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Aim: To assess the cost-effectiveness of diabetic nephropathy treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors in Japanese clinical practice, considering diabetes-related complications., Materials and Methods: A population-based Monte Carlo simulation was used to estimate the cost-effectiveness for people with diabetic nephropathy who initiated pharmacotherapy with an SGLT2 inhibitor plus conventional treatment or conventional treatment alone, based on quality-adjusted life-years (QALYs) and healthcare costs. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) and the Japanese Society for Dialysis Research statistical survey were the primary sources of probability and mortality, while Japanese Health Insurance Claims Data were the cost source. The state transition model included diabetic nephropathy, hospitalization due to cardiovascular disease, dialysis, and death. One-way and probabilistic sensitivity analyses were used to explore model uncertainty., Results: Using the threshold of JPY 5 000 000 per QALY, SGLT2 inhibitor plus conventional treatment was more cost-effective than conventional treatment alone, with an incremental cost-effectiveness ratio of JPY 654 309 per QALY. Treating 100 000 people, SGLT2 inhibitor plus conventional treatment prevented 2234 deaths and reduced 5793 fewer heart failure cases, 3967 fewer myocardial infarctions and stroke events. Sensitivity analysis affirmed the robustness of these results for patients aged under 70 years., Conclusions: The SGLT2 inhibitor treatment appeared to be cost-effective for the overall population of our study and particularly for younger patients (<70 years old). For older patients (≥70 years old), the cost-effectiveness was less clear and may require further evaluation. Decision-makers should consider this age-based heterogeneity when making recommendations about SGLT2 inhibitor treatment., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Selective perturbation of protein interactions with chemical compounds enables dissection and control of developmental processes. Differentiation of stomata, cellular valves vital for plant growth and survival, is specified by the basic-helix-loop-helix (bHLH) heterodimers. Harnessing a new amination reaction, we here report a synthesis, derivatization, target identification, and mode of action of an atypical doubly-sulfonylated imidazolone, Stomidazolone, which triggers stomatal stem cell arrest. Our forward chemical genetics followed by biophysical analyses elucidates that Stomidazolone directly binds to the C-terminal ACT-Like (ACTL) domain of MUTE, a master regulator of stomatal differentiation, and perturbs its heterodimerization with a partner bHLH, SCREAM in vitro and in plant cells. On the other hand, Stomidazolone analogs that are biologically inactive do not bind to MUTE or disrupt the SCREAM-MUTE heterodimers. Guided by structural docking modeling, we rationally design MUTE with reduced Stomidazolone binding. These engineered MUTE proteins are fully functional and confer Stomidazolone resistance in vivo. Our study identifies doubly-sulfonylated imidazolone as a direct inhibitor of the stomatal master regulator, further expanding the chemical space for perturbing bHLH-ACTL proteins to manipulate plant development., (© 2024. The Author(s).)

Background and objective Periosteal stripping and periosteal division (PSPD) can help promote the growth of the long bone in children with leg length discrepancy (LLD). We performed PSPD in a cohort of patients when LLD was observed at the time of implant removal surgery after proximal femoral osteotomy for Perthes disease. This study aimed to clarify the efficacy and safety of PSPD for acquired LLD related to Perthes disease. Methods This retrospective study enrolled 10 patients treated with PSPD and six controls who declined PSPD for LLD associated with Perthes disease. The lengths of the femur, tibia, and entire leg were measured in the full-length standing radiographs at baseline and final follow-up. The baseline was defined as the time of the last preoperative observation. LLD and changes in LLD (ΔLLD) were measured. The correlation of ΔLLD with age at the time of surgery, follow-up period, and extent of PSPD was investigated. Results In the PSPD group, the mean age of the patients was 9.4 years and the mean LLD at baseline was 20.5 ± 4.6 mm, while it was 10.2 years and 11.5 ± 10.0 mm in the control group. With a mean follow-up period of 4.3 years, the PSPD group showed a mean ΔLLD decrease of 13.9 mm, which was significantly greater than that of the control group at 3.2 mm with a mean follow-up period of 5.4 years. Logistic regression analysis revealed that age at the time of surgery was a significant factor for obtaining >10 mm ΔLLD with PSPD and the cutoff value by the receiver operating characteristic curve was 9.6 years (sensitivity: 0.83; specificity: 0.83). Conclusions PSPD seems to be a safe and effective surgical option for LLD associated with Perthes disease. The age at the time of surgery negatively correlated with the amount of LLD correction. Obtaining >10 mm LLD correction is more likely if the patients are <10 years of age., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kitta et al.)

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous syndrome associated with systemic complications that involve multiple organs, including the skin, central nervous system, eyes, and skeleton. LNSS is considered to be caused by mosaic RAS gene mutation. In this report, we present an autopsy case of LNSS in a Japanese boy. The affected neonate had hydrops fetalis and was born at 28 weeks and 4 days of gestation, weighing 2104 g. He had bilateral inverted eyelids, verrucous linear nevus separated along Blaschko's line, myocardial hypertrophy, and pharyngeal constriction, and underwent intensive treatment in NICU for arrhythmia, hydrocephalus, and respiratory distress. The hydrocephalus progressed gradually and he died at the age of 181 days, 12 days after a sudden cardiac arrest and recovery. KRAS G12D mutation was found in a skin biopsy specimen but not in blood cells, suggesting a postzygotic mosaicism. Autopsy revealed novel pathological findings related to LNSS, including intracranial lipomatous hamartoma and mesenteric lymphangioma, in addition to previously reported findings such as multicystic dysplastic kidney. There was the limited expression of mutated KRAS protein in kidneys., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, aberrant immune activation, and extensive tissue fibrosis of the skin and internal organs. Because of the complicated nature of its pathogenesis, the underlying mechanisms of SSc remain incompletely understood. Angiogenic factor with a G-patch domain and a Forkhead-associated domain 1 (AGGF1) is a critical factor in angiogenesis expressed on vascular endothelial cells, associated with inflammatory and fibrotic responses. To elucidate the possible implication of AGGF1 in SSc pathogenesis, we investigated the association between serum AGGF1 levels and clinical manifestations in SSc patients. We conducted a cross-sectional analysis of AGGF1 levels in sera from 60 SSc patients and 19 healthy controls with enzyme-linked immunosorbent assay. Serum AGGF1 levels in SSc patients were significantly higher than those in healthy individuals. In particular, diffuse cutaneous SSc patients with shorter disease duration had higher levels compared to those with longer disease duration and limited cutaneous SSc patients. Patients with higher serum AGGF1 levels had a higher incidence of digital ulcers, higher modified Rodnan Skin Scores (mRSS), elevated serum Krebs von den Lungen-6 (KL-6) levels, C-reactive protein levels, and right ventricular systolic pressures (RVSP) on the echocardiogram, whereas they had reduced percentage of vital capacity (%VC) and percentage of diffusing capacity of the lungs for carbon monoxide (%DLCO) in pulmonary functional tests. In line, serum AGGF1 levels were significantly correlated with mRSS, serum KL-6 and surfactant protein D levels, RVSP, and %DLCO. These results uncovered notable correlations between serum AGGF1 levels and key cutaneous and vascular involvements in SSc, suggesting potential roles of AGGF1 in SSc pathogenesis., (© 2024 Japanese Dermatological Association.)

Objective: There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer (mCRPC). However, the efficacy of enzalutamide rechallenge for mCRPC has not been evaluated., Methods: We retrospectively reviewed 63 consecutive patients who received enzalutamide for mCRPC at our institution between 2014 and 2022. Eight of these patients underwent rechallenge with enzalutamide after disease progression on prior enzalutamide and other therapy and were the focus of this study. The prostate-specific antigen (PSA) response (PSA decrease >50%), PSA progression-free survival, treatment duration, overall survival (OS) after CRPC, and treatment-related adverse events were evaluated., Results: PSA decline to enzalutamide rechallenge was observed in 6 patients (75%), of which 2 patients had a PSA response. The median treatment duration was 4 months (range 1-12) and median PSA progression-free survival was 3 months (range 1-7). Median OS after CRPC was 41 months. OS after CRPC was not increased in patients with a PSA response. No toxicities were worse than grade ≥3., Conclusion: Enzalutamide rechallenge achieved a PSA response in a quarter of our patients with mCRPC after disease progression on prior enzalutamide. However, no improvement of OS was identified in these patients.

It was reported that the consumption of Saccharina japonica (SJ) lowers blood pressure (BP) in hypertensive rats. Hypertension is related to gut microbiota, and hypertensive patients develop dysbiosis. It was reported that the intake of dietary fiber and polysaccharides contained in SJ changes gut microbiota and increases short-chain fatty acids (SCFAs). The present study examined the effect of BP lowering by SJ in spontaneously hypertensive rats (SHRs) and observed changes in gut microbiota composition and SCFAs concentration. Male SHRs and Wistar Kyoto rats (WKYs) were fed a diet containing 5% SJ or a control diet for six weeks. We measured systolic BP (SBP) weekly, as well as mean arterial BP (MAP), the 16S rRNA gene, and SCFAs in the cecal contents at the end of the period. As a result, the intake of SJ significantly decreased SBP and MAP in SHRs. As well, it significantly changed the microbial diversity by altering the gut microbiota composition. Particularly, it increased the abundance of Bacteroides acidifaciens , which may be associated with the antihypertensive effect of SJ. Thus, SJ intake suppressed the increase in BP and altered the gut microbiota composition, although it did not significantly change the SCFAs concentration in the cecal contents.

Objective: The Pavlik harness (PH) has been widely used as the standard treatment for infants with developmental dysplasia of the hip (DDH). When the initial application of the PH fails, alternative treatments, such as closed reduction, open reduction, and reapplication of the PH will be considered. Compared with other treatments, reapplication of the PH offers certain advantages, including simplicity and reduced physical, and psychological stress, on both infants and caregivers. This study aims to investigate the effectiveness of reapplying the PH in patients with DDH., Methods: This study included patients with DDH (complete dislocation) who were treated by reapplication of PH between 1988 and 2012. Patients who were able to follow-up for more than 5 years were included. We examined the reduction rate and several factors to identify indicators associated with successful reduction during reapplication, including age, sex, side of hip dislocation, and the presence of the Ortolani sign. At the final follow-up, hip development was assessed using the Severin classification, whereas avascular necrosis (AVN) was evaluated using the Kalamchi classification and the Salter criteria., Results: A total of 56 patients (48 females and 8 males) and 57 hips were included in this study. The mean age at first and second application of PH was 4.2 months old (range: 0.12 to 6.4), and 5.8 months old (3.0 to 11.4), respectively. The reduction rate was 49% (28 out of 57 hips). Among the successfully reduced hips, the AVN rate was 3.6% (1 out of 28 hips). The Severin classification revealed 27 hips in class I and 1 hip in class III. Statistical analysis indicated a significantly higher proportion of left hip involvement in the reduction group (85% vs 41%, χ 2 test, P < 0.001). Although not statistically significant, the rate of positive Ortolani sign tended to be higher in the reduction group (61% vs 38%, χ 2 test, P = 0.06)., Conclusion: The reapplication method demonstrated a 49% reduction rate and a low AVN rate of 3.6% in our study. It is worth considering for patients who fail the initial PH treatment, particularly in cases of left-side dislocation and a positive Ortolani sign during the initial application., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In welded maraging steels, mechanical properties, particularly ductility and toughness, are often compromised in the heat-affected zone (HAZ). This study focuses on 300-grade maraging steel bars, solution annealed at 1123 K for 1.5 h (5.4 ks) and welded using gas tungsten arc welding, followed by a post-weld heat treatment at 753 K for 13.33 h (48 ks). In situ observations during three-point bending tests on HAZ samples featuring coarsened prior austenite grain sizes were conducted to examine damage behavior and the crack path near the crack tip. The main crack initiated at the peak applied load during the bending test and, upon further loading, exhibited significant deflection and extension accompanied by numerous microcracks and localized crack branching. Distinctive damage features, such as transgranular cracking across block regions, intense intergranular cracking along packet boundaries with a pronounced shear component, and crowding of microcracks ahead of the crack tip, were observed in the HAZ sample during the in situ test. The interaction between the main crack tip and microcracks and its influence on the local crack propagation driving force was discussed using fracture mechanics. Experimental results, including tensile fracture surface observations and in situ images, along with analysis of the stress anti-shielding effect by microcracks, suggest that the HAZ sample exhibits embrittlement fracture behavior with lower ductility and toughness compared to the base metal sample.

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential., Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system., Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021., Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels., Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point., Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03)., Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

The synthesis of polycyclic arenes composed of four-, five-, six-, and eight-membered rings via an unexpected four-membered ring formation reaction is reported. The carbonylation of an octalithiated tetraphenylene yielded a tricarbonylated arene containing a four-membered ring or a tetracarbonylated one, depending on the carbonyl reagents. The structures were determined by X-ray crystallography, and their electronic properties were examined by using absorption spectroscopy and cyclic voltammetry. The antiaromaticity of the four-, five-, and eight-membered rings of these compounds was studied by theoretical calculations.

Fluorinated cycloparaphenylenes (FCPPs) have attracted attention as electron-accepting CPPs as well as strained fluoroarenes. Herein, we report the synthesis and properties of novel FCPPs; F 16 [8]CPP and F 12 [6]CPP. Furthermore, the derivatization of F 16 [8]CPP afforded a new carbon nanoring where sixteen pyrrole rings are densely substituted on the CPP framework.

Palmoplantar pustulosis (PPP) is a chronic skin inflammatory disease characterized by sterile pustules on the palms and soles. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP, frequently affecting the anterior chest wall. PPP and PAO are thought to be closely associated with focal infection. We report a female in her 40s who developed pustules on her palms and soles with tenderness of both sternoclavicular and left sacroiliac joints, which were not improved with non-steroidal anti-inflammatory drugs. Of note, she showed a great response to amoxicillin, resulting in the almost complete resolution of her skin lesions and arthralgia. We also reviewed previous reports to learn more about the potential therapeutic options of antibiotics for PAO., (© 2023 Japanese Dermatological Association.)

Purpose of Review: The pathogenesis of systemic sclerosis (SSc) has been linked to dysfunctional B cells as demonstrated in previous research. This review aims to show the evidence and ongoing clinical trials of B cell-targeted therapy and overview the various aspects of B cell involvement in SSc., Recent Findings: We provide an overview of the current understanding and therapeutic strategies targeting B cells in SSc patients. Several molecular targets of B cells have been identified for treating SSc, including CD20, CD19, B-cell activating factor (BAFF), and proteasome., Summary: Many clinical trials have demonstrated that B cells play a critical role in the pathogenesis of SSc and may be a potential therapeutic target to improve disease symptoms. Although large-scale clinical studies are needed, various B cell-targeted therapies have the potential to address the unmet needs of SSc patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Residual acetabular dysplasia in children after reduction of hip dislocation is often treated using Salter innominate osteotomy to prevent future osteoarthritis. Preventive surgery for asymptomatic patients, which could result in overtreatment, should be carefully applied with consideration of patients' opinions. In this study, we aimed to describe opinions on Salter innominate osteotomy as preventive surgery for children among adult patients who had undergone periacetabular osteotomy for hip pain due to hip dysplasia., Methods: A mail-in questionnaire survey was conducted with 77 patients who underwent periacetabular osteotomy. Participants responded whether they would recommend Salter innominate osteotomy as preventive surgery for children and the reason for their opinion. We also performed a patient-based evaluation using the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire and assessed clinical outcome measures with the Japanese Orthopedic Association score. Their recommendations and reasons were evaluated, and associations between their opinions and demographic and clinical characteristics were analyzed., Results: Forty-three patients (56%) responded to the questionnaire. Of these, 10 (23%) patients recommended undergoing Salter innominate osteotomy, 28 (65%) patients did not, and 5 (12%) patients responded they were undecided. No significant association was observed between their opinions and demographic/clinical characteristics evaluated in the survey. The most frequent reason for why they do not recommend Salter innominate osteotomy was related to uncertainty about future hip pain., Conclusions: In total, 65% of the study participants did not recommend Salter innominate osteotomy for children with risk of dysplasia in the future. Participants' preferences regarding preventive surgery were not influenced by demographic and clinical characteristics., Competing Interests: Disclosure of conflict of interest None., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2'-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study., (© 2023. The Author(s).)

Penta- and hexa(3,4-thienylene)s were synthesized as a potential precursor for thiophene-containing polyarenes, and the structures were determined via X-ray crystallography. The interconversion of thiophene rings is fast in penta(3,4-thienylene), and slow in hexa(3,4-thienylene) reflecting the activation energy for enantiomerization. Size-dependent bathochromic shifts were observed in UV-vis absorption spectra.

Background: This study examined how radiologic indices at 10 years postreduction change over time and influence the final outcome through a comparative study of 3 reduction methods for developmental dysplasia of the hip, including the Pavlik harness, closed reduction, and open reduction (OR)., Methods: Patients treated from 1990 to 2000 for dysplasia of the hip and followed up for >20 years were included in this study. Radiologic indices at 10 years postreduction and final follow-up (average 24 years postreduction) were measured in the 3 groups. The relative joint space of <66% compared with the healthy side was defined as positive osteoarthritis (OA) at the final follow-up. The relationship between OA and factors such as age, sex, method of reduction, radiologic indices, and Severin and Kalamchi classifications at 10 years postreduction were examined. Clinical evaluation was performed using the modified Harris Hip Score; a score of ≥80 was defined as good performance at the final follow-up., Results: Sixty-five patients (totaling 74 hips) were included. There were no significant differences in radiologic indices between the 10-year postreduction time and final follow-up. Excluding 9 bilateral patients, based on the relative joint space, 21% of the patients (13/56 hips), were positive for OA. Univariate analysis showed that the incidence of positive OA was significantly associated with OR and Kalamchi grade 4 at 10 years postreduction. The modified Harris Hip Score was 80 or higher in 90% of the cases at the final follow-up., Conclusions: No significant changes in hip morphology were observed at 10 years postreduction. The Kalamchi classification at 10 years postreduction and OR were significantly associated with the incidence of OA at the final follow-up. Therefore, patients who undergo OR and/or display Kalamchi grade 4 have a high risk of developing OA and would require individual instructions for their daily lives to prevent further progression of OA and longer follow-up., Level of Evidence: Level Ⅲ-case-control study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sodium alginate (SALG) is a substance derived from brown seaweed that has been shown to reduce blood pressure (BP). However, its effects on renovascular hypertension caused by 2-kidney, 1-clip (2K1C) are not yet clear. Previous research suggests that hypertensive rats have increased intestinal permeability, and that SALG improves the gut barrier in inflammatory bowel disease mouse models. Therefore, the goal of this study was to determine whether the antihypertensive effects of SALG involve the intestinal barrier in 2K1C rats. Rats were fed either a 1.0% SALG diet or a control diet for six weeks after being subjected to 2K1C surgery or a sham operation. The systolic BP was measured weekly, and the mean arterial BP was measured at the end of the study. Intestinal samples were taken for analysis, and plasma lipopolysaccharide (LPS) levels were measured. The results showed that BP in 2K1C rats was significantly higher than in SHAM rats when fed CTL, but not when fed SALG. The gut barrier in 2K1C rats was improved by SALG intake. Plasma LPS levels also differed depending on the animal model and diet. In conclusion, dietary SALG may alleviate 2K1C renovascular hypertension by altering the gut barrier.

The synthesis, characterization, and catalytic performance of an iridium(III) catalyst with an electron-deficient cyclopentadienyl ligand ([Cp E IrI 2 ] 2 ) are reported. The [Cp E IrI 2 ] 2 catalyst was synthesized by complexation of a precursor of the Cp E ligand with [Ir(cod)OAc] 2 , followed by oxidation, desilylation, and removal of the COD ligand. The electron-deficient [Cp E IrI 2 ] 2 catalyst enabled C-H amidation reactions assisted by a weakly coordinating ether directing group. Experimental mechanistic studies and DFT calculations suggested that the high catalytic performance of [Cp E IrI 2 ] 2 is due to its electron-deficient nature, which accelerates both C-H activation and Ir V -nitrenoid formation., (© 2023 Wiley-VCH GmbH.)

Background: In utero intestinal volvulus with intestinal atresia is a rare and life-threatening condition that can cause torsion of the dilated bowel. The management and outcomes of this disease remain unclear., Case Presentation: A 19-year-old woman noticed a decrease in fetal motion at 35 weeks. Fetal ultrasound showed dilated fetal bowel and the whirlpool sign. The patient was referred to our hospital for an emergency cesarean section. The neonate's abdomen was dark and severely distended, and a laparotomy was performed. Necrotic ileum and cord-type intestinal atresia (Type II) were observed in the dilated terminal ileum. The necrotic ileum was resected, and a second-look surgery was performed the following day. Then, we anastomosed the remaining intestine, and the total intestine length was 52 cm. There were no surgical complications, and the patient was discharged without requiring total parenteral nutrition or fluid infusion. The patient's height and weight were within the - 2 standard deviation range of the growth curve at 5 months., Conclusions: Emergency and appropriate management of intestinal volvulus in utero causing torsion of the dilated bowel resulted in good outcomes in a patient with intestinal atresia. Perinatal physicians should be aware of this emergency condition and plan their treatment approach accordingly., (© 2023. The Author(s).)

A 63-year-old man visited our hospital with a complaint of penile swelling caused by metallic ring entrapment in the penis. He had put the ring around his penis 4 hours prior and was subsequently unable to remove it. We attempted to remove the ring using a ring cutter but that was unsuccessful. We then inserted two 18 G needles into the corpus cavernosum through the glans penis and removed blood by manual compression according to a technique called the "string method." The swelling gradually decreased, and we successfully removed the ring without destroying it. The total duration of strangulation was about 5 hours. The patient was subsequently discharged after ensuring he had no urinary difficulties. No complications were observed during the follow-up period.In almost all penile strangulation cases caused by hard objects, such as metallic rings, reported in Japan, the objects were typically destroyed and penile puncture and blood removal, as was performed in our case, was rare. Although penile puncture and blood removal is not commonly performed in Japan, this technique can be performed quickly and inexpensively in the emergency room and should be considered an initial treatment for penile strangulation caused by hard objects.

Background: Hypoglycemia is a significant problem for all neonates and requires minimally invasive and reliable monitoring. The primary objective of this study was to verify the safety and accuracy of the continuous glucose monitoring (CGM) of full-term neonates using Freestyle Libre, a flash glucose monitoring (FGM) device., Methods: The study was conducted on 20 neonates. Shortly after birth, we placed the FGM sensor on the outside of the neonates' thighs. We scanned the CGM values at 60, 120, 180, and 360 min after birth and simultaneously obtained blood glucose values with plantar capillaries by heel puncture. The neonates wore the sensors for up to 6 h and then they were removed., Results: Of the 75 data points to be measured, 65 points (86.7%) were obtained by scan. There was no change in the sensor attachment site in 12 of 18 completed cases in this study but we observed slight induration in four cases (22.2%) and slight redness in one case (5.5%) at the sensor puncture site. A moderate correlation was observed between the CGM and blood glucose values. The CGM values tended to be low at 120, 180, and 360 min after birth, and tended to be high only at 60 min after birth., Conclusions: The CGM device was safe to wear on the neonate and the CGM data correlated well with blood glucose levels. There was dissociation between CGM data and blood glucose levels in the acute period soon after birth when the blood glucose levels changed rapidly., (© 2023 Japan Pediatric Society.)

Local skin flap from the surrounding area is often chosen for reconstruction of skin defects in the nasal region, but it is problematic because it creates new facial scar and requires skill of design. On the other hand, full-thickness skin graft is associated with problems such as color mismatch and scar contracture at the recipient site. We reconstructed nasal defects of seven patients using modified dermis graft technique. In this method, de-epithelialized full-thickness skin graft is transplanted and then epithelialized from the surrounding area. This is a simple and easy procedure without causing a new scar on the face and is aesthetically and functionally superior to a standard full-thickness skin graft; therefore, it is a useful method of reconstruction of the nasal area., (© 2022 Japanese Dermatological Association.)

The design and synthesis of nitrogen (N)-doped molecular nanocarbons are of importance since N-doped nanocarbons have received significant attention in materials science. Herein, we report the synthesis and X-ray crystal structure of a nitrogen-inserted nonalternant aromatic belt. The palladium-catalyzed six-fold annulative double N-arylation provided an aromatic belt bearing six nitrogen atoms in one step from cyclo[6]paraphenylene- Z -ethenylene, the precursor of the (6,6)carbon nanobelt. The C 3i -symmetric structure of the aromatic belt in the solid state was revealed using X-ray crystallography. The multistep (electro)chemical oxidation behavior of the belt, which was facilitated by the six p -methoxyaniline moieties, was studied, and a stable dication species was successfully identified by X-ray crystallography. The present study not only shows the unique structure and properties of the N-doped nonalternant aromatic belt but also expands the scope of accessibility of synthetically difficult belt molecules by the conventional intramolecular contraction pathway., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Perfluorinated aromatic compounds, the so-called perfluoroarenes, are widely used in materials science owing to their high electron affinity and characteristic intermolecular interactions. However, methods to synthesize highly strained perfluoroarenes are limited, which greatly limits their structural diversity. Herein, we report the synthesis and isolation of perfluorocycloparaphenylenes (PFCPPs) as a class of ring-shaped perfluoroarenes. Using macrocyclic nickel complexes, we succeeded in synthesizing PF[n]CPPs (n = 10, 12, 14, 16) in one-pot without noble metals. The molecular structures of PF[n]CPPs (n = 10, 12, 14) were determined by X-ray crystallography to confirm their tubular alignment. Photophysical and electrochemical measurements revealed that PF[n]CPPs (n = 10, 12, 14) exhibited wide HOMO-LUMO gaps, high reduction potentials, and strong phosphorescence at low temperature. PFCPPs are not only useful as electron-accepting organic materials but can also be used for accelerating the creation of topologically unique molecular nanocarbon materials., (© 2022. The Author(s).)

A carbazole-incorporated photochromic radical complex is synthesized. The long-wavelength photosensitivity of the photochromic reaction of the molecule is enhanced up to ∼580 nm by substituting a triphenylamine group into the 3-position of the carbazole moiety. These photochromic reactions are investigated by subpicosecond-to-microsecond transient absorption measurements.

Background: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP., Patients and Methods: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1., Results: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed., Conclusions: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP., Competing Interests: Disclosure JT: reports personal fees from AstraZeneca K.K., Boehringer-Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Merck Sharp & Dohme (MSD) K.K., Taiho Pharmaceutical Co. Ltd, outside the submitted work. KY: reports personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo, Eizai, Eli Lilly, Fuji Film Pharma, Genmab K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd, Pfizer Japan Inc., Taiho, Pharmaceutical, Takeda Pharmaceutical Company Limited, outside the submitted work. Grant from AstraZeneca K.K., Boehringer Ingelheim, Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo, Eizai, Eli Lilly, Kyowa-Kirin, Nihon Kayaku, MSD, Novartis Pharmaceuticals K.K., Oncotherapy Science, Ono Pharmaceutical Co. Ltd, Pfizer Japan Inc., Sanofi, Seagen, Taiho Pharmaceutical, Takeda Pharmaceutical Company Limited, outside the submitted work. HM: reports grants, personal fees and other from Bristol Myers Squibb, Ono Yakuhin, during the conduct of the study; personal fees from Abbvie, grants from Asahi-Kasei Pharma, grants from Astellas, other from AstraZeneca, grants, personal fees, and other from Bayer, grants and personal fees from Boehringer, grants, personal fees, and other from Bristol Myers Squibb, personal fees from Celgene, grants, personal fees, and other from Chugai, grants from CSL Behring, grants, personal fees, and other from Daiichi Sankyo, grants and personal fees from DaiNihonSumitomo, grants and personal fees from Eizai, grants, personal fees from Genomic Health, personal fees from Janssen, grants and personal fees from Kyowa-Kirin, grants and personal fees from Lilly, grants and personal fees from Merck Serono, grants, personal fees, and other from MSD, grants from Nihon Kayaku, grants from Nihon Shinyaku, personal fees and other from Novartis, personal fees and other from Ono Yakuhin, personal fees from Otsuka, grants, personal fees, and other from Pfizer, grants and personal fees from Sanofi, personal fees from Shire Japan, grants from Shionogi, grants, personal fees, and other from Taiho, grants and personal fees from Takeda, grants from Teijin Pharma, grants from Yakult, outside the submitted work. YT: reports grants, personal fees, and other from Bristol Myers Squibb, Ono Pharmaceutical Co. Ltd, during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chugai Pharmaceutical Co. Ltd, grants from Daiichi Sankyo, grants and personal fees from Eli Lilly, grants from Kyowa-Hakko Kirin, grants and personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from Taiho Pharmaceutical Co. Ltd, grants from Takeda, outside the submitted work. YM: reports personal fees from Ono Pharmaceutical, Bristol Myers Squibb, MSD, and Chugai, research funding from MSD, outside the submitted work. YS: reports grants from Kindai University, during the conduct of the study; grants from Eisai Co., Ltd, personal fees from Japanese Society of Medical Oncology, grants from Novartis Pharma K.K., grants and personal fees from Taiho Pharmaceutical Co., Ltd, outside the submitted work. ST: reports grants from Ono, during the conduct of the study; personal fees from Asahi Kasei, personal fees from Bayer, personal fees from Chugai, personal fees from Japan blood products organization, personal fees from Medicon, grants and personal fees from Merck Biopharma, personal fees from Nippon Kayaku, personal fees from Taiho, personal fees from Yakult, outside the submitted work. YC: reports personal fees from Chugai Pharmaceutical Co., Ltd, outside the submitted work. KS: reports personal fees from Roche Diagnostics, Bio-Rad, AstraZeneca, Chugai Pharmaceutical, and Hitachi outside the submitted work. KN: received grants and personal fees from Eli Lilly, Nippon Boehringer Ingelheim, grants from Ignyta, Korea Otsuka Pharmaceutical, Thoracic Oncology Research Group, North East Japan Study Group, and personal fees from Chugai Pharmaceutical, Eisai, Pfizer, Novartis Pharma, MSD, Ono Pharmaceutical, Bristol Myers Squibb, SymBio Pharmaceuticals, Life Technologies Japan, Solasia Pharma, Yakult Honsha, Roche Diagnostics, AstraZeneca, Otsuka Pharmaceutical, Sanofi, Guardant Health, Amgen, outside the submitted work. KN: reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd, grants from Daiichi Sankyo Co., Ltd, personal fees and other from Eli Lilly Japan K.K., grants and personal fees from Merck Biopharma Co., Ltd, grants and personal fees from MSD K.K., grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd, personal fees and other from Ono Pharmaceutical Co., Ltd, grants, personal fees, and other from Pfizer Japan Inc., personal fees from Care Net, Inc., personal fees from 3H Clinical Trial Inc., grants from EPS International Co., Ltd, grants from EPS Corporation, grants from Kissei Pharmaceutical Co., Ltd, personal fees from Kyowa Kirin Co., Ltd, personal fees from Nippon Kayaku Co., Ltd, grants from Parexel International Corp., grants from IQVIA Services Japan K.K., grants from SymBio Pharmaceuticals Limited, grants from Syneos Health, personal fees and grants from Takeda Pharmaceutical Co., Ltd, grants from Taiho Pharmaceutical Co., Ltd, personal fees from Medical Review Co., Ltd, personal fees from Medical Mobile Communications co., Ltd, personal fees from Nikkei Business Publications, Inc., personal fees from Amgen Inc., grants from Eisai Co., Ltd, grants from PRA Health Sciences, grants from Mochida Pharmaceutical Co., Ltd, grants from Covance Japan Inc., grants from Japan Clinical Research Operations, grants from GlaxoSmithKline K.K., grants from MSD K.K., grants from Sanofi K.K., grants from PPD-SNBL K.K, grants from SymBio Pharmaceuticals Limited, grants from Sysmex Corporation, grants from Medical Research Support, personal fees from Yodosha Co., Ltd, personal fees from Yomiuri Telecasting Corporation, personal fees from 3H Clinical Trial Inc., outside the submitted work. HH: reports grants from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd, and Ono Pharmaceutical Co. Ltd, personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd, Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd, MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd, Pfizer Japan Inc., Shanghai Haihe Biopharm, Taiho Pharmaceutical Co. Ltd outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The intake of Saccharina japonica (SJ), a widely consumed brown seaweed, has been reported to decrease blood pressure (BP) in hypertensive rats. It has been suggested that this effect is related to an increase in fecal sodium excretion (SE) by alginate (Alg) to the gastrointestinal tract; however, the mechanism is still unclear. This study investigated how different seaweeds with different amounts of Alg suppressed BP increase and enhanced fecal SE in 2-kidney, 1-clip renovascular hypertensive (2K1C) rats given SJ diet., Methods: Rats with 2K1C or sham operation were fed a normal-/high-salt diet with some kinds of seaweeds (5.0%, w/w) or SJ extract with different Alg contents for 6 weeks. We measured systolic BP every week and mean arterial pressure at the end, and measured the total and molecular weights of Alg in each seaweed. Then, we evaluated the relationship of the Alg amount in each seaweed with the suppression of BP increase in 2K1C rats. Finally, urinary and fecal SE for 24 h was measured., Results: The intake of SJ, SJ extract, Saccharina ochotensis (SO) blades and SO roots suppressed BP increase in 2K1C rats, but the strength was not proportional to the amounts of Alg contained in the seaweeds. Although SJ intake increased fecal SE in 2K1C rats fed a high-salt diet, the fecal SE was much less than urinary SE., Conclusion: The sodium excretion in feces by Alg in SJ may not be one of the major mechanisms by which SJ intake attenuates hypertension in 2K1C rats.

The stepwise chemical reduction of a molecular warped nanographene (WNG) having a negatively curved π-surface and defined C 80 H 30 composition with Cs metal used as the reducing and complexing agent allowed the isolation of three different reduced states with one, two, and three electrons added to its π-conjugated system. This provided a unique series of nanosized carbanions with increasing negative charge for in-depth structural analysis of consequences of controlled electron charging of non-planar nanographenes, using X-ray crystallographic and computational tools. The 3D molecular electrostatic potential (MEP) maps identified the negative charge localization at the central part of the WNG surface where selective coordination of Cs + ions is confirmed crystallographically. In-depth theoretical investigation revealed a complex response of the WNG to the stepwise electron acquisition. The extended and contorted π-surface of the WNG undergoes subtle swinging distortions that are accompanied by notable changes in the electronic structure and site-dependent aromaticity of the resulting carbanions., (© 2021 Wiley-VCH GmbH.)

The layered structures of graphite and related nanographene molecules play key roles in their physical and electronic functions. However, the stacking modes of negatively curved nanographenes remain unclear, owing to the lack of suitable nanographene molecules. Herein, we report the synthesis and one-dimensional supramolecular self-assembly of negatively curved nanographenes without any assembly-assisting substituents. This curved nanographene self-assembles in various organic solvents and acts as an efficient gelator. The formation of nanofibers was confirmed by microscopic measurements, and an unprecedented double-helix assembly by continuous π-π stacking was uncovered by three-dimensional electron crystallography. This work not only reports the discovery of an all-sp 2 -carbon supramolecular π-organogelator with negative curvature but also demonstrates the power of three-dimensional electron crystallography for the structural determination of submicrometer-sized molecular alignment.

Free-standing graphene has a three-dimensional (3D) structure, called a ripple, rather than a perfect two-dimensional (2D) crystal. Since theoretical calculations suggest that a ripple strongly influences various fundamental physicochemical properties of graphene, it is important to clarify the ripple structure quantitatively in experiments. This paper proposes a new method of measuring the 3D atomic structure of a ripple by using aberration-corrected transmission electron microscopy (TEM). The method utilizes the fact that the 2D contrast of a TEM image is sensitive to the height of a six-membered ring. The proposed method is experimentally applied to a monolayer graphene, and the 3D atomic arrangements of consecutively acquired TEM images are reconstructed. In that experiment, the specimen is found to be moving upward. Furthermore, the atomic arrangement can be approximated as a composite of two structures consisting of a 3D ripple and a 2D plane. The ripple is represented as a superposition of sinusoidal waves, with their wave vectors coinciding with the specific direction of the six-membered ring. The time dependences of the height and lateral size of the ripple are also measured.

The structure-selective precise synthesis of carbon nanotubes (CNTs) has been long sought in materials science. The aromatic molecules corresponding to segment structures of CNTs, that is, carbon nanobelts (CNBs), are of interest as templates for CNT growth. Among the three types of CNB (armchair, chiral and zigzag CNBs), zigzag CNBs have been considered the most difficult type to synthesize. Here we report the synthesis, isolation and structural characterization of a zigzag CNB. The synthesis involves an iterative Diels-Alder reaction sequence followed by reductive aromatization of oxygen-bridged moieties. As predicted by theoretical calculations, this CNB was isolated as a stable compound. The structure of the zigzag CNB was fully characterized by X-ray crystallography and its wide energy gap with blue fluorescence properties was revealed by photophysical measurements. With synthetic strategies towards all three types of CNB in hand, the road to the precise synthesis of CNTs can now proceed to the next stage.

Background: Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X., Case Presentation: A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever　for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin., Conclusions: An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Three-dimensional cage-shaped molecules formed from chainlike structures hold potential as unique optoelectronic materials and host compounds. Their optical, structural, and dynamical features are tunable by changes in shape and size. We perform a comparison of these properties for three sizes of strained conjugated [ n . n . n ]carbon nanocages composed of three paraphenylene chains (bridges) of length n = 4, 5, or 6. The exciton intramolecular redistribution occurring during nonradiative relaxation has been explored using nonadiabatic excited-state molecular dynamics. Our results provide atomistic insight into the conformational features associated with the observed red- and blue-shift trends in the absorption and fluorescence spectra, respectively, with increasing nanocage size. Their internal conversion processes involve intramolecular energy transfer that leads to exciton self-trapping on a few phenylene units at the center of a single bridge. The dependence of these dynamical features on the size of the nanocage can be used to tune their host-guest chemical properties and their use for organic electronics and catenane-like applications.

In this study, the theoretical analysis of the strain energy of helicene-containing carbon nanobelts is reported. It was found that the combined method of linear regression analysis and suitable homodesmotic reactions can successfully estimate the strain energies of various helicene-containing carbon nanobelts including previously synthesized chiral (18,12) carbon nanobelts.

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach., Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP., Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan., Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations., Main Outcomes and Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations., Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months., Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP., Trial Registration: UMIN Identifier: UMIN000016794.

The development of carbon nanobelts and related belt-shaped polycyclic aromatic hydrocarbons has gained momentum in recent years. This Minireview focuses on the synthetic strategies used in constructing these aesthetically appealing molecular nanocarbons. Examples of carbon nanobelts and related belt-shaped polycyclic aromatic hydrocarbons reported in recent years as well as some representative synthetic attempts in earlier times are discussed., (© 2020 Wiley-VCH GmbH.)

Background: Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC)., Methods: This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses., Results: Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4-60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group., Conclusions: Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial., Clinical Trial Registration: UMIN000010638.

Background: IgA nephropathy is the most common glomerulonephritis. Secondary IgA nephropathy complicated with systemic diseases, including psoriasis, is also often reported. Generalized pustular psoriasis is a form of psoriasis characterized by sterile pustules on reddened skin and fever. Infliximab, one of the first-line therapies for severe psoriasis, has also been reported to cause systemic vasculitis and IgA nephropathy. We herein report a case of IgA nephropathy activated during infliximab treatment for generalized pustular psoriasis., Case Presentation: A 28-year-old woman presented with episodic gross hematuria, increasing proteinuria, and renal dysfunction. She had been receiving anti-TNFα therapy with infliximab because of generalized pustular psoriasis for 3 years, but her skin symptoms worsened following withdrawal during pregnancy. After delivery, her skin symptoms improved with the resumption of infliximab, but clinical signs suggested glomerulonephritis, and renal biopsy showed active IgA nephropathy. Infliximab was discontinued, and the combination of corticosteroids, tonsillectomy, and secukinumab, an IL-17A inhibitor, improved both the skin symptoms and the glomerulonephritis., Conclusions: In our case, the activity of IgA nephropathy was exacerbated by anti-TNFα therapy but was improved by the combination of corticosteroids, tonsillectomy, and an IL-17A inhibitor against the original disease. Autoimmune diseases may underlie the development of secondary IgA nephropathy associated with anti-TNFα therapy, and so further studies are needed to better understand the association between molecular-targeted drugs and IgA nephropathy.

Influenza virus, respiratory syncytial virus, and human metapneumovirus commonly cause acute upper and lower respiratory tract infections, especially in children and the elderly. Although rapid antigen detection tests for detecting these infections have been introduced recently, these are less sensitive than nucleic acid amplification tests. More recently, highly sensitive point-of-care testings (POCTs) have been developed based on nucleic acid amplification tests, which are easy to use in clinical settings. In this study, loop-mediated isothermal amplification (LAMP)-based POCT "Simprova" to detect influenza A and B viruses, respiratory syncytial virus, and human metapneumovirus was developed. Simprova system is fully automated and does not require skilled personnel. In addition, positive results can be achieved faster than with PCR. In this study, the accuracy of the POCT was retrospectively analyzed using 241 frozen stocked specimens. Additionally, the usability of the Simprova at clinical sites was assessed in a prospective clinical study using 380 clinical specimens and compared to those of real-time PCR and rapid antigen detection test. The novel LAMP-based POCT demonstrated high sensitivity and specificity in characterizing clinical specimens from patients with influenza-like illnesses. The Simprova is a powerful tool for early diagnosis of respiratory viral infections in point-of-care settings.

The synthesis, structure, and properties of methylene-bridged [6]cycloparaphenylene ([6]CPP), a nonalternant aromatic belt, are described. This belt-shaped methylene-bridged [6]CPP, in which each phenylene unit is tethered to its neighbors by methylene bridges, was constructed through 6-fold intramolecular nickel-mediated aryl-aryl coupling of triflate-functionalized pillar[6]arene in 18% isolated yield. As compared to the analogous [6]CPP, the methylene bridges coplanarize neighboring paraphenylene units and enhance the degree of π-conjugation, which results in a significant decrease in energy gap. Moreover, the incorporation of small molecules in the defined pocket of methylene-bridged [6]CPP makes it an attractive supramolecular architecture. Methylene-bridged [6]CPP is characterized by high internal strain energy reaching 110.2 kcal mol -1 , attributed to its restricted structure. This work not only exhibits an efficient strategy to construct a new family of aromatic belt, but also showcases their properties, which combine the merits of CPPs and pillararenes.

The synthesis of each of the cycloiptycene derivatives was achieved in one step from the (6,6)carbon nanobelt. It was revealed that the carbon nanobelt reacted as a diene in the Diels-Alder reaction with arynes and alkynes. The structures of all products were identified by X-ray crystallography to confirm that the Diels-Alder reactions took place at the six central benzene rings of the carbon nanobelt. DFT calculations indicated that the release of strain energy is the driving force to promote the Diels-Alder reaction. By using this method, we have successfully synthesized cyclotetracosiptycene, the largest iptycene ever synthesized., (This journal is © The Royal Society of Chemistry 2020.)

Background : Capsaicin, a pungent component of chili pepper, has been reported to decrease blood pressure (BP) and to cause vasorelaxation via nitric oxide (NO) production. However, it is still unclear how dietary capsaicin effects on renovascular hypertension. To examine this, we observed the effects of dietary capsaicin on BP in 2-kidney, 1-clip renovascular hypertension (2K1C) rats, and investigated the participation of NO in the mechanism. Methods : Rats with 2K1C or sham-operated rats (SHAM) were treated with 0.006% capsaicin diet (CAP) or control diet (CTL) for 6 weeks. Systolic BP (SBP) was measured by tail-cuff method once a week. In the end, mean arterial BP (MAP) was measured in the rats under anesthesia. These observations were performed also in the rats taking a NO synthase (NOS) inhibitor (LN). After rats were euthanized, thoracic aortas were collected and used for western blot analyses to evaluate the phosphorylated ratio of endothelial NOS (eNOS), protein kinase A (PKA) and B (Akt), in order to explore a mechanism of the effects on BP by dietary capsaicin. Results : SBP and MAP in 2K1C rats were significantly higher than in SHAM rats when fed CTL, but not when fed CAP. Those in 2K1C-CAP rats were significantly lower than in 2K1C-CTL rats. LN suppressed the effect of dietary capsaicin. The ratios of phosphorylated (p-) eNOS/eNOS and p-Akt/Akt, but not p-PKA/PKA, were significantly increased in rats fed CAP compared with rats fed CTL. Conclusion : Dietary capsaicin may alleviate 2K1C renovascular hypertension, probably via enhancing phosphorylation of Akt and eNOS. Abbreviations: 2K1C: 2-kidney, 1-clip hypertension model; Akt: protein kinase B; Ang II: angiotensin II; ANOVA: measures analysis of variance; BP: blood pressure; EC: endothelial cell; eNOS: endothelial nitric oxide synthase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; L-NAME, LN: Nω-Nitro-L-arginine methyl ester hydrochloride; MA: mesenteric arteries; MAP: mean arterial blood pressure; NO: nitric oxide; PKA: protein kinase A; PVDF: polyvinylidene difluoride; SBP: Systolic blood pressure; SHR: spontaneously hypertensive rats; SN: sympathetic nervous; TRPV1: transient receptor potential vanilloid type 1; WKY: Wistar Kyoto rats.