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Background We aimed to assess the association of atrial fibrillation (AF) on outcomes in a post hoc analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) and how this association is modified by baseline imaging features. Methods Inverse probability of treatment weight was used to remove baseline imbalances between those with and without AF. The primary outcome was the modified Rankin Scale (mRS) scores at 90 days. Secondary outcomes were symptomatic intracerebral haemorrhage (sICH), early neurological deterioration or death within 24 h, and death at 90 days. The logistic regression model was used to determine the associations. Results Of the 3285 patients included in this analysis, 636 (19%) had AF at baseline. Compared with non-AF, AF was not significantly associated with an unfavourable shift of mRS (odds ratio 1.09; 95% confidence interval, 0.96–1.24), but with sICH (2.82; 1.78-4.48; IST-3 criteria), early neurological deterioration or death within 24 h (1.31; 1.01-1.70), and death (1.42; 1.12-1.79). Among patients with acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions), AF was associated with the increased risk of all the poor outcomes (all P Conclusions We found AF increased risk of sICH, early neurological deterioration or death and death, but not unfavourable functional recovery at day 90 after thrombolysis in patients with AIS. The presence of acute ischaemic brain imaging signs at stroke presentation could be used to improve risk stratification in the presence of AF. Trial registration The trial is registered at ClinicalTrials.gov (NCT01422616).

[Introduction] Personalized health care is recommended for the prevention and early detection of breast cancer. Advances in technology have made it possible to estimate genetic risk, PGV (pathogenic/likely-pathogenic germline variant) or PRS (polygenic risk score), in practice. However, linkage after risk assessment to personalized health care is still developing. One of the issues is how to tell the result especially in case of newly diagnosed PGV after Genetic Panel Testing or PRS. In this study, we evaluated genetic counseling (GC) using an established patient-reported outcome measure for clinical genetics services scale (Genetic Counseling Outcome Scale24 (GCOS24)) at genetic counseling for disclosure the results of the previous study, and examined the association with management after GC. [Method] We performed targeted sequencing for 11 breast cancer-related genes using peripheral blood DNA from 1995 female breast cancer patients. Of 1995 cases, 101 patients were PGV carriers, who were candidates of this study. Participants were referred to the Clinical Genetics unit, Kyoto University Hospital from 10 institutions (January 2018-March 2022). GCOS24 and relating questionaries were asked before and after GC. GCOS24 is a scale consisting of 24 items that assess five factors: decision control, cognitive control, behavioral control, emotional regulation, and hope. (In light of the current status of hereditary breast cancer care in Japan, 23 items were used.) Each item is rated on a scale of 1-7 points, for a total score of 23-161. In addition, we reviewed medical records to evaluate the post-GC management. [Results] Of the 101 cases, 38 cases were enrolled. The reasons of 63 not-enrolled cases were: 30 cases without follow-up (deaths or transfer to another hospital), 11 cases already diagnosed in clinical practice, 18 cases that did not wish to know their results, and 4 cases whose hospital were developing for hereditary breast cancer care. Median age at the time of genetic GC was 55 (min-max 30-83) years. Details of PGV cases were: BRCA2 23 cases, BRCA1 2, PALB2 4, PTEN 3, TP53 3, ATM 1, CHEK2 1 and NF1 1. GCOS24 after GC were improved than before GC. (Average 99 (min-max 17-124) vs 114 (91-138), Mean difference 23.9, 95% Confidence intervals (CI) 29.6 to 18.3). Thirty patients (79%) had higher increase in scores than 10.3, which was the previously reported Minimum Clinically Important Difference (MCID) of this scale. In all items except 4 items (#6,11,13,21), GCOS24 after GC were significantly improved than before GC. In post-GC management, 8 patients received or planned RRSO (risk reducing salpingo-oophorectomy) among 25 BRCA1/2 cases. There was a case with dysplastic cells detected in the resected ovary. After GC, average of GCOS24 in RRSO cases was 120 (95% CI 110 to 129), while average of GCOS24 of other BRCA1/2 cases was 110 (95% CI 104 to 116). On the other hand, two patients stopped visiting to the hospital because of fear after GC. Average of GCOS24 of 15 junior-high/high school graduate cases were 111 (95% CI 105 to 117), while average of GCOS24 of 23 college graduate cases were 117 (95% CI 111 to 122). [Discussion] In patients diagnosed with hereditary breast cancer by genetic panel testing, GC worked well except for 4 items. These 4 items (#6,11,13,21) were related to emotion. This study revealed there was also a risk to reject surveillance due to fear, suggesting that it is necessary to provide psychological support in some cases. Although the limitation of this study is the small number of cases, GCOS24 were high in RRSO cases, suggesting that GC played an important role when proceeding with intervention. We believe that the findings are helpful for the future implementation of genetic panel testing or PRS testing in healthy subjects for personalized health care. Citation Format: Nobuko Kawaguchi-Sakita, Noriko Senda, Yukiko Inagaki-Kawata, Hiromi Murakami, Sayaka Honda, Takahiro Yamada, Yuki Kataoka, Shoko Takahara, Shigeru Tsuyuki, Kazuhiko Yamagami, Yoshio Moriguchi, Masae Torii, Tatsushi Kato, Hirofumi Suwa, Wakako Tsuji, Eiji Suzuki, Akira Yamauchi, Ryuji Okamura, Shinji Kosugi, Masakazu Toi. Potential Empowerment and risk of Genetic Counseling with Genetic Breast cancer risk assessment in Personalized Health Care: Prospective Cohort Study using Genetic Counseling Outcome Scale (GCOS-24) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-05-02.

Yuka Tsukahara,1,2 Hiroshi Kamada,2,3 Suguru Torii,2,4 Hiroshi Yamamoto,5 Fumihiro Yamasawa2 1Department of Sports Medicine, Tokyo Women’s College of Physical Education, Kunitachi, Japan; 2Medical Committee, Japan Association of Athletics Federations (JAAF), Tokyo, Japan; 3Department of Orthopaedic Surgery, University of Tsukuba, Tsukuba, Japan; 4Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan; 5School of Sports and Health, Hosei University, Tokyo, JapanCorrespondence: Yuka Tsukahara, Department of Sports Medicine, Tokyo Women’s College of Physical Education, 4-30-1 Fujimidai, Kunitachi, Japan, Email yuka.voila@gmail.comIntroduction: Little is known regarding medical knowledge pertaining to female athletes among track and field coaches and their interactions with female athletes regarding medical problems.Methods: Participants were track and field coaches (369 males and 43 females) with Japan Sport Association certification and they completed an anonymous survey on their knowledge of medical problems pertinent to female athletes including whether the coaches knew about the female athlete triad and relative energy deficiency in sports; their feelings about female athletes’ use of contraceptive pills; whether they speak about menses with the female athletes; and whether they have a gynecologist for consultation regarding their medical problems.Results: Females coaches were significantly more likely to be aware of the triad (odds ratio (OR), 3.44; p = 0.003); to have access to a physician able to address the gynecological problems of female athletes (OR, 9.22; p < 0.001); and to talk to their female athletes about menses (OR, 2.30; p = 0.015) than their male counterparts. Coaches with more experience tended to be aware of the triad and relative energy deficiency in sports compared with those with ≤ 5 years of experience.Conclusion: Females coaches are aware of the triad, talk about menses with their female athletes, and have access to a physician who can address gynecological problems with compared to male counterparts. Educating all coaches on these problems is essential to provide adequate support to female athletes.Keywords: track and field, relative energy deficiency in sports, female athlete triad syndrome

Background: Abemaciclib is a selective CDK4 and CDK6 inhibitor with demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The most common adverse event across previous trials was early-onset diarrhea, affecting the patients’ quality of life and necessitating dose reductions. However, the exact mechanism for the lower rate of diarrhea in the other CDK4 and CDK6 inhibitors compared with abemaciclib is unknown. Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with the anti-tumor response; however, reported microbial signatures associated with adverse events by anti-cancer agent are inconsistent. To determine the underlying mechanism, we evaluated the correlation between diarrhea with abemaciclib and microbiota signatures in a metastatic breast cancer cohort. Methods: The KBCRN-A002 study is a multicenter, prospective cohort study, which aims to evaluate the association between gut microbiota signatures and abemaciclib-induced diarrhea in breast cancer patients. Patients with metastatic breast cancer who were receiving abemaciclib were eligible. The primary objective of this study is the correlation between diarrhea and the microbiota signatures and immune profile. Incidence and severity of diarrhea were evaluated by the Bristol stool scale at baseline, from day 1 to day 14, and at day 90 of treatment. Stool samples were collected at baseline and at day 90 after the start of abemaciclib treatment. The gut microbiota signature was evaluated by 16S rRNA analysis. Blood samples were collected at baseline and at days 14 and 90 after starting abemaciclib to evaluate the correlation between the gut microbiota signatures and the systemic immune profile in peripheral blood mononuclear cells (PBMCs). The immune profile was evaluated by mass cytometry, multi-plex cytokines assay, and RNA-sequencing of bulk PBMCs. We characterized the gut microbiota signatures, immune cell composition, immune cell signature, comprehensive cytokines, and severity of diarrhea in all patients. Results: We analyzed 39 patients, 77 stool samples, and 117 blood samples. In the preplanned interim analysis, among the 39 patients, 90% experienced diarrhea. Depleted gut microbiome α-diversity was positively associated with abemaciclib treatment and the severity of diarrhea. The relative abundances of 10 intestinal bacteria species increased and those of 18 intestinal bacteria decreased significantly after abemaciclib treatment, including bacteria known to be involved in diarrhea severity and anti-tumor immunity, such as Faecalibacterium (Table). The immune cell and cytokine profiles in PBMCs were also associated with the gut microbiota signatures. Conclusions: Gut microbiota signatures are associated with abemaciclib-induced diarrhea and the immune profile in metastatic breast cancer patients. These findings can help to elucidate the mechanism of diarrhea caused by abemaciclib and offer strategies for its management and prevention. Intestinal Microbiota Altered by Abemaciclib Citation Format: Kosuke Kawaguchi, Yurina Maeshima, Hiroshi Ishiguro, Kazuhiko Yamagami, Sachiko Takahara, Hirofumi Suwa, Masae Torii, Shigenori Nagai, Yasuaki Sagara, Wakako Tsuji, Hiroyasu Yamashiro, Takeshi Kotake, Shinji Fukuda, Kuniaki Saito, Yasuko Yamamoto, Masako Kataoka, Yuki Himoto, Atsushi Yonezawa, Yukiko Fukui, Yuki Nakamura, Wei Li, Sunao Tanaka, Satoshi Morita, Masakazu Toi. Alteration of gut microbiota signatures and its association with diarrhea during abemaciclib treatment: A multicenter prospective cohort study (KBCRN-A002 study) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-07.

OBJECTIVE Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in ET patients by analyzing resting-state networks (RSNs). METHODS Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and HCs. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. RESULTS Preoperatively, ET patients showed a significant decrease in FC in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in FC in the SMN correlated with the severity of tremor. After MRgFUS thalamotomy, ET patients still exhibited a significant decrease in FC in a small area of the SMN, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post-MRgFUS patients, the FC in the SMN and the VSN significantly increased after treatment. Quantitative evaluation of the FCs in these three groups showed that the SMN and VSN increased postoperatively and demonstrated a trend toward those of HCs. CONCLUSIONS The SMN and CN, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in ET patients compared with HCs, tended to normalize postoperatively. This could be related to the hypothesis that visual feedback is involved in tremor severity in ET patients. Overall, the analysis of the RSNs by rsfMRI reflected the pathophysiology with the intervention of MRgFUS thalamotomy in ET patients and demonstrated a possibility of a biomarker for successful treatment.

Deer have been a major resource for human populations for thousands of years. Anthropogenic activities, such as hunting, have influenced the genetic structure and distribution of deer populations. In Japan, wild Japanese sika deer (Cervus nippon) have been hunted since ancient times but have also been historically protected as sacred animals in several sanctuaries. Sika deer have been protected for over a thousand years in the religious sanctuary around the Kasuga Taisha Shrine on the Kii Peninsula, located in the center of Japan. Here, we used short sequence repeats (SSR) and mitochondrial DNA (mtDNA) to investigate the genetic diversity, population structure, and demography of Japanese sika deer inhabiting the Kii Peninsula, Japan, and discuss possible anthropogenic influences. Using SSR, three distinct genetic groups were distinguished on the Kii Peninsula: an Eastern genetic group, a Western genetic group, and an isolated genetic group with individuals in the religious sanctuary of Kasuga Taisha Shrine in Nara city. The isolated genetic sanctuary group had only the mtDNA haplotype S4. The SSR genotype data suggested a newer divergence time of the genetic groups of the religious sanctuary than would have occurred as a result of Late Quaternary climate change. This time scale coincided with the establishment of the sanctuary with Kasuga Taisha Shrine. Thus, the religious protection conserved genetic variation over a thousand years.

New structure-selective G-quadruplex ligands identified by a simple and fast screening system showed a structural selectivity–cytotoxicity relationship of G-quadruplex ligands.

Hintergrund: Die chronische myeloische Leukämie ist eine hämatologische Malignität, die mit der Fusion von zwei Genen einhergeht: BCR und ABL1. Diese Fusion resultiert aus einer Translokation zwischen den Chromosomen 9 und 22, auch als Philadelphia Chromosom bekannt. Obwohl das Philadelphia-Chromosom bei mehr als 90% der Patienten mit chronischer myeloischer Leukämie vorhanden ist, weisen 5-8% der Patienten mit chronischer myeloischer Leukämie komplexe Translokationsvarianten auf. Wir berichten hier über einen Fall einer dreifachen Translokationsvariante bei chronischer myeloischer Leukämie in der chronischen Phase. Vorstellung des Falles: Bei einem 40-jährigen asiatischen Mann, der sich mit Leukozytose vorstellte, wurde eine chronische myeloischen Leukämie in chronischer Phase diagnostiziert. Die zytogenetische Karyotypisierungsanalyse ergab 46,XY,t(4;9;22)(q21;q34;q11.2). Er wurde behandelt mit Bosutinib und dann wegen Unverträglichkeit auf Dasatinib umgestellt, und nach 17 Monaten kontinuierlicher Behandlung wurde MR4,5 (BCR-ABL/ABL ≤ 0,0032%, internationale Skala) erreicht. Schlussfolgerung: Dies war der 14. Fall von t(4;9;22), im Speziellen einer neue Variante der Ph-Translokation, bei der das Chromosom 4q21 beteiligt ist, und der erste weltweit erfolgreiche Fall, der mit Tyrosinkinase-Inhibitoren behandelt wurde. Wir fassen frühere Fallberichte über die dreifache Chromosomenverschiebung t(4;9;22) zusammen und erörtern, wie diese seltene Verschiebung mit der Prognose zusammenhängt.

Microtubule-associated protein Tau is primarily expressed in axons of neurons, but also in Olig2-positive oligodendrocytes in adult rodent and monkey brains. In this study, we sought to determine at what cell stage Tau becomes expressed in the oligodendrocyte lineage. We performed immunostaining of adult mouse brain sections using well-known markers of oligodendrocyte lineage and found that Tau is expressed in mature oligodendrocytes, but not in oligodendrocyte progenitors and immature pre-oligodendrocytes. We also investigated Tau expression in developing mouse brain. Surprisingly, Tau expression occurred after the peak of myelination and even exceeded GSTπ expression, which has been considered as a marker of myelinating oligodendrocytes. These results suggest Tau as a novel marker of oligodendrocyte maturation. We then investigated whether Tau is important for oligodendrocyte development and/or myelination and how Tau changes in demyelination. First, we found no changes in myelination and oligodendrocyte markers in Tau knockout mice, suggesting that Tau is dispensable. Next, we analyzed the proteolipid protein 1 transgenic model of Pelizaeus-Merzbacher disease, which is a rare leukodystrophy. In hemizygous transgenic mice, the number of Tau-positive cells were significantly increased as compared with wild type mice. These cells were also positive for Olig2, CC1, and GSTπ, but not PDGFRα and GPR17. In stark contrast, the expression level of Tau, as well as GSTπ, was dramatically decreased in the cuprizone-induced model of multiple sclerosis. Taken together, we propose Tau as a new marker of oligodendrocyte lineage and for investigating demyelination lesions.

Plants sense a myriad of signals through cell-surface receptors to coordinate their development and environmental response. The Arabidopsis ERECTA receptor kinase regulates diverse developmental processes via perceiving multiple EPIDERMAL PATTERNING FACTOR (EPF)/EPF-LIKE peptide ligands. How the activated ERECTA protein is turned over is unknown. Here we identify two closely related plant U-box ubiquitin E3 ligases, PUB30 and PUB31, as key attenuators of ERECTA signalling for two developmental processes: inflorescence/pedicel growth and stomatal development. Loss-of-function pub30 pub31 mutant plants exhibit extreme inflorescence/pedicel elongation and reduced stomatal numbers owing to excessive ERECTA protein accumulation. Ligand activation of ERECTA leads to phosphorylation of PUB30/31 via BRI1-ASSOCIATED KINASE1 (BAK1), which acts as a coreceptor kinase and a scaffold to promote PUB30/31 to associate with and ubiquitinate ERECTA for eventual degradation. Our work highlights PUB30 and PUB31 as integral components of the ERECTA regulatory circuit that ensure optimal signalling outputs, thereby defining the role for PUB proteins in developmental signalling.

Chromatin architecture and transcription factor (TF) binding underpin cell-fate specification during development, but their mutual regulatory relationships remain unclear. Here we report an atlas of dynamic chromatin landscapes during stomatal cell-lineage progression, in which sequential cell-state transitions are governed by lineage-specific bHLH TFs. Major reprogramming of chromatin accessibility occurs at the proliferation-to-differentiation transition. We discover novel co-cis regulatory elements (CREs) signifying the early precursor stage, BBR/BPC (GAGA) and bHLH (E-box) motifs, where master-regulatory bHLH TFs, SPEECHLESS and MUTE, consecutively bind to initiate and terminate the proliferative state, respectively. BPC TFs complex with MUTE to repress SPEECHLESS expression through a local deposition of repressive histone marks. We elucidate the mechanism by which cell-state-specific heterotypic TF complexes facilitate cell-fate commitment by recruiting chromatin modifiers via key co-CREs.

Nivolumab, an immune checkpoint inhibitor (ICI), is now used to treat many advanced cancers, including non-small cell lung cancer (NSCLC) and renal cancer. Immune-related adverse events are characteristic side effects of ICIs. Among them, fulminant type 1 diabetes mellitus is an infrequent but potentially life-threatening and clinically significant concern. Cabozantinib is known as a multikinase inhibitor. In recent years, combination therapy with nivolumab and cabozantinib has begun to be used to treat renal cell carcinoma. A 74-year-old man with no history of diabetes was treated with nivolumab for 5 years for NSCLC, followed by the combination of nivolumab and cabozantinib for clear cell renal cell carcinoma. He was diagnosed with fulminant type 1 diabetes 5 weeks after starting combination therapy, with symptoms of nausea and dry mouth. He was admitted to the intensive care unit and improved clinically with continuous insulin infusion and saline. The involvement of cabozantinib in the development of fulminant type 1 diabetes with long-term nivolumab use, which has not been reported previously, is unknown, but caution may be necessary in terms of glycemic control in combination therapy with nivolumab and cabozantinib.

After the accident at the Fukushima Daiichi Nuclear Power Plant, artificial radionuclides such as radioactive cesium and iodine were released into the environment. It caused great anxiety not only in the vicinity of the Fukushima Daiichi Nuclear Power Plant but also in other regions of the world. Some members of the Japan Health Physics Society (JHPS), a leading academic society in Japan in the field of radiation protection, volunteered to establish a website called “Question and Answer (Q&A) about radiation in daily life” shortly after the accident to help reduce the residents’ anxiety about the health effects of radiation. In August 2011, “Committee for Q&A about radiation in daily life” was established in JHPS, making the website-related activities a responsibility of JHPS. The Q&A website continued to respond to the questions from the general public with expertise and sincerity until February 2013 when the Committee members decided to end the activities because the number of questions received had gradually decreased with the passage of time. This paper aims to introduce the following: the activities of the Q&A website during the two years (2011–2013), the stance chosen for the activities, the information related to the website activities and the analysis of Twitter data. Building on the experience and the knowledge obtained from the activities, it also discusses issues and experiences that can be utilized in the initial response to emergencies for radiation protection experts as well as those in other fields.

Background and ObjectivesTo assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease.MethodsFemale carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers.ResultsWe enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers.DiscussionThe present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

[Purpose] The current study aimed to determine the association between serum uncarboxylated osteocalcin (ucOC) levels and dietary vitamin K intake in female Japanese athletes.[Methods] The nutritional profile and food group intake of 52 Japanese female athletes were investigated using a digital photographic method with data obtained from 3-day dietary records. The food groups were categorized into 18 groups in line with the standard tables of food composition in Japan. Fasting blood samples were collected for serum ucOC levels, and dual-energy X-ray absorptiometry (DXA) evaluated body composition and bone parameters.[Results] The results showed that dietary vitamin K intake level was 235 ± 148 µg/day, and approximately 70% (n = 36) of participants consumed more than the adequate intake (AI) level, based on the Dietary Reference Intakes for Japanese females aged 18–29. Serum ucOC levels were negatively associated with daily vitamin K intake (r = −0.388, P = 0.004) and calcium (r = −0.596, P = 0.004) after adjusting for energy intake.[Conclusion] Our study revealed that serum ucOC levels were negatively associated with dietary vitamin K intake in female Japanese athletes. Serum ucOC levels reflected dietary vitamin K intake in female athletes. In summary, female athletes consume more vitamin K than the general population to maintain bone health. Furthermore, our results indicated that serum ucOC levels might be linked to dietary calcium intake.

Ultrathin bronchoscopy aids in the diagnosis of peripheral pulmonary lesions. However, both the working channel and the specimens are small. A 1.1-mm ultrathin cryoprobe that can enter the working channel of the ultrathin bronchoscope is now available, which may overcome the limitations of small specimen size. The aim of this study was to evaluate the feasibility, efficacy and safety of ultrathin bronchoscopic cryobiopsy using an ultrathin cryoprobe for diagnosing peripheral pulmonary lesions.Patients with peripheral pulmonary lesions ≤30 mm in diameter were prospectively enrolled in the study. All patients underwent forceps biopsy followed by cryobiopsy using a 3.0-mm ultrathin bronchoscope under radial probe endobronchial ultrasound guidance, virtual bronchoscopic navigation and fluoroscopic guidance. The primary endpoint was the feasibility of cryobiopsy.In total, 50 patients with peripheral pulmonary lesions were enrolled in the study; the median longest diameter on computed tomography was 17.9 mm. Cryobiopsy was performed successfully in 49 patients (98%). Forceps biopsy, cryobiopsy and the combination of these two methods provided a specific diagnosis in 54% (27/50), 62% (31/50) and 74% (37/50) of patients, respectively. The median size of specimens obtained via cryobiopsy was significantly larger than the median size obtained via forceps biopsy (7.0 vs. 1.3 mmUltrathin bronchoscopic cryobiopsy is feasible, effective and sufficiently safe for the diagnosis of peripheral pulmonary lesions.

Regression of thrombus in response to treatment with direct oral anticoagulants (DOACs) in patients with extensive deep vein thrombosis (DVT) has not been fully evaluated. This study aimed to determine the therapeutic efficacy of rivaroxaban in the treatment of extensive DVT.We retrospectively evaluated 76 patients treated with rivaroxaban among 728 new DVT patients, at our hospital from January 2018 to March 2021. Extensive DVT was defined as thrombus connecting to 2 or more segments of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. Localized DVT was defined as a thrombus confined to 1 segment of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. We compared the changes in thrombus between the extensive DVT group (36 patients) and the localized DVT group (40 patients).In the localized DVT group, 14 (37%) had total recanalization within 3 weeks after DOAC initiation, and 30 (79%) had total recanalization within 3 months. In the extensive DVT group, only 3 (9%) had total recanalization within 3 weeks after starting DOAC, and even after 3 months, only 5 (15%) had total recanalization. Symptoms (P = 0.01) and extensive DVT (P 0.01) were significantly associated with the risk for failure of total recanalization.Rivaroxaban was highly effective for total recanalization of localized DVT but not for symptomatic or extensive DVT. In patients with symptomatic extensive DVT, catheter-based thrombolysis may be considered in selected cases.

Cryptogenic bilateral fibrosing pleuritis is a rare condition, and its pathogenesis and clinical course are poorly understood, with no established therapy available. A 61-year-old man presented with bilateral pleural thickening and lymphocytic exudative effusions. The patient was diagnosed with fibrosing pleuritis with no evidence of a known etiology on a surgical pleural biopsy. Within 16 months from the onset of respiratory symptoms, restrictive ventilatory impairment progressed rapidly, resulting in hypercapnic respiratory failure requiring home oxygen and non-invasive positive pressure ventilation therapies.

There is an urgent need to stop the coronavirus disease 2019 (COVID-19) pandemic through the development of efficient and safe vaccination methods. Over the short term, plasmid DNA vaccines can be developed as they are molecularly stable, thus facilitating easy transport and storage. pVAX1-SARS-CoV2-co was designed for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) S protein. The antibodies produced led to immunoreactions against the S protein, an anti-receptor-binding-domain, and a neutralizing action of the pVAX1-SARS-CoV2-co, as previously confirmed. To promote the efficacy of the pVAX1-SARS-CoV2-co vaccine a pyro-drive jet injector (PJI) was used. An intradermally adjusted PJI demonstrated that the pVAX1-SARS-CoV2-co vaccine injection caused a high production of anti-S protein antibodies, triggered immunoreactions, and neutralized the actions against SARS-CoV-2. A high-dose pVAX1-SARS-CoV2-co intradermal injection using PJI did not cause any serious disorders in the rat model. A viral challenge confirmed that intradermally immunized mice were potently protected from COVID-19. A pVAX1-SARS-CoV2-co intradermal injection using PJI is a safe and promising vaccination method for overcoming the COVID-19 pandemic.

This review summarizes the evidence for the management of sarcopenia in patients with rheumatoid arthritis (RA) in terms of drugs, exercise, and nutrition. Sarcopenia is a decrease in skeletal muscle mass and muscle strength or physical function. The prevalence of sarcopenia in patients with RA is higher than that in the general population. The treatment and management of sarcopenia in patients with RA are clinically important for long-term prognosis. One of the mechanisms of muscle metabolism is the pro-inflammatory cytokine pathway, which involves tumour necrosis factor α and interleukin-6, and is a common pathway in the pathogenesis of RA. Thus, tumour necrosis factor α and interleukin-6 inhibitors may play a potential role in controlling sarcopenia. In exercise therapy, a combination of moderate resistance and aerobic exercise may be effective in improving muscle strength, muscle mass, and physical function; however, intense exercise may exacerbate the inflammatory response in RA. Regarding nutrition, protein intake is generally considered beneficial, but other nutrients such as vitamin D and carotenoids have also been studied. Overall, there remains a lack of concrete evidence on sarcopenia treatment and management in patients with RA from any perspective; more longitudinal and intervention studies are needed in the future.

Patients with COVID-19 and cardiovascular disease risk factors (CVDRF) have been reported to develop coagulation abnormalities frequently. However, there are limitations in conventional predictive models for the occurrence of thromboembolism in patients with COVID-19 and CVDRF.Among data on 1518 hospitalized patients with COVID-19 registered with CLAVIS-COVID, a Japanese nationwide cohort study, 693 patients with CVDRF were subjected to least absolute shrinkage and selection operator (LASSO) analysis; a method of shrinking coefficients for reducing variance and minimizing bias to increase predictive accuracy. LASSO analysis was performed to identify risk factors for systemic thromboembolic events; occurrence of arterial and venous thromboembolism during the index hospitalization as the primary endpoint.LASSO analysis identified a prior systemic thromboembolism, male sex, hypoxygenemia requiring invasive mechanical ventilation support, C-reactive protein levels and D-dimer levels at admission, and congestion on chest X-ray at admission as potential risk factors for the primary endpoint. The developed risk model consisting of these risk factors showed good discriminative performance (AUC-ROC: 0.83, 95 % confidence interval [CI]: 0.77-0.90), which was significantly better than that shown by D-dimer (AUC-ROC: 0.70, 95 % CI: 0.60-0.80) (p 0.001). Furthermore, systemic embolic events were independently associated with in-hospital mortality (adjusted odds ratio: 3.29; 95 % CI: 1.31-8.00).Six parameters readily available at the time of admission were identified as risk factors for thromboembolic events, and these may be capable of stratifying the risk of in-hospital thromboembolic events, which are associated with in-hospital mortality, in patients with COVID-19 and CVDRF.

Aims The potential effect of alcohol consumption on coronary heart disease (CHD) remains unclear. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in subclinical and clinical CHD. Methods We conducted two Mendelian randomization studies: a cross-sectional study of coronary artery calcification (CAC) on computed tomography of 1029 healthy men (mean age, 63.8 years) and a case–control study of 421 men with CHD [acute coronary syndrome (ACS) or stable angina pectoris] who underwent coronary revascularization and 842 age-matched male controls. Results In the CAC study, medians (25%tiles, 75%tiles) of alcohol consumption by ALDH2-rs671 *2 homozygotes [n = 86 (8.4%)], *1*2 heterozygotes [n = 397 (38.5%)], and *1 homozygotes [n = 546 (53.1%)] were 0.0 (0.0, 0.0), 28.0 (0.0, 129.0), and 224.0 (84.0, 350.0) g/week, respectively. In age-adjusted Poisson regression with robust error variance, compared with *2 homozygotes, relative risks for prevalent CAC score >0, ≥100, and ≥300 in *1 homozygotes were 1.29 (95% confidence interval, 1.06–1.57), 1.76 (1.05–2.96), and 1.81 (0.80–4.09), respectively. In age-adjusted ordinal logistic regression for CAC distributions, we observed higher odds among *1 homozygotes [odds ratio, 2.19 (1.39–3.46)] and even among *1*2 heterozygotes [1.77 (1.11–2.82)] compared with *2 homozygotes. In the case–control study, conditional logistic regression revealed lower prevalence of *1 homozygotes among men with CHD [odds ratio, 0.54 (0.35–0.82)], especially ACS [0.46 (0.27–0.77)], than controls. Conclusion Our findings indicate a positive association of alcohol consumption with CAC burden but an inverse association with clinical CHD, especially ACS.

Well-leg compartment syndrome (WLCS) is a potentially life-threatening postoperative complication related to the Lloyd-Davies surgical position, which can place increased external pressure on the calf region. We conducted this study to analyze external pressure changes, by applying a leg holder system to the left calf region of patients placed in the Lloyd-Davies position during laparoscopic surgery.The study participants were 50 patients who underwent laparoscopic surgery for colorectal cancer in the Lloyd-Davies position. We assessed the maximum external pressure (MEP) on the left calf region using a pressure-distribution measurement system. Intraoperative measurements were taken continuously, and the MEP was evaluated with the patient horizontal and every 30 min during surgery in the head and right-down tilt position.The intraoperative MEP increased gradually when the patient was in the head and right-down tilt position and decreased when the patient was returned to the horizontal position. The MEP was higher in patients aged 60 years, those who were obese, and those with a thick calf circumference. Both body mass index (BMI) and the maximum left calf circumference (MLCC) were found to correlate with the MEP.In addition to a high BMI, which is a well-known risk factor for WLCS, a high MLCC should be considered another risk factor, especially for patients under 60 years.

Ciclesonide (Cic) is approved as an inhalant for asthma and was clinically tested as a candidate therapy for coronavirus disease 2019 (COVID-19). Its active metabolite Cic2 was recently reported to suppress genomic RNA replication of severe acute respiratory syndrome coronavirus 2. In this study, we designed and synthesized a set of ciclesonide-acetal (Cic-acetal) derivatives. Among designated compounds, some Cic-acetal derivatives with a linear alkyl chain exhibited strong viral copy-number reduction activities compared with Cic2. These compounds might serve as lead compounds for developing novel anti-COVID-19 agents.