COVID-19 mRNA vaccination is associated with IgA nephropathy: an analysis of the Japanese adverse drug event report database.

Purpose: Coronavirus disease 2019 (COVID-19) mRNA vaccines are used worldwide to prevent severe symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IgA nephropathy (IgAN) is the most common form of glomerular injury after COVID-19 vaccination; however, because of the low frequency of such events, only a few reports have been published. A large pharmacovigilance database of real-world spontaneous adverse event (AE) reports is essential for evaluating the drug-associated safety signals regarding rare AEs. Herein, we aimed to investigate the frequency of IgAN after the COVID-19 vaccination, using the Japanese Adverse Drug Event Report (JADER) database. Methods: Data on drug-associated AEs reported between April 2004 and May 2022 were obtained from the JADER database on the Pharmaceuticals and Medical Devices Agency website. To evaluate the safety signals for the targeted AEs, reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) were calculated using two-by-two contingency tables. Results: A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38-9.61; IC: 2.27, 95% CI: 1.70-2.83). Of 30 cases for IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination. Conclusion: These results suggest that, compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.

Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex.

The novel human betacoronavirus SARS-CoV-2 has caused an unprecedented pandemic in the 21st century. Several studies have revealed interactions between SARS-CoV-2 viral proteins and host nucleoporins, yet their functions are largely unknown. Here, we demonstrate that the open-reading frame 6 (ORF6) of SARS-CoV-2 can directly manipulate localization and functions of nucleoporins. We found that ORF6 protein disrupted nuclear rim staining of nucleoporins RAE1 and NUP98. Consequently, this disruption caused aberrant nucleocytoplasmic trafficking and led to nuclear accumulation of mRNA transporters such as hnRNPA1. Ultimately, host cell nucleus size was reduced and cell growth was halted.

Reverse radiodorsal artery-pedicled thumb metacarpal vascularized bone graft for osteochondral fracture of the thumb interphalangeal joint with a bone defect: A case report.

Osteochondral fractures of the fingers are challenging to treat, and it is mandatory to acquire early bone union and joint surface reconstruction to obtain satisfactory outcomes. These injuries sometimes occur as open fractures with poor soft tissue condition and bone defect adjacent to osteochondral fragment. For such cases, surgical treatment can be more difficult, and vascularized bone graft (VBG) could be a useful method for joint reconstruction. Here, we report reverse-pedicled VBG based on the radiodorsal artery of the thumb for reconstructing a traumatic bone defect of the thumb. A 36-year-old man, who had ulcerative colitis and was taking immunosuppressive agents, sustained open fracture-dislocation of the thumb interphalangeal joint with a free osteochondral fragment of the proximal phalanx and 6 × 5 × 4 mm of subcondylar bone defect. We harvested 5 × 5 × 5 mm VBG at the base of the first metacarpal bone and dissected running the radiodorsal artery. The vascularized bone was grafted into the bone defect site through the subcutaneous tunnel created on the radial aspect of the proximal phalanx and fixed with a Kirschner wire. Bony union was obtained 2 months after surgery. At 7 months after the operation, the patient complained no pain, and the range of motion of the thumb interphalangeal joint was extension 0° and flexion 42°. Radiographs showed no avascular necrosis of the united fragment and osteoarthritis of the interphalangeal joint. This method could be a useful option for reconstruction of the thumb with bone defects.

Pharmacological characterization of M-II, the major human metabolite of ramelteon.

The duration of action of melatonin may be important for improvements in sleep efficiency in insomniacs. Ramelteon, a selective melatonin agonist, is primarily metabolized to the active metabolite M-II, which has a longer half-life and greater systemic exposure than ramelteon. Hence, M-II may contribute significantly to the hypnotic benefits of ramelteon. We assessed the ramelteon-like activity of M-II in vitro and in vivo using cats. Binding and functional studies in Chinese hamster ovary cells expressing human melatonin receptors (MT1 or MT2) revealed that M-II binds melatonin receptors with lower affinity (Ki: 114 and 566 pmol/l for MT1 and MT2, respectively) and has lower potency (IC50: 208 and 1,470 pmol/l for MT1 and MT2, respectively) compared with ramelteon. However, higher M-II doses significantly improved sleep in cats. Thus, M-II may contribute to the clinical efficacy of ramelteon.

Prediction Model for Severe Thrombocytopenia Induced by Gemcitabine Plus Cisplatin Combination Therapy in Patients with Urothelial Cancer.

BACKGROUND: Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. OBJECTIVE: A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. METHODS: We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. RESULTS: Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). CONCLUSIONS: Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

A rare case of sacral epidural arteriovenous fistula with concomitant occult multiple lumbar epidural arteriovenous fistulas.

We describe a rare case of sacral epidural arteriovenous fistulas (edAVFs) with atypical clinical course of treatment. A 78-year-old man with a history of spinal surgery presented progressive gait disturbance and urinary incontinence. Spinal angiography demonstrated a sacral spinal AVF fed by bilateral lateral sacral arteries, draining to the venous pouch with subdural drainage. The first treatment by direct interruption of a subdural drainer was incompletely finished. Postoperative reassessment by 3D imaging analysis led to the diagnosis of sacral edAVF and 3D understanding of its angioarchitecture. The second treatment by transarterial embolization (TAE) resulted in complete occlusion of a sacral edAVF. However, spinal venous congestion didn't improve, because the recruitment of occult edAVFs at the multiple lumbar levels and complex-shaped sacral ventral epidural venous plexus (VEP) were involved in the remnant of prior subdural drainage. The third treatment was performed by TAE for three occult edAVFs and the VEP compartment connecting between a patent edAVF and subdural drainage, which resulted in complete disappearance of spinal cord edema. Endovascular embolization of VEP compartment connecting to subdural drainage in addition to fistulous occlusion may be one of the treatment options for several edAVFs at the multiple spinal levels.

C-X-C domain ligand 14-mediated stromal cell-macrophage interaction as a therapeutic target for hand dermal fibrosis.

Dupuytren's contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren's contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren's contractures, we demonstrate that the activation of Wnt/ß-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/ß-catenin signalling are closely related to stromal cell-macrophage interactions, and Wnt/ß-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-ß-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell-macrophage interaction is a promising therapeutic target for Wnt/ß-catenin-induced fibrosis.

A Rare Case of Cervical Myelopathy Caused by an Anomaly of the Axis: A Case Report and a Review of Current Comprehensive Literature.

Introduction: Cervical myelopathy due to anomalies of the posterior elements of the axis is rare, and limited cases have been reported. This study reports such a unique case of congenital anomaly of the laminae of the axis, which is treated by partial removal of the anomalous bony structure surgically, and provides a comprehensive review of the present literature on this pathological condition. Case Presentation: A 65-year-old man presented with a 3-year history of numbness in both arms with a sensory change in the right arm. Six months before admission, he noticed weakness in his right upper extremities and stiffness of the right lower extremity. Magnetic resonance imaging (MRI) showed a bilaterally compressed spinal cord with an anomalous bony structure at the C2-3 level. Computed tomography (CT) showed an invaginated abnormal bony structure at the C2-3 level and an abnormal lateral mass on the right side at the C2-3 level. The patient underwent posterior decompression surgery using the conventional open approach. One year after surgery, his myelopathy partially ameliorated, with his cervical radiograph showing no signs of the secondary instability and MRI showing sufficient decompression of the spinal cord. The age of onset, symptoms, and surgical treatment in our case was similar to those in the 14 previously reported cases; however, the morphology of the anomaly had variations. Conclusion: This is a report of a rare anomaly in the laminae of the axis. MRI and reconstructed CT scans were useful for the treatment of this case. Partial surgical removal was an appropriate treatment for this patient, resulting in a satisfactory outcome.

Frequency of Immune Checkpoint Inhibitor-Induced Vasculitides: An Observational Study Using Data From the Japanese Adverse Drug Event Report Database.

Information on immune checkpoint inhibitor-induced vasculitides is limited, and predictors for this condition have not been identified. Therefore, we have examined the frequency of immune checkpoint inhibitor-induced vasculitides by analyzing the data recorded in the Japanese Adverse Drug Event Report database. Data from April 2004 to March 2020 were extracted, and vasculitides as an immune-related adverse event was defined according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Adverse event signals were recognized as significant when the reporting odds ratio estimates and lower limits of the corresponding 95% confidence intervals exceeded 1. The use of nivolumab showed a significant signal for vasculitides. Furthermore, significant signals of polymyalgia rheumatica were found when the patients were treated with nivolumab, pembrolizumab, and ipilimumab. In addition, the frequencies of nivolumab- and pembrolizumab-induced polymyalgia rheumatica were higher in patients aged ≥70 years and female patients, respectively. Polymyalgia rheumatica was reported in 38 patients treated with nivolumab; 31 (82%) of these were either in recovery or in remission. Further, polymyalgia rheumatica was reported in 17 patients treated with pembrolizumab; 13 (76%) of these were in recovery or remission, while three (18%) were not. Polymyalgia rheumatica was reported in 12 patients treated with ipilimumab; seven (58%) of these were in recovery or remission. Our study highlights that careful monitoring for the symptom of PMR (e.g., bilateral pain in shoulder and pelvic girdles) is required when the patients are aged >70 years and have been treated with nivolumab and when the patients are women and have been treated with pembrolizumab.

Transrenal Ureter Embolization for Refractory Urine Leaks from Iatrogenic Ureteric Injury Following Colorectal Surgery.

We present the cases of two patients who underwent ureteral occlusion using coils and/or Amplatzer Vascular Plug with N-butyl cyanoacrylate glue after extensive advanced rectal surgery. Both patients had complex urine leaks unresponsive to urinary diversion. In view of the progress of the disease and the history of polysurgery, reconstructive surgery or anterograde ureteral stent insertion was not chosen. All patients had immediate resolution of urinary leakage after ureteral embolization, resulting in symptom relief throughout the follow-up period. There were no procedure-related complications or side effects.

Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.

Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure-activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn 294 and Asp 123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.

Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists.

Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.

Surgical procedures for the prevention of extension-flexion gap imbalance in total knee arthroplasty.

The purpose of this study was to identify preoperative and intraoperative factors that influence extension-flexion gap imbalance in total knee arthroplasty (TKA). Ninety-three knees undergoing TKA with the modified gap balancing technique were included. Preoperative range of motion, intraoperative extension-flexion gap balance, thickness of the resected bone and radiological parameters were investigated. The preoperative flexion contracture, bone resection thickness in the medial proximal tibia, and the medial distal femur all correlated with the extension-flexion gap balance in TKA. Bone resection thickness in the medial proximal tibia and the medial distal femur were predictive of extension-flexion imbalance.

Prospective cohort study on the incidence and risk factors of emergency home visits among Japanese home care patients.

BACKGROUND: Population aging requires more physician home visits, and various measures need to be taken to reduce the burden on visiting physicians. However, the incidence and associated factors of burdensome emergency home visits remain unclear. We aimed to reveal the incidences of emergency home visits among cancer and noncancer patients and examine how visiting nurses affect those. METHODS: We performed a prospective cohort study across three clinics in Japan and enrolled the patients receiving home visits within a 3-month study period. We calculated the incidence rates using person-time at risk and conducted a Cox regression in the analysis of risks for emergency home visits. RESULTS: A total of 278 patients were analyzed. The incidences of emergency home visits among the overall, the cancer, and the noncancer home care patients were 1.61, 7.23, and 1.37 per 10 person-months, respectively. The adjusted hazard ratios of a cancer-bearing state and visiting nurse service use were 4.71 (95% confidence interval [CI], 2.60-8.52) and 1.85 (95% CI, 1.77-1.94), respectively. CONCLUSIONS: The incidence of emergency home visits among cancer patients was around five times greater than noncancer patients. Our study did not demonstrate that visiting nurses prevent emergency home visits. Further studies are needed to clarify how visiting nurses reduce physicians' burden.

Surgical Management of Thoracolumbar Scoliosis Secondary to Hip Joint Ankylosis and Severe Pelvic Obliquity.

We report a rare case of a rigid spinal deformity with severe pelvic obliquity (PO) resulting from hip ankylosis caused by childhood tuberculosis (TB). A 66-year-old woman presented with left knee pain, chronic low back pain, and fatigability during walking. She presented with leg length discrepancy (LLD) due to an ankylosed right hip joint, severe PO, and secondary lumbar scoliosis. Total hip arthroplasty (THA) and adductor tendonectomy were performed prior to spine surgery, and posterior spinal correction and fusion were performed from T10 to the pelvis. Prior to spinal correction surgery, we predicted that it would be impossible to make the pelvis perfectly horizontal. Therefore, we positioned a prosthetic acetabular cup at a small inclination angle at the upper limit of anteversion; spinal correction and fusion were then performed. Her symptoms including fatigability during walking resolved and the sagittal spinal balance on standing improved dramatically. The preoperative and postoperative values of the thoracolumbar Cobb angle was 40° and 25°, lumbosacral Cobb angle was 60° and 14°, C7 plumb line shift was 24 and 0 mm, pelvic tilt was 15° and 19°, lumbar lordosis (LL) was 23° and 60°, pelvic incidence minus lumbar lordosis (PI-LL) was 38° and 1°, the sagittal vertical axis was 80 and 0 mm, and PO was 28° and 15°, respectively. We present a case of rigid spinal deformity accompanied by hip joint ankylosis and PO. Performing THA prior to spinal correction surgery is an alternative and feasible option for the treatment of this challenging pathology.