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Momoko Miyakawa,1 Shutaro Kubo,1 Hirotsugu Oda,1 Noriko Motoki,2 Masaru Mizuki,2 Teruomi Tsukahara,2 Miyuki Tanaka,1 Koji Yamauchi,1 Fumiaki Abe,1 Tetsuo Nomiyama2 1Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd, Zama, Kanagawa, Japan; 2Department of Preventive Medicine and Public Health, Shinshu University School of Medicine, Matsumoto, Nagano, JapanCorrespondence: Momoko MiyakawaFood Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 1-83, 5-Chome, Higashihara, Zama-City, Kanagawa-Pref. 252-8583, JapanTel +81 46252 3045Fax +81 46252 3017Email mo-miyakawa@morinagamilk.co.jpPurpose: To investigate preliminarily the effect of lactoferrin (LF)-fortified formula on sleep conditions in children.Study Design: A preliminary, randomized, double-blind, placebo-controlled trial.Methods: Healthy children between the ages of 12 and 32 months who attended nursery schools in Japan were divided into two groups and assigned a placebo or LF (48 mg/day)-fortified formula. Children’s sleep conditions were investigated before and after the 13-week intervention using the Japanese Sleep Questionnaire for Preschoolers (JSQ-P).Results: Altogether, 109 participants were randomized. Eight participants were eliminated due to lost to follow-up, withdrawal of consent, and ineligibility, with 101 participants (placebo, n = 48; LF, n = 53) included in the full analysis set (FAS) and used for analysis. Wake-up time, bedtime, and nighttime sleep were comparable between the two groups before and after intervention. The change in total JSQ-P T scores tended to improve in the LF group (placebo vs LF: 0.5 ± 6.5 vs − 1.9 ± 6.1, p = 0.074), in particular, morning symptoms significantly improved (grumpy in the morning, hard to wake-up, and hard to get out of bed) (placebo vs LF: 0.8 ± 6.2 vs − 1.9 ± 6.2, p = 0.028). A better trend was also observed in the LF group regarding restless legs syndrome (RLS)-motor (rubs feet at night and touches feet at night) (placebo vs LF: 2.3 ± 10.7 vs − 0.6 ± 13.5, p = 0.083) and insufficient sleep (stays up more than one hour later the day before a holiday and wakes up more than one hour later on a holiday) (placebo vs LF: 0.1 ± 9.8 vs − 1.7 ± 8.8, p = 0.095). No adverse drug reactions were found.Conclusion: LF intake may improve sleep condition, especially morning symptoms in children above one year of age.Keywords: lactoferrin, sleep, growing-up formula, children

Hirotsugu Oda,1 Momoko Miyakawa,1 Masaru Mizuki,2 Yuka Misawa,3 Teruomi Tsukahara,2 Miyuki Tanaka,1 Koji Yamauchi,1 Fumiaki Abe,1 Tetsuo Nomiyama2 1Food Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd, Zama, Kanagawa 252-8583, Japan; 2Department of Preventive Medicine and Public Health, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; 3Department of Rehabilitation, Nagano Children’s Hospital, Nagano 399-8288, JapanCorrespondence: Hirotsugu OdaFood Ingredients and Technology Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Zama, Kanagawa 252-8583, JapanTel +81 46 252 3045Fax +81 46 252 3017Email h-oda@morinagamilk.co.jpObjective: To investigate the effects of lactoferrin (LF) on subjective skin conditions in winter.Design: A preliminary, randomized, double-blinded, placebo-controlled trial.Setting and subjects: Healthy adults in Japan.Interventions: Intake of placebo, 200 mg, or 600 mg of LF for 12 weeks in winter.Endpoints: Changes in the scores of subjective skin conditions.Results: Three hundred and forty-six subjects were randomized. Nine subjects (placebo, n=0; 200 mg, n=5; 600 mg, n=4) withdrew consent, and 7 subjects (placebo, n=4; 200 mg, n=2; 600 mg, n=1) were lost to follow-up, resulting in 330 for a full analysis set.Outcomes: Changes in the scores of moisture were greater in the 600 mg group than in the placebo group. Changes in the scores of moisture were greater in the 200 mg and 600 mg groups, and of texture were greater in the 600 mg group than in the placebo group in female subjects.Conclusion: Intake of LF may improve moisture or texture of skin in winter.Keywords: lactoferrin, winter, skin, moisture, texture

Abstract Background Paternal allele-specific DNA methylation of the imprinting control region (H19 ICR) controls genomic imprinting at the Igf2/H19 locus. We previously demonstrated that the mouse H19 ICR transgene acquires imprinted DNA methylation in preimplantation mouse embryos. This activity is also present in the endogenous H19 ICR and protects it from genome-wide reprogramming after fertilization. We also identified a 118-bp sequence within the H19 ICR that is responsible for post-fertilization imprinted methylation. Two mutations, one in the five RCTG motifs and the other a 36-bp deletion both in the 118-bp segment, caused complete and partial loss, respectively, of methylation following paternal transmission in each transgenic mouse. Interestingly, these mutations overlap with the binding site for the transcription factor Kaiso, which is reportedly involved in maintaining paternal methylation at the human H19 ICR (IC1) in cultured cells. In this study, we investigated if Kaiso regulates imprinted DNA methylation of the H19 ICR in vivo. Results Neither Kaiso deletion nor mutation of Kaiso binding sites in the 118-bp region affected DNA methylation of the mouse H19 ICR transgene. The endogenous mouse H19 ICR was methylated in a wild-type manner in Kaiso-null mutant mice. Additionally, the human IC1 transgene acquired imprinted DNA methylation after fertilization in the absence of Kaiso. Conclusions Our results indicate that Kaiso is not essential for either post-fertilization imprinted DNA methylation of the transgenic H19 ICR in mouse or for methylation imprinting of the endogenous mouse H19 ICR.

Key Clinical Message CYP3A4 and CYP3A5 are the most abundant and important enzymes of the CYP3A subfamily, distributed in the liver, intestinal mucosa and kidney, and involved in tacrolimus metabolism. Here, we report a case of tacrolimus dosage refractoriness due to a genetic polymorphism of CYP3A5.

Reproductive toxicity is one of the major concerns in drug development. Thus, we have developed its screening system using Caenorhabditis elegans, which has a life cycle of three days and similar coding genes as humans. Antiviral nucleoside analogs used for acute infections are known to cause reproductive toxicity, contraindicated for pregnant women, and are used for comparing their reproductive toxicity in C. elegans and experimental animals. None of the drug treatments affected the number of offspring and the concentrations without toxicity to nematodes were consistent with no cytotoxicity or toxicity in experimental animals or humans. Favipiravir, ribavirin, molnupiravir (NHC), acyclovir, ganciclovir, zidovudine, and thalidomide significantly increased the incidence of arrested embryos but amenamevir, letermovir, and guanosine did not. RNA-dependent RNA polymerase (RdRp) inhibitors, in the order of favipiravir, ribavirin, and NHC increased the incidence of arrested embryos, possibly due to the specificity of favipiravir for RdRp and less cytotoxicity. RdRp inhibitors would impair RNA interference through RdRp expressed by telomerase reverse transcriptase during embryogenesis and cause embryo-fetal toxicity. The incidence of arrested embryos may be affected by differences in the substrate specificity of DNA polymerases and metabolism between C. elegans, animals, and humans. The concordance between the results of the screening system for reproductive toxicity of antivirals in C. elegans and those in experimental animals based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, reproductive toxicology confirms its appropriateness as a screening system for reproductive toxicity. Favipiravir and zidovudine were the least toxic to C. elegans among the antiviral drugs examined.

Summary:. Temporary intravascular shunting (TIVS) is an effective method to shorten the duration of ischemia and contribute to limb salvage in the treatment of popliteal artery injury (PAI). Traditionally used shunt tubes require ligation or clamping to the blood vessel, which has the disadvantage of causing secondary damage to the vessel. We present two cases in which TIVS was performed using the Pruitt-F3 Carotid Shunt (LeMaitre Vascular Inc., Burlington, Mass.) for traumatic PAI and report the effectiveness of the method. Two patients diagnosed with PAI had pallor of the feet and complete motor and sensory paralysis. The patients were immediately transferred to the operating room. PAI was confirmed in one patient by the medial approach and in the other by the posterior approach. In both patients, the vascular injury extended to the vicinity of the bifurcation into the anterior tibial artery. TIVS was performed using a 9Fr Pruitt-F3 Carotid Shunt. In both patients, the color tone of the feet improved. No vascular damage occurred secondary to TIVS. The popliteal artery was reconstructed using a great saphenous vein graft on the contralateral lower extremity, and the limb was salvaged. If the artery is injured near its bifurcation, it may be possible to preserve the branch vessel by using the Pruitt-F3 Carotid Shunt for TIVS.

Age of cetaceans is an important data set for their conservation and management. Although the chronological age of a toothed whale has traditionally estimated from the number of annual tooth growth layer groups (GLGs), this method has potential difficulties such as errors due to the subjectivity of the age-readers and time-consuming sample processing, in addition to lethal tooth sampling in many cases. To overcome these difficulties through a non-lethal approach, considerable amount of efforts has been made in recent years to construct chronological age estimation models based on the correlation between chronological and biological age expressed as the frequency of DNA methylation at CpG (cytosine-phosphate-guanine) sites. The present study, by using next-generation sequencing on DNA extracted from the skin tissues of 30 individuals (15 males and 15 females), performed methylation analysis on multiple CpG sites in the three genes previously reported as age-linked in cetaceans (GRIA2, TET2, and CDKN2A) to construct an age estimation model for Risso’s dolphins. Key aspects of this study are: (1) the chronological ages of Risso’s dolphins of wild origins used in this study had been determined by the GLGs of teeth prior to this study, and (2) as Risso’s dolphins are said to have a lifespan of 30 years, samples were collected from individuals aged 1–29 years, covering from young to old ages. Among the 11 CpG sites in GRIA2, 6 CpG sites in TET2, and 7 CpG sites in CDKN2A analyzed, the CpG sites in GRIA2 showed a statistically significant correlation with age, whereas those in TET2 and CDKN2A did not show such a strong correlation. Using multiple regression analysis on the CpG sites in the three genes, the best fitted model was expressed as follows: y=-0.7548 + 5.6164x(GRIA2_CpG3)+2.6187x(TET2_CpG6)-1.5907x(CDKN2A_CpG3) (R²=0.7062, residual mean=2.98, standard deviation=2.3). With the mean error of 2.98 years between the estimated and known chronological ages, the accuracy of this model was found to be comparable to or higher than that of previously reported age estimation models for cetaceans. This study demonstrated for the future that the age of wild Risso’s dolphins can be estimated by using their skin samples collected with minimal invasiveness.

Pseudorhombus elevatus Ogilby, 1912 and P. quinquocellatus Weber and de Beaufort, 1929 (Teleostei: Paralichthyidae) are newly recorded from Japan, based on 35 and two specimens, respectively, from Okinawa Island, Ryukyu Islands. Although both species have previously been recorded from Taiwan, no Japanese records are known to date. Pseudorhombus elevatus is characterized, and readily distinguished from Japanese congeners, by numerous minute teeth on both jaws, three dark blotches along the straight section of the ocular-side trunk lateral line, and dorsal- and anal-fin ray numbers. Pseudorhombus quinquocellatus resembles P. pentophthalmus Günther, 1862 and P. oculocirris Amaoka, 1969, all sharing five dark ocelli on the ocular-side body (two pairs of ocelli above and below the lateral line plus a single ocellus on the posterior portion of the lateral line). However, the former is characterized by strong caniniform teeth on both jaws (vs. no strong caniniform teeth in P. pentophthalmus and P. oculocirris); fewer lower gill rakers (9–11 in Japanese specimens) (vs. 15–21); and two dark skin flaps along the gill opening below the pectoral-fin base (vs. absent). The status of the type specimens of P. quinquocellatus was also considered, all three being regarded as syntypes, in the absence of a formal lectotype proposal. New standard Japanese names, “Maru-ganzō-birame” and “Niten-ganzō-birame,” are proposed for P. elevatus and P. quinquocellatus, respectively, the name “Itsutsume-ganzō” now being referred to P. megalops Fowler, 1934.

Background: This study aimed to establish an automatic and accurate method for identifying patient activity using wearable devices to facilitate simple measurement of the severity of disease, such as chronic obstructive pulmonary disease (COPD), and accurate diagnosis of arrhythmias using Holter electrocardiogram (ECG). Methods: Nine-axis accelerometers were attached to five different parts of the body of 30 healthy participants, and nine different activities were performed in sequence. Results: Overall, the dominant wrist, non-dominant wrist, and chest yielded high recognition accuracy, whereas the hip and thigh yielded lower recognition accuracy for some activities. Lying in the supine position, standing, walking, and running were identified with high accuracy by the accelerometer on the non-dominant wrist. Lying in the supine position, brushing teeth, walking, ascending/descending the stairs, and running were identified with high accuracy by the accelerometer on the chest. Conclusions: The movements related to the severity of COPD and those related to a diagnosis made via Holter ECG could be identified with reasonable accuracy when the nine-axis accelerometer was attached to one part of the body: the dominant wrist, non-dominant wrist, and chest. The accuracy was higher when the accelerometers were attached to five parts of the body.

Abstract Background Depression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls. Methods We assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18–50-year-olds with depression, 30 older individuals (ages 51–90) with depression, 28 with early AD (Braak tangle stages III–IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aβ, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood–brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry. Results There was no evidence of chronic cerebral hypoperfusion or increased Aβ/tau in either depression group. There was also no indication of pericyte damage, increased blood–brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups. Conclusions Contrary to some previous findings, we have not found evidence of impaired vascular function or increased Aβ in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency.

Objective To clarify the reasons for consultation, advice sought by frontline physicians and relationship between the patient’s pathology and the type of advice provided to guide the future development of telecritical care services.Design Secondary analysis of transcripts of telephone calls originally recorded for quality control purposes was conducted using a thematic content analysis. The calls were conducted between December 2019 and April 2021 (total cases: 70; total time: ~15 hour).Settings Intensivists provided consultation services to frontline physicians at secondary care institutions in the Kansai and Chubu regions.Participants Non-intensive care frontline physicians working in five secondary care institutions in the Kansai and Chubu regions and intensivists providing a consultation service (n=26).Interventions Not applicable.Primary and secondary outcome measures The main outcome was the themes emerging from the language used during telephone and video consultations, indicating the gap filled by the telecritical care service.Findings We analysed 70 cases and approximately 15 hours of anonymised audio data. We identified the following reasons for consultation: ‘lack of competence in treatment and diagnostic testing’ and ‘lack of access to consultation in their own hospital’. Frontline physicians most often sought advice related to ‘treatment’, followed by ‘patient triage and transfer’, ‘diagnosis’ and ‘diagnostic testing and evaluation’. Regarding the relationship between the patient’s pathology and type of advice provided, the most commonly sought advice by frontline physicians varied based on the patient’s pathology.Conclusion This study explored the characteristics of 70 telecritical sessions and identified the reasons for and nature of the consultations. These findings can be used to guide the future provision and scale up of telecritical services.

Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.

Background Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. Methods and Results Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, apoptosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several humoral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor‐β signaling pathways were significantly affected in DCM CFs. In contrast, single‐cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. Conclusions Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell–cell contact.

The electrochemical reduction conditions of the reaction of alkyl 2-chloroacetates in Bu4NBr/DMF using a divided cell equipped with Pt electrodes to produce the corresponding cyclopropane derivatives in moderate yields were discovered. The reaction conditions were optimized, the scope and limitations, as well as scale-up reactions were investigated. The presented method for the electrochemical production of cyclopropane derivatives is an environmentally friendly and easy to perform synthetic procedure.

Plants retain the ability to generate a pluripotent tissue called callus by dedifferentiating somatic cells. A pluripotent callus can also be artificially induced by culturing explants with hormone mixtures of auxin and cytokinin, and an entire body can then be regenerated from the callus. Here we identified a pluripotency-inducing small compound, PLU, that induces the formation of callus with tissue regeneration potency without the external application of either auxin or cytokinin. The PLU-induced callus expressed several marker genes related to pluripotency acquisition via lateral root initiation processes. PLU-induced callus formation required activation of the auxin signaling pathway though the amount of active auxin was reduced by PLU treatment. RNA-seq analysis and subsequent experiments revealed that Heat Shock Protein 90 (HSP90) mediates a significant part of the PLU-initiated early events. We also showed that HSP90-dependent induction of TRANSPORT INHIBITOR RESPONSE 1, an auxin receptor gene, is required for the callus formation by PLU. Collectively, this study provides a new tool for manipulating and investigating the induction of plant pluripotency from a different angle from the conventional method with the external application of hormone mixtures.

Recent studies have illuminated the importance of tet-methylcytosine-dioxygenase-2 (TET2) in pulmonary arterial hypertension (PAH). We aimed to clarify the frequency of TET2 variants in Japanese PAH patients. Among whole-exome sequencing of 145 Japanese patients with idiopathic or heritable PAH, 3 patients (2.1%) had a germline heterozygous missense variant in TET2 (c.3116C > T, p.Ser1039Leu). The allele frequency is 0.15% in the gnomAD database, and 0.2% among 3554 in the general Japanese population. These 3 patients needed combination therapy including continuous prostacyclin infusion. Our study identified a novel TET2 variant, and TET2 may have effects on the onset and/or disease progression of PAH. Résumé: Des études récentes ont mis en lumière l’importance de TET méthylcytosine dioxygénase 2 (TET2) dans l’hypertension artérielle pulmonaire (HTAP). Nous avons cherché à préciser la fréquence des mutations du gène TET2 chez des patients japonais atteints d’HTAP. Lors du séquençage de l’exome entier de 145 patients japonais présentant une HTAP idiopathique ou héréditaire, une mutation germinale hétérozygote faux-sens du TET2 (c.3116C > T, p.Ser1039Leu) a été détectée chez trois patients (2,1 %). La fréquence allélique est de 0,15 % dans la base de données gnomAD et de 0,2 % parmi 3 554 personnes au sein de la population japonaise en général. Les trois patients ont dû suivre un traitement d’association faisant notamment appel à la prostacycline administrée en perfusion continue. Notre étude a permis de découvrir une nouvelle mutation du gène TET2, et le TET2 peut avoir des effets sur l’apparition et/ou la progression de l’HTAP.

Power beaming is one of the core technologies for microwave power transmission (MPT) systems. Effective plane-to-plane power beaming requires not only high point-to-point efficiency but also appropriately-shaped beam to extract the best performance of receivers (rectennas). Flat-top beam plays an important role in plane-to-plane power beaming for drones where the output dc power from rectennas should be maximized to drive motors. It is challenging to develop a large-scale flat-top-beam array with appropriate distribution circuits. Sequential array is also required to suppress axial ratio on the receiving plane. In this paper, we proposed a simplified but effective way to create a large-scale sequential array for flat-top beam at C-band. The series feed and block-oriented sequential array were adopted to keep the circuit design and fabrication simple while obtaining a sufficient point-to-point efficiency and good axial ratio on the receiving plane. A 196-element phased array with microstrip antennas was developed by subdividing the whole array into four 49-element blocks for simplicity of the circuit design and implementation of block-oriented sequential array. The efficiency between the transmitting ports and the receiving ports was 50.6 % in simulations and 32.0 % in measurements. In the measured flat-top beam, the transmitted power was uniformly concentrated within the receiving plane and the axial ratio of the beam was successfully suppressed to less than 3 dB on most of the receiving area. A flight test of a microwave-powered drone was conducted where a micro-drone successfully flew for seven minutes only with wireless power.

Background: The 6 min walk test is widely used to measure the severity of COPD, but this test imposes an extensive burden on patients and medical staff. As an alternative to this test, the measurement of activity amount during daily activities that cause COPD patients to feel shortness of breath can be acquired using wearable devices, and the measurements between COPD patients and healthy people can be compared. Accordingly, based on machine learning, we first evaluated the accuracy of the accelerometers in recognizing such activities. Methods: Forty-six healthy participants wore tri-axial accelerometers on the wrist and hip, and performed nine activities: changing clothes, sitting, standing, lying in a supine position, brushing teeth, moving luggage, going up/down the stairs, running, and walking. Features were extracted from 10 s windows of 31 datasets and input into a machine-learning classifier model. Results: The wrist+hip classifier recognized the activities of changing clothes, standing, lying in a supine position, brushing teeth, moving luggage, going up/down the stairs, walking, and running. Sitting and other movements were not appropriately recognized. Conclusions: Sedentary movements such as sitting were difficult to recognize. However, changing clothes, standing, lying in a supine position, brushing teeth, moving luggage, going up/down the stairs, walking, and running were recognizable. These recognized activities tend to cause shortness of breath in COPD patients. Thus, the findings confirm the feasibility of an algorithm that could determine the severity of COPD by comparing activity amount for each of these activities with those of the healthy people of the same age.

Background. Lumbar spinal stenosis (LSS) patients have been reported to have neuropathic pain and central sensitivity syndrome (CSS). These associations have been reported in other diseases but are unknown in preoperative LSS patients. We aimed to investigate the association between neuropathic pain and CSS in preoperative LSS patients using the painDETECT and the Central Sensitization Inventory (CSI) questionnaires. Methods. This cross-sectional study was conducted from November 2021 to March 2022. The data were collected regarding demographics and pain, including neuropathic pain, numbness, LSS severity, physical function, quality of life, and CSS. Patients were divided into two groups, patients with acute and chronic pain, and further classified into three categories based on the clinical phenotype of patients in each group. Independent variables included age, gender, type of LSS (bilateral or unilateral symptoms), Numerical Rating Scale of leg pain, CSI, and the Zurich Claudication Questionnaire (ZCQ) for symptom severity and physical function. The dependent variable was painDETECT. Multiple regression analysis using the forced entry method examined the association between painDETECT and CSI. Results. Of the 119 patients with preoperative LSS, 106 were included. The mean age of the participants was 69.9 years, and 45.3% were female. Neuropathic pain was present in 19.8%, and CSS was present in 10.4%. The CSI (β = 0.468, p

Definitive diagnosis of familial hypercholesterolemia (FH) is paramount for the risk management of patients and their relatives. The present study aimed to investigate the frequency of gene variants contributing to low-density lipoprotein cholesterol (LDL-C) metabolism and their clinical relevance in patients with early-onset coronary artery disease (EOCAD). Among 63 consecutive patients with EOCAD (men G) harbored variants of uncertain significance. Both the patients harboring the variants were male, showing no history of diabetes mellitus or chronic kidney disease, no family history of EOCAD, and no physical findings of FH (i.e., tendon xanthomas or Achilles tendon thickening). Patients harboring the LDLR variant had three-vessel disease, were on a statin prescription at baseline, and had stable LDL-C levels; however, the case showed a poor response to the intensification of medication after PCI. Approximately 3.8% of patients with EOCAD harbored variants of gene related to LDL-C metabolism; there were no notable indicators in the patients’ background or clinical course to diagnose FH. Given the difficulty in diagnosing FH based on clinical manifestations and family history, genetic testing could enable the identification of hidden risk factors and provide early warnings to their relatives.

BackgroundFractional flow reserve (FFR) is the current gold standard for identifying myocardial ischemia in individuals with coronary artery stenosis. However, FFR is not penetrated as much worldwide due to time consumption, costs associated with adenosine, FFR-related discomfort, and complications. Resting physiological indexes may be widely accepted alternatives to FFR, while the discrepancies with FFR were found in up to 20% of lesions. The saline-induced Pd/Pa ratio (SPR) is a new simplified option for evaluating coronary stenosis. However, the clinical implication of SPR remains unclear.ObjectivesIn the present study, we aimed to compare the accuracies of SPR and resting full-cycle ratio (RFR) and to investigate the incremental value of SPR in clinical practice.MethodsIn this multicenter prospective study, 112 coronary lesions (105 patients) were evaluated by SPR, RFR, and FFR.ResultsThe overall median age was 71 years, and 84.8% were men. SPR was correlated more strongly with FFR than with RFR (r = 0.874 vs. 0.713, respectively; p < 0.001). Using FFR < 0.80 as the reference standard variable, the area under the receiver-operating characteristic (ROC) curve for SPR was superior to that of RFR (0.932 vs. 0.840, respectively; p = 0.009).ConclusionSaline-induced Pd/Pa ratio predicted FFR more accurately than RFR. SPR could be an alternative method for evaluating coronary artery stenosis and further investigation including elucidation of the mechanism of SPR is needed (225 words).

Abstract Recently, research has been conducted to automatically control anesthesia using machine learning, with the aim of alleviating the shortage of anesthesiologists. In this study, we address the problem of predicting decisions made by anesthesiologists during surgery using machine learning; specifically, we formulate a decision making problem by increasing the flow rate at each time point in the continuous administration of analgesic remifentanil as a supervised binary classification problem. The experiments were conducted to evaluate the prediction performance using six machine learning models: logistic regression, support vector machine, random forest, LightGBM, artificial neural network, and long short-term memory (LSTM), using 210 case data collected during actual surgeries. The results demonstrated that when predicting the future increase in flow rate of remifentanil after 1 min, the model using LSTM was able to predict with scores of 0.659 for sensitivity, 0.732 for specificity, and 0.753 for ROC-AUC; this demonstrates the potential to predict the decisions made by anesthesiologists using machine learning. Furthermore, we examined the importance and contribution of the features of each model using Shapley additive explanations—a method for interpreting predictions made by machine learning models. The trends indicated by the results were partially consistent with known clinical findings.

In this case report, we describe a 60-year-old man who presented with headaches for 1 year and mild confusion for 3 weeks and was initially diagnosed as having a cerebral tumor on the basis of finding a round lesion in the right lenticular nucleus with ring enhancement on gadolinium-enhanced T1-weighted brain magnetic resonance imaging. However, the discovery of positive serology for Treponema pallidum infection on routine tests on admission prompted analysis of cerebrospinal fluid, which was also positive on Treponema pallidum hemagglutination (TPHA), rapid plasma reagin (RPR), and treponemal antibody absorption (FTA-ABS) tests. Thus, he was diagnosed as having an intracranial syphilitic gumma. After commencing treatment with penicillin G, the lesion temporarily increased in size, but subsequently resolved completely with continuing antibiotic treatment. In the present era of increasing prevalence of syphilitic infection and because they are eminently treatable, syphilitic gummas should be included in the differential diagnosis of apparent brain tumors. Additionally, temporary enlargement of a probable gumma after instituting antibiotic treatment should not prompt cessation or change of the antibiotics.

Objectives There are many occasions in modern life when people must deliver presentations in front of audiences. Most people feel nervous before and while giving a speech. If there were a simple way to ease their stress, speakers would be able to perform better and their quality of life would improve. Consequently, this study aimed to alleviate the stress of speakers giving speeches by regulating breathing using a simple device. Methods To achieve this goal, a popular device, the Apple Watch, was chosen. Twenty-eight participants were divided into two groups: the Breathe app group and the non-Breathe app group. The Breathe app group regulated their breathing using the Breathe app installed on an Apple Watch before speech preparation. The non-Breathe app group listened to an explanation of the experiment so that they could not undertake their own stress-easing strategies. Participants prepared speeches about themselves and delivered them in front of the researcher. Results The Breathe app exercise eased stress during the exercise itself and the preparation phase of the speech task based on participants’ cardiac activity. However, stress was not alleviated during speech delivery. Conclusions Based on the experimental setting and results of this study, together with the findings of previous studies, introducing pre-training sessions and performing stress-easing tasks before and/or during a speech, such as sending vibrations to participants’ wearable devices, might be an effective way to reduce stress when delivering speeches immediately after the breath-regulating task.

Summary: Knowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees (Pan troglodytes) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos (Pan paniscus). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees.

Abstract Background Bronchial necrosis is a rare but fatal complication after radiation therapy. Because of the anatomical complexity and rarity of this condition, determining the most appropriate management for individual patients is extremely challenging. Lung autotransplantation is a surgical technique that has been applied to hilar neoplastic lesions to preserve pulmonary function and avoid pneumonectomy. We herein report a case of bronchial necrosis secondary to radiotherapy that was treated with lung autotransplantation. Case presentation A 46-year-old man developed broad necrosis and infection of the right bronchus secondary to previous stereotactic body-radiation therapy. This treatment was supplied close to a right hilar metastatic pulmonary tumor derived from a mediastinal malignant germ cell tumor that had been surgically resected with the left phrenic nerve. The bronchial necrosis accompanied by infection with Aspergillus fumigatus was progressive despite antibiotics and repetitive bronchoscopic debridement. Because of the patient’s critical condition and limited pulmonary function, right lung autotransplantation with preservation of the right basal segment was selected. An omental flap was placed around the bronchial anastomosis to prevent later complications. The postoperative course involved multiple complications including contralateral pneumonia and delayed wound healing at the bronchial anastomosis with resultant stenosis, the latter of which was overcome by placement of a silicone stent. The patient was discharged 5 months postoperatively. Three months after discharge, however, the patient developed hemoptysis and died of bronchopulmonary arterial fistula formation. Conclusions We experienced an extremely challenging case of bronchial necrosis secondary to radiotherapy. The condition was managed with lung autotransplantation and omental wrapping; however, the treatment success was temporary and the patient eventually died of bronchopulmonary arterial fistula formation. This technique seems to be a feasible option for locally advanced refractory bronchial necrosis, although later complications can still be fatal.

Fucosylated proteins are widely used as biomarkers of cancer and inflammation. Fucosylated alpha-fetoprotein (AFP-L3) is a specific biomarker for hepatocellular carcinoma. We previously showed that increases in serum AFP-L3 levels depend on increased expression of fucosylation-regulatory genes and abnormal transport of fucosylated proteins in cancer cells. In normal hepatocytes, fucosylated proteins are selectively secreted in the bile duct but not blood. In cases of cancer cells without cellular polarity, this selective secretion system is destroyed. Here, we aimed to identify cargo proteins involved in the selective secretion of fucosylated proteins, such as AFP-L3, into bile duct-like structures in HepG2 hepatoma cells, which have cellular polarity like, in part, normal hepatocytes. α1-6 Fucosyltransferase (FUT8) is a key enzyme to synthesize core fucose and produce AFP-L3. Firstly, we knocked out the FUT8 gene in HepG2 cells and investigated the effects on the secretion of AFP-L3. AFP-L3 accumulated in bile duct-like structures in HepG2 cells, and this phenomenon was diminished by FUT8 knockout, suggesting that HepG2 cells have cargo proteins for AFP-L3. To identify cargo proteins involved in the secretion of fucosylated proteins in HepG2 cells, immunoprecipitation and the proteomic Strep-tag system experiments followed by mass spectrometry analyses were performed. As a result of proteomic analysis, seven kinds of lectin-like molecules were identified, and we selected vesicular integral membrane protein gene VIP36 as a candidate of the cargo protein that interacts with the α1-6 fucosylation (core fucose) on N-glycan according to bibliographical consideration. Expectedly, the knockout of the VIP36 gene in HepG2 cells suppressed the secretion of AFP-L3 and other fucosylated proteins, such as fucosylated alpha-1 antitrypsin, into bile duct-like structures. We propose that VIP36 could be a cargo protein involved in the apical secretion of fucosylated proteins in HepG2 cells.

BackgroundMalnutrition and sarcopenia are frequently observed in patients undergoing maintenance hemodialysis (MHD). To elucidate whether malnutrition is associated with sarcopenia in those cases, the relationship of nutritional status with sarcopenia was investigated.MethodsNutritional status was assessed using a nutritional risk index (NRI) developed for patients undergoing MHD. This retrospective cross-sectional study included 315 MHD patients (199 males, 116 females), who were divided into low-risk (score 0–7) and medium-/high-risk (score 8–13) groups. Sarcopenia and severe sarcopenia, along with low muscle mass, low muscle strength, and low physical performance were defined using the Asian Working Group for Sarcopenia 2019 criteria.ResultsThe median NRI score was 5.0, while the prevalence of medium-/high-risk cases among the patients was 31.1%. Additionally, the rates of those with low muscle mass, low muscle strength, and low physical performance were 55.9, 60.6, and 31.4%, respectively, while those of sarcopenia and severe sarcopenia were 44.1 and 20.0%, respectively. Multivariable logistic regression analyses revealed a significant (P < 0.001) association of NRI score with sarcopenia [odds ratio (OR) 1.255, 95% confidence interval (CI) 1.143–1.377] and severe sarcopenia (OR 1.257, 95% CI 1.122–1.407), as well as low muscle mass (OR 1.260, 95% CI 1.157–1.374), low muscle strength (OR 1.310, 95% CI 1.178–1.457), and low physical performance (OR 1.216, 95% CI 1.104–1.339). Furthermore, medium-/high-risk status showed a significant (P < 0.05) association with sarcopenia (OR 2.960, 95% CI 1.623–5.401) and severe sarcopenia (OR 2.241, 95% CI 1.151–4.362), as well as low muscle mass (OR 2.141, 95% CI 1.219–3.760), low muscle strength (OR 7.665, 95% CI 3.438–17.091), and low physical performance (OR 2.570, 95% CI 1.401–4.716).ConclusionsThese results suggest that malnutrition contributes to sarcopenia/severe sarcopenia in MHD patients by reducing muscle mass and strength, and physical performance.

Abstract Malignant gastrointestinal neuroectodermal tumors (GNETs) are rare malignant mesenchymal neoplasms. To our knowledge, only 99 cases have been reported worldwide. The tumor has an aggressive malignancy, with a rapid progression. The histological features of GNET overlap with those of clear cell sarcoma, which contain Ewing sarcoma breakpoint region 1 mutation. GNETs lack melanocyte‐specific markers, while clear cell sarcoma exhibits melanocytic differentiation. Various symptoms have been reported previously, and the most reported lesion is in the small bowel. The patient was a 69‐year‐old man who presented with abdominal pain and vomiting. Computed tomography revealed a nodule in the small bowel, which induced small intestinal obstruction. Enteroscopic images revealed a submucosal tumor. Surgery was performed, and the patient was diagnosed with GNET. Only two patients whose primary lesions were in the small intestine, including the patient in this report, have undergone enteroscopy before surgery. This is a rare case of GNET in which a patient underwent enteroscopy before surgical treatment.

Abstract Background Recently, more electronic data sources are becoming available in the healthcare domain. Electronic health records (EHRs), with their vast amounts of potentially available data, can greatly improve healthcare. Although EHR de-identification is necessary to protect personal information, automatic de-identification of Japanese language EHRs has not been studied sufficiently. This study was conducted to raise de-identification performance for Japanese EHRs through classic machine learning, deep learning, and rule-based methods, depending on the dataset. Results Using three datasets, we implemented de-identification systems for Japanese EHRs and compared the de-identification performances found for rule-based, Conditional Random Fields (CRF), and Long-Short Term Memory (LSTM)-based methods. Gold standard tags for de-identification are annotated manually for age, hospital, person, sex, and time. We used different combinations of our datasets to train and evaluate our three methods. Our best F1-scores were 84.23, 68.19, and 81.67 points, respectively, for evaluations of the MedNLP dataset, a dummy EHR dataset that was virtually written by a medical doctor, and a Pathology Report dataset. Our LSTM-based method was the best performing, except for the MedNLP dataset. The rule-based method was best for the MedNLP dataset. The LSTM-based method achieved a good score of 83.07 points for this MedNLP dataset, which differs by 1.16 points from the best score obtained using the rule-based method. Results suggest that LSTM adapted well to different characteristics of our datasets. Our LSTM-based method performed better than our CRF-based method, yielding a 7.41 point F1-score, when applied to our Pathology Report dataset. This report is the first of study applying this LSTM-based method to any de-identification task of a Japanese EHR. Conclusions Our LSTM-based machine learning method was able to extract named entities to be de-identified with better performance, in general, than that of our rule-based methods. However, machine learning methods are inadequate for processing expressions with low occurrence. Our future work will specifically examine the combination of LSTM and rule-based methods to achieve better performance. Our currently achieved level of performance is sufficiently higher than that of publicly available Japanese de-identification tools. Therefore, our system will be applied to actual de-identification tasks in hospitals.

Post-operative systolic anterior motion associated with mitral regurgitation can be a challenging combination. We present the case of a 64-year-old male patient managed by MitraClip (Abbott Laboratories, Abbott Park, Illinois) implantation for systolic anterior motion and severe mitral regurgitation in the early post-operative period after aortic dissection surgery. This is the first description of MitraClip use post–aortic dissection. (Level of Difficulty: Intermediate.)

Current data collection strategies in electron cryo-microscopy (cryo-EM) record multiframe movies with static optical settings. This limits the number of adjustable parameters that can be used to optimize the experiment. Here, a method for fast and accurate defocus (FADE) modulation during movie acquisition is proposed. It uses the objective lens aperture as an electrostatic pole that locally modifies the electron beam potential. The beam potential variation is converted to defocus change by the typically undesired chromatic aberration of the objective lens. The simplicity, electrostatic principle and low electrical impedance of the device allow fast switching speeds that will enable per-frame defocus modulation of cryo-EM movies. Researchers will be able to define custom defocus `recipes' and tailor the experiment for optimal information extraction from the sample. The FADE method could help to convert the microscope into a more dynamic and flexible optical platform that delivers better performance in cryo-EM single-particle analysis and electron cryo-tomography.

Abstract Background Metabarcoding of vertebrate DNA found in invertebrates (iDNA) represents a potentially powerful tool for monitoring biodiversity. Preliminary evidence suggests fly iDNA biodiversity assessments compare favorably with established approaches such as camera trapping or line transects. Aims and Methods To assess whether fly‐derived iDNA is consistently useful for biodiversity monitoring across a diversity of ecosystems, we compared metabarcoding of the mitochondrial 16S gene of fly pool‐derived iDNA (range = 49–105 flies/site, N = 784 flies) with camera traps (range = 198–1,654 videos of mammals identified to the species level/site) at eight sites, representing different habitat types in five countries across tropical Africa. Results We detected a similar number of mammal species using fly‐derived iDNA (range = 8–15 species/site) and camera traps (range = 8–27 species/site). However, the two approaches detected mostly different species (range = 6%–43% of species detected/site were detected with both methods), with fly‐derived iDNA detecting on average smaller‐bodied species than camera traps. Despite addressing different phylogenetic components of local mammalian communities, both methods resulted in similar beta‐diversity estimates across sites and habitats. Conclusion These results support a growing body of evidence that fly‐derived iDNA is a cost‐ and time‐efficient tool that complements camera trapping in assessing mammalian biodiversity. Fly‐derived iDNA may facilitate biomonitoring in terrestrial ecosystems at broad spatial and temporal scales, in much the same way as water eDNA has improved biomonitoring across aquatic ecosystems.

BackgroundXanthine oxidoreductase (XOR) inhibition reduces reactive oxygen species (ROS) production and enhances adenosine triphosphate (ATP) synthesis. We investigated the protective effects of XOR inhibitor treatment on sarcopenia, frequently observed in patients undergoing hemodialysis (HD), in which increased ROS and ATP shortage are known to be involved.MethodsThis retrospective cross-sectional study included 296 HD patient (203 males, 93 females). Muscle mass, physical performance, and muscle strength were assessed using dual-energy X-ray absorptiometry, five-time chair stand testing, and handgrip strength, respectively. The Asian Working Group for Sarcopenia 2019 criteria were used to define low muscle mass, low physical performance, and low muscle strength, as well as sarcopenia and severe sarcopenia.ResultsSarcopenia and severe sarcopenia prevalence rates were 42.2 and 20.9%, respectively. XOR inhibitor users (n = 119) showed a significantly (p < 0.05) lower prevalence of sarcopenia and severe sarcopenia, as well as reduced muscle mass, physical performance, and muscle strength than non-users (n = 177). Multivariate logistic regression analyses also revealed XOR inhibitor use to be significantly associated with low muscle mass [odds ratio (OR), 0.384; 95% confidence interval (CI), 0.183–0.806; p = 0.011] and low physical performance (OR, 0.286; 95% CI, 0.142–0.578; p < 0.001), while significance with low muscle strength was borderline. Furthermore, XOR inhibitor use was significantly associated with sarcopenia (OR, 0.462; 95% CI, 0.226–0.947; p = 0.035) and severe sarcopenia (OR, 0.236; 95% CI, 0.091–0.614; p = 0.003).ConclusionsXOR inhibitor use was significantly associated with reduced risk of sarcopenia/severe sarcopenia in HD patients, suggesting that XOR inhibitor treatment has protective effects on sarcopenia in HD patients.

Antibiotics disrupt normal gut microbiota and cause dysbiosis, leading to a reduction in intestinal epithelial barrier function. Disruption of the intestinal epithelial barrier, which is known as "leaky gut", results in increased intestinal permeability and contributes to the development or exacerbation of gastrointestinal diseases such as inflammatory bowel disease and irritable bowel syndrome. We have previously reported on a murine model of intestinal epithelial barrier dysfunction associated with dysbiosis induced by the administration of ampicillin and vancomycin. Saireito, a traditional Japanese herbal medicine, is often used to treat autoimmune disorders including ulcerative colitis; the possible mechanism of action and its efficacy, however, remains unclear. In this study, we examined the efficacy of Saireito in our animal model for leaky gut associated with dysbiosis. C57BL/6 mice were fed a Saireito diet for the entirety of the protocol (day1-28). To induce colitis, ampicillin and vancomycin were administered in drinking water for the last seven consecutive days (day22-28). As previously demonstrated, treatment with antibiotics caused fecal occult bleeding, cecum enlargement with black discoloration, colon inflammation with epithelial cell apoptosis, and upregulation of pro-inflammatory cytokines. Oral administration of Saireito significantly improved antibiotics-induced fecal occult bleeding and cecum enlargement by suppressing inflammation in the colon. Furthermore, Saireito treatment ensured the integrity of the intestinal epithelial barrier by suppressing apoptosis and inducing cell adhesion proteins including ZO-1, occludin, and E-cadherin in intestinal epithelial cells, which in turn decreased intestinal epithelial permeability. Moreover, the reduced microbial diversity seen in the gut of mice treated with antibiotics was remarkably improved with the administration of Saireito. In addition, Saireito altered the composition of gut microbiota in these mice. These results suggest that Saireito alleviates leaky gut caused by antibiotic-induced dysbiosis. Our findings provide a potentially new therapeutic strategy for antibiotic-related gastrointestinal disorders.

Coronary angiography (CAG) is still considered the reference standard for coronary artery assessment, especially in the treatment of acute coronary syndrome (ACS). Although aging causes changes in coronary arteries, the age-related imaging features on CAG and their prognostic relevance have not been fully characterized. We hypothesized that a deep neural network (DNN) model could be trained to estimate vascular age only using CAG and that this age prediction from CAG could show significant associations with clinical outcomes of ACS. A DNN was trained to estimate vascular age using ten separate frames from each of 5,923 CAG videos from 572 patients. It was then tested on 1,437 CAG videos from 144 patients. Subsequently, 298 ACS patients who underwent percutaneous coronary intervention (PCI) were analysed to assess whether predicted age by DNN was associated with clinical outcomes. Age predicted as a continuous variable showed mean absolute error of 4 years with R squared of 0.72 (r = 0.856). Among the ACS patients stratified by predicted age from CAG images before PCI, major adverse cardiovascular events (MACE) were more frequently observed in the older vascular age group than in the younger vascular age group (p = 0.017). Furthermore, after controlling for actual age, gender, peak creatine kinase, and history of heart failure, the older vascular age group independently suffered from more MACE (hazard ratio 2.14, 95% CI 1.07 to 4.29, p = 0.032). The vascular age estimated based on CAG imaging by DNN showed high predictive value. The age predicted from CAG images by DNN could have significant associations with clinical outcomes in patients with ACS.

The effective therapy for pulmonary arterial hypertension (PAH) with inadequate clinical response is scarce except for lung transplantation when prostacyclin infusion is ineffective. The purpose of this study is to investigate the efficacy and safety of selexipag in addition to the infusion of prostacyclin. Nine patients [median 38 (36–49) years of age; 78% female] with PAH whose clinical response was inadequate despite the use of prostacyclin infusion analogs, were evaluated. Addition of selexipag significantly improved hemodynamics and no serious adverse events were observed. Selexipag with prostacyclin infusion analogs can be an effective therapeutic strategy for the PAH patients with inadequate clinical response.