induced NET formation. Peptidylarginine deiminase 4 (PAD4) inhibitor reduced MAC-induced NET formation but did not affect MAC escape from neutrophils. PAD4 inhibition attenuated the MAC-induced matrix metalloproteinase (MMP)-8 and 9 release to the levels of MMPs from non-pathogenic mycobacteria. MAC also induced interleukin (IL)-8 release by neutrophils, a process independent of MAC-induced NET formation. Taken together, these findings suggest that MAC induce NET formation, IL-8 release and NETs-dependent release of MMP-8 and -9 from neutrophils, leading to neutrophil accumulation and further inflammation, thereby enhancing the progression of infection in the lungs.

Objectives: Super-spreading events caused by overdispersed secondary transmission are crucial in the transmission of COVID-19. However, the exact level of overdispersion, demographics, and other factors associated with secondary transmission remain elusive. In this study, we aimed to elucidate the frequency and patterns of secondary transmission of SARS-CoV-2 in Japan. Methods: We analyzed 16,471 cases between January 2020 and August 2020. We generated the number of secondary cases distribution and estimated the dispersion parameter (k) by fitting the negative binomial distribution in each phase. The frequencies of the secondary transmission were compared by demographic and clinical characteristics, calculating the odds ratio using logistic regression models. Results: We observed that 76.7% of the primary cases did not generate secondary cases with an estimated dispersion parameter k of 0.23. The demographic patterns of primary-secondary cases differed between phases, with 20–69 years being the predominant age group. There were higher proportions of secondary transmissions among older individuals, symptomatic patients, and patients with 2 days or more between onset and confirmation. Conclusions: The study showed the estimation of the frequency of secondary transmission of SARS-CoV-2 and the characteristics of people who generated the secondary transmission.

Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.

Abstract Background There are more than 7000 rare diseases, most of which have no specific treatment. Disease profiles, such as prevalence and natural history, among the population of a specific country are essential in determining for which disease to research and develop drugs. In Japan, disease profiles of fewer than 2000 rare diseases, called Nanbyo, have been investigated. However, non-Nanbyo rare diseases remain largely uninvestigated. Accordingly, we revealed the prevalence and natural history of rare diseases among the Japanese population. This cross-disease study is the first to analyze rare-disease epidemiology in Japan with high accuracy, disease coverage, and granularity. Method We applied for permission to use the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which covered 99.9% of public health insurance claims from hospitals and 97.9% from clinics as of May 2015. Then, we obtained 10 years of data on the number of patients of approx. 4500 rare diseases, by sex and age. We translated disease names and established correspondences between rare diseases in NDB and those in Orphanet. Accordingly, we compared the prevalence and natural history between them. Results About 3000 diseases in NDB are included in Orphanet and other medical databases. The data indicates that even if the Nanbyo systems do not cover a rare disease, its patients survive in many cases. Regarding natural history, genetic diseases tend to be diagnosed later in Japan than in the West. The data shown in this research are available in the Additional file 1 and the website of NanbyoData. Conclusions Our research revealed the basic epidemiology and natural history of Japanese patients with some rare diseases using a health insurance claims database. The results imply that the coverage of the present Nanbyo systems is inadequate for rare diseases. Therefore, fundamental reform might be needed to reduce unfairness between rare diseases. Most diseases in Japan follow a tendency of natural history similar to those reported in Orphanet. However, some are detected later, partly because fewer clinical genetic tests are available in Japan than in the West. Finally, we hope that our data and analysis accelerate drug discovery for rare diseases in Japan.

Aims: Although venous invasion is an important prognostic factor for colorectal cancer, it may be significantly underestimated in actual daily diagnosis. In this study, hematoxylin–eosin (HE)- and Elastica van Gieson (EVG)-stained specimens of colorectal cancer (pT2–pT4) were obtained, and the influence of the number of specimens and the number of EVG-stained specimens on the prognosis were examined. Methods and results: The presence or absence of venous invasion in 100 colon cancer (pT2–pT4) specimens obtained after surgical resection was observed. Assessments were made by comparing the sections, of either the specimens of the deepest part of the tumor or the whole tumor, stained with only HE, as well as a combination of HE and EVG stains. There was a relative low agreement rate between the assessments made using whole-tumor EVG-stained sections and those employing other methods. With respect to relapse-free survival, no significant difference was observed in the prognosis of cases evaluated using HE-stained samples alone relative to the presence of venous invasion. However, for evaluations made using EVG staining, a significant difference was seen even for deepest-section assessments, and this trend was even stronger when whole-tumor sections were evaluated (EVG [deepest]: P = 0.0128, EVG [whole sections]: P = 0.0069). When the whole-tumor sections were observed with EVG staining, all 15 cases without venous invasion showed no recurrence within the observation period. Conclusions: The addition of EVG staining allowed the identification of venous invasion in patients with colorectal cancer, which eventually affects prognosis. Increasing the number of EVG-stained samples improves the possibility of accurate prediction.

Rice koji is a raw material used in the production of sake; however, details regarding the microbial flora and their dynamics in rice koji during the production process are poorly understood. Clarifying these issues can contribute to proposing a method and evaluation that will improve the quality of rice koji and sake. The aim of this study was to determine the microflora in rice koji and the effectiveness of the traditional microbial control techniques used in the sake production process. We analyzed the diversity and changes in bacterial flora during rice koji production by amplicon sequencing of the 16S rRNA gene. The predominant taxon in all rice koji samples was family Staphylococcaceae. The microbial population and the changes in its distribution for five consecutive stages in rice koji production were examined by direct colony counting. Bacteria counts in all samples were below the limit of detection initially, then increased rapidly toward the final stage. The predominant bacterial colonies from all samples were yellow and were identified as Staphylococcus gallinarum through 16S rRNA gene sequence similarity. The S. gallinarum isolates exhibited faster growth in pregelatinized rice medium. Interestingly, the growth of S. gallinarum isolates was suppressed by low temperature (12 °C), ethanol concentration (≥6%) and the addition of lactic acid, which are traditional microbial control methods used during sake fermentation. Therefore, proper control of the traditional sake production process can effectively inhibit the growth of undesirable bacteria such as S. gallinarum that emerge during the production of rice koji.

Background and Aims: Radiofrequency ablation (RFA) is a widely accepted, minimally invasive treatment for hepatocellular carcinoma (HCC). This study aimed to develop a machine learning (ML) model to predict the risk of HCC recurrence after RFA treatment for individual patients. Methods: We included a total of 1778 patients with treatment-naïve HCC who underwent RFA. The cumulative probability of overall recurrence after the initial RFA treatment was 78.9% and 88.0% at 5 and 10 years, respectively. We developed a conventional Cox proportional hazard model and 6 ML models—including the deep learning–based DeepSurv model. Model performance was evaluated using Harrel’s c-index and was validated externally using the split-sample method. Results: The gradient boosting decision tree (GBDT) model achieved the best performance with a c-index of 0.67 from external validation, and it showed a high discriminative ability in stratifying the external validation sample into 2, 3, and 4 different risk groups (P < .001 among all risk groups). The c-index of DeepSurv was 0.64. In order of significance, the tumor number, serum albumin level, and des-gamma-carboxyprothrombin level were the most important variables for the prediction of HCC recurrence in the GBDT model. Also, the current GBDT model enabled the output of a personalized cumulative recurrence prediction curve for each patient. Conclusion: We developed a novel ML model for the personalized risk prediction of HCC recurrence after RFA treatment. The current model may lead to the personalization of effective follow-up strategies after RFA treatment according to the risk stratification of HCC recurrence.

Rice (Oryza sativa L.) is one of the most important cereals, which provides 20% of the world’s food energy. However, its productivity is poorly assessed especially in the global South. Here, we provide a first study to perform a deep-learning-based approach for instantaneously estimating rice yield using red-green-blue images. During ripening stage and at harvest, over 22,000 digital images were captured vertically downward over the rice canopy from a distance of 0.8 to 0.9 m at 4,820 harvesting plots having the yield of 0.1 to 16.1 t·ha−1 across 6 countries in Africa and Japan. A convolutional neural network applied to these data at harvest predicted 68% variation in yield with a relative root mean square error of 0.22. The developed model successfully detected genotypic difference and impact of agronomic interventions on yield in the independent dataset. The model also demonstrated robustness against the images acquired at different shooting angles up to 30° from right angle, diverse light environments, and shooting date during late ripening stage. Even when the resolution of images was reduced (from 0.2 to 3.2 cm·pixel−1 of ground sampling distance), the model could predict 57% variation in yield, implying that this approach can be scaled by the use of unmanned aerial vehicles. Our work offers low-cost, hands-on, and rapid approach for high-throughput phenotyping and can lead to impact assessment of productivity-enhancing interventions, detection of fields where these are needed to sustainably increase crop production, and yield forecast at several weeks before harvesting.

The dataset described in this paper contains pairs of images collected from the Web and their tags of keywords, which are linked to appropriate entity pages of Wikipedia, and programs to reproduce experiments. It is assumed for evaluating the disambiguation task, in which given an image and its tags to be disambiguated, an appropriate Wikipedia page is selected for each of the given tag. We collected images tagged keywords of animal names for that ambiguity and their tags since animal names may refer to not only names of animal but names of other types of objects, e.g., nicknames of sports teams from the photo sharing site Flickr. The tags are linked to the correspondence Wikipedia page judged by annotators. The dataset includes 420 images and 2,464 tags. It is useful for developing a system to link a keyword of an image to an entry of a knowledgebase as well as an image classification system, which include fine-grained classes, e.g. proper nouns of objects, as their classification targets.

Digital technologies ranging from biosensors to virtual reality have revolutionized the healthcare landscape by offering innovations that hold great promise in addressing the challenges posed by rapidly aging populations. To optimize healthcare experiences for older people, it is crucial to understand their user experience (UX) with digital health technologies. This systematic review, covering articles published from 2013 to 2023, aimed to explore frequently used questionnaires for assessing digital healthcare UX among older people. The inclusion criteria were original studies assessing UX in digital health for individuals aged ≥65 years. Of 184 articles identified, 17 were selected after rigorous screening. The questionnaires used included the System Usability Scale (SUS), the User Experience Questionnaire (UEQ), and the Post-Study System Usability Questionnaire. Customized questionnaires based on models such as the Technology Acceptance Model and the Almere model were developed in some studies. Owing to its simplicity and effectiveness in assessing digital health UX among older people, the SUS emerged as the go-to tool (52.9%). Combining the SUS with the UEQ provided comprehensive insights into UX. Specialized questionnaires were also used, but further research is needed to validate and adapt these tools for diverse cultural contexts and evolving technologies.