Long-term outcomes for Asian patients with X-linked hypophosphataemia : rationale and design of the SUNFLOWER longitudinal, observational cohort study

Introduction X-linked hypophosphataemic rickets/osteomalacia (XLH) is a chronic, debilitating genetic disease characterised by skeletal abnormalities and growth disorder. The burden of XLH begins in childhood and continues throughout life. Conventional medical therapy with phosphate, active vitamin D and surgery do not address the underlying pathophysiology of the disease. While treatment during childhood may improve bone deformity and growth retardation, a large proportion of adult patients still fail to reach normal stature. Furthermore, adult patients with XLH report comorbidities associated with unresolved childhood disease, as well as newly developed disease-related complications and significantly impaired quality of life (QOL). Despite the multiple negative aspects of XLH, Asian consensus statements for diagnosis and management are lacking. Methods and analysis The Study of longitUdinal observatioN For patients with X-Linked hypOphosphataemic rickets/osteomalacia in collaboration With Asian partnERs study is a longitudinal observational cohort study of patients with XLH, designed to determine the medical characteristics and burdens (physical, emotional and financial) of this progressive disease and to evaluate the impact of treatment (including the use of burosumab) on clinical outcomes. The study was initiated in April 2018, and registration will remain open until 30 April 2022. The sample size planned for analyses is 160 patients, consisting of 100 patients in Japan and 60 patients in Korea. Up to 5 years of observation are planned per patient, from enrolment through to April 2023. Prospective and retrospective data will be collected to evaluate variables, including height/growth, rickets severity score, QOL, motor function and biomarkers for phosphate metabolism and bone turnover. Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Osaka University, the Ethics Committee of Kyowa Kirin Co and by the Ethics Committee of each participating medical institution. Two interim analyses and associated publications are planned using retrospective and enrolment data at year 1 and results at year 3

Bundling of collagen fibrils influences osteocyte network formation during bone modeling

Osteocytes form a cellular network by gap junctions between their cell processes. This network is important since intercellular communication via the network is essential for bone metabolism. However, the factors that influence the formation of this osteocyte network remain unknown. As the early stage of osteocyte network formation occurs on the bone surface, we observed a newly formed trabecular bone surface by orthogonal focused ion beam-scanning electron microscopy. The embedding late osteoblast processes tended to avoid bundled collagen fibrils and elongate into sparse collagen fibrils. Then, we examined whether the inhibition of bundling of collagen fibrils using a potent lysyl oxidase inhibitor, beta-aminopropionitrile (BAPN) changed the cellular network of the chick calvaria. The osteocyte shape of the control group was spindle-shape, while that of the BAPN group was sphere-shaped. In addition, the osteocyte processes of the control group were elongated vertically to the long axis of the cell body, whereas the osteocyte processes of the BAPN group were elongated radially. Therefore, it was suggested that the bundling of collagen fibrils influences normal osteocyte network formation during bone modeling

A surgical case of mitral valve replacement for a patient with Fabry disease complicated with hemodialysis

　Fabry disease is a rare genetic disease, and surgical reports for the patients with Fabry disease are also rarer.　A 58-year-old man presented with chest pain. At the age of 40, he commenced dialysis due to chronic renal failure and at the age of 50, he developed shortness of breath on exertion, and echocardiography showed mitral regurgitation and left ventricular hypertrophy. He was then diagnosed with Fabry disease due to decreased alpha-galactosidase activity. This diagnosis led to enzyme replacement therapy (ERT). The ERT was effective as he had not never experienced further exacerbation of congestive heart failure. While the CHF was put under control, his mitral stenosis gradually worsened, and the patient began to have more chest pain and became hypotensive. He then referred to our section for mitral valve replacement. His mitral annulus was severely calcified and we removed mitral annulus calcification (MAC) at minimum so that we could stich needles and implanted mechanical valve. Paroxysmal atrial fibrillation and bradycardia made his hemodynamics unstable against ERT, which also caused low dialysis efficiency. It took longer than usual to wean him off catecholamines. His hemodynamics became more stable and dialysis efficiency generally improved, so he moved from ICU to ward on postoperative day 11. On day 32, he was transferred back to the referring hospital for his rehabilitation.　We have reported a surgical case of Fabry disease, that are not only rare but have high perioperative risk due to Fabry disease’s specific complications

Case report on a coronary artery bypass graft for a patient with antiphospholipid antibody syndrome associated with systemic lupus erythematosus

　Antiphospholipid antibody syndrome (APS) is an immune disease in which antiphospholipid antibodies cause hypercoagulability and thromboembolic complications. We experienced APS cases associated with systemic lupus erythematosus with three-vessel lesions of the coronary artery. After a below knee amputation on a 60-year-old woman with APS, she complained of chest pain at rest. An electrocardiogram showed an ST depression and a coronary angiography showed complicated three-vessel disease, as a result she was referred to the cardiac surgery department. A coronary artery bypass with arterial grafts was performed along with postoperative anticoagulant and antiplatelet therapy, and the short-term graft patency was good. Case reports of coronary artery bypass grafts for secondary APS are rare, so we report here on our case and our strategy to treat thromboembolic complications

Minimally invasive cardiac surgery via a right mini-thoracotomy

　Minimally invasive surgery, which has become very active outside the cardiovascular field, has recently come to the fore in this area. Then, procedures such as offpump coronary artery bypass grafts without extracorporeal circulation and stent grafts for treating aortic aneurysms have been frequently performed.　In cardiac surgery, as in other surgical fields, more and more surgeries that are less and less invasive have been introduced in recent years. Off-pump coronary artery bypass grafting has contributed to the development of these less invasive surgeries. For example, cardiac surgery utilizing a partial sternotomy was introduced as a way to better access the surgical location. However, minimally invasive cardiac surgery (MICS) through a right mini-thoracotomy, a portaccess cardiac surgery, is said to be trending recently because it avoids a sternotomy and has less bleeding and wound infection. All of these factors not only promote early recovery, but are also expected to have a positive impact on early discharge and the health care economy.　With surgeons and hospitals accumulating experience, MICS is being applied to more complex lesions and has begun to be used to treat the aortic valve in addition to the mitral valve. Off-the-job training and team building are also key factors for implementing a successful program. This type of port-access cardiac surgery is already beginning to be developed into a robotically assisted heart surgery by various facilities around the world

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target