Treatment Burden on Once-Weekly Omarigliptin Versus Daily Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes: Randomized Controlled Trial (ONWARD-DPP4 Study).

INTRODUCTION: Preference for quality of life is important in deciding the treatment strategy for patients with type 2 diabetes mellitus. This study aimed to assess the effect of omarigliptin on patients' psychological attitudes and responses compared with daily dipeptidyl peptidase-4 inhibitors (DPP4is) by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ). METHODS: Patients with type 2 diabetes mellitus who were taking daily DPP-4is were enrolled and randomized to a group that switched to omarigliptin or a group that continued daily DPP4is and were monitored for 12 weeks. The primary endpoint was the change in the DTBQ score from baseline to week 12. The secondary endpoints included changes in blood test results, medication preferences and medication adherence. RESULTS: The DTBQ total score significantly decreased from baseline to week 12 in both groups; however, no significant intergroup differences were observed. The DTBQ subscale, implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, although no significant intergroup difference in the change was observed. DTBQ scores and medication preferences were associated with improvements in the DTBQ scores. CONCLUSION: Although this study failed to demonstrate the improvement of DTBQ total score by switching from daily DPP4is to omarigliptin compared with continuing the daily DPP4is, the DTBQ subscale score implementation and flexibility burden score were significantly improved only in the group that switched to omarigliptin, suggesting the possibility of switching from daily DPP4is to omarigliptin to decrease the patients' medication burden. TRIAL REGISTRATION: jRCTs031200437.

Impact of the TRPV2 Inhibitor on Advanced Heart Failure in Patients with Muscular Dystrophy: Exploratory Study of Biomarkers Related to the Efficacy of Tranilast.

Cardiomyopathy is the leading cause of death in patients with muscular dystrophy (MD). Tranilast, a widely used anti-allergic drug, has displayed inhibitory activity against the transient receptor potential cation channel subfamily V member 2 and improved cardiac function in MD patients. To identify urinary biomarkers that assess improved cardiac function after tranilast administration, we performed a urinary metabolomic study focused on oxidative fatty acids. Accompanying the clinical trial of tranilast, urine specimens were collected over 24 weeks from MD patients with advanced heart failure. Urinary levels of tetranor-PGDM (tetranor-prostaglandin D metabolite), a metabolite of prostaglandin D2, significantly decreased 12 weeks after tranilast administration and were correlated with BNP. These results suggest that prostaglandin-mediated inflammation, which increases with the pathological progression of heart failure in MD patients, was attenuated. Urinary prostaglandin E3 (PGE3) levels significantly increased 4 weeks after tranilast administration. There were positive correlations between the urinary levels of PGE3 and 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker. High PGE3 levels may have a protective effect against cardiomyopathy in MD patients with high oxidative stress. Although further validation studies are necessary, urinary tetranor-PGDM and PGE3 levels may help the current understanding of the extent of advanced heart failure in patients with MD after tranilast administration.

Changes in prescription patterns and doses of oral antidiabetic drugs in Japanese patients with type 2 diabetes (JDDM70).

We assessed the prescription patterns of oral antidiabetic drugs in Japanese patients with type 2 diabetes between 2002 and 2020 using data from the Computerized Diabetes Care database. Among 172,960 patients treated with oral antidiabetic drugs, both the sulfonylurea prescription rate and dose decreased from 2002 to 2020. Prescriptions of biguanides, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors increased; their dose and dose frequency remained relatively stable. Trends in oral antidiabetic drug prescriptions changed over time, reflecting guideline recommendations and existing evidence.

Removal of Subfoveal Massive Hard Exudates through an Intentional Macular Hole in Patients with Diabetic Maculopathy: A Report of Three Cases.

Recently, good postoperative visual acuity has been reported using surgical removal of hard exudates (HEs) through an intentional macular hole (iMH). We report 3 cases of subfoveal HE secondary to diabetic maculopathy (DM) treated with HE removal via an iMH. Pars plana vitrectomy (PPV) was performed in three eyes of 3 patients with subfoveal HE secondary to DM. In all eyes, after PPV, internal limiting membrane (ILM) peeling of the lower half was performed within the range of papilla diameter 2 centered on the fovea, leaving the upper half for subsequent inverted ILM flap technique. Then, by grabbing the inner layer of the fovea using ILM forceps, an iMH was created. The HE was then flushed from the iMH with a balanced salt solution as much as possible. Finally, the inverted ILM flap technique was performed using the upper half of the ILM that was left during the previous maneuver. At the end of the surgery, the eyes were flushed with 50 mL of 20% sulfur hexafluoride (SF6) after the fluid-air exchange of the vitreous cavity. After surgery, HE was adequately removed, iMH was completely closed, and visual acuity improved in all eyes. This surgical procedure did not cause a central scotoma but rather improved the central sensitivity of the visual field in all eyes. No serious surgery-related complications occurred. In conclusion, HE removal via an iMH hole can be one of the treatment options for patients with subfoveal HE secondary to DM.

[A Patient Developing Guillain-Barré Syndrome After Receiving the BNT162b2 COVID-19 mRNA Vaccine].

We report a 71-year-old woman who presented with paresthesia, progressive weakness, difficulty walking, diarrhea, and bladder dysfunction one week after she received the BNT162b2 COVID-19 vaccine. Her neurological signs and symptoms gradually worsened up to 27 days after onset, after which her weakness slowly improved without immunotherapy. Analysis of serial cerebrospinal fluid specimens showed gradually increasing protein levels. Results of a nerve conduction study suggested functional axonal disturbance. The clinical findings together with the monophasic clinical course were consistent with Guillain-Barré syndrome. Her previous history was negative for symptomatic infection. Serological and bacterial tests, including the presence of anti-glycolipid antibodies, were negative for prior infection. Few cases have been reported on the development of Guillain-Barré syndrome after the BNT162b2 vaccine. Our patient's syndrome was characterized by atypical proximal weakness of the dominant lower limb. (Received January 28, 2022; Accepted April 4, 2022; Published August 1, 2022).

Trends in glycemic control in patients with insulin therapy compared with non-insulin or no drugs in type 2 diabetes in Japan: a long-term view of real-world treatment between 2002 and 2018 (JDDM 66).

INTRODUCTION: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model. RESULTS: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin. CONCLUSIONS: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

[An 11 year old woman with myelin-oligodendrocyte glycoprotein antibody showing various phenotypes of central nervous system disorders in one year].

An 11-year-old woman with myelin-oligodendrocyte glycoprotein (MOG) antibody developed cortical encephalitis twice, followed by acute disseminated encephalomyelitis (ADEM) and optic neuritis in one year. Although optic neuritis was refractory after corticosteroid therapy, plasma exchange was effective and complete remission was achieved. We considered that episodes of cortical encephalitis, ADEM and optic neuritis occurred in the present patient can be included in MOG IgG-associated disorders. Also, we recommend plasma exchange for refractory MOG IgG-associated optic neuritis, even in pediatric patient.

Current status of oral antidiabetic drug prescribing patterns based on the body mass index for Japanese type 2 diabetes mellitus patients and yearly changes in diabetologists' prescribing patterns from 2002 to 2019 (JDDM61).

AIMS/INTRODUCTION: Type 2 diabetes mellitus is caused by a relative imbalance between insulin secretion and sensitivity related to the body mass index (BMI). Seven categories of oral antidiabetic drugs (OADs) are available in Japan. It is important to assess the OAD utilization patterns based on patients' BMI levels. MATERIALS AND METHODS: OAD prescribing patterns from 2002 to 2019 were analyzed using the data collected in the computerized diabetes care database provided by the Japan Diabetes Clinical Data Management Study Group; OAD utilization patterns in 25,751 OAD-treated type 2 diabetes mellitus patients registered in 2019 were analyzed after classifying them into five categories of BMI. RESULTS: Comparing OAD usage between 2002 and 2019, sulfonylureas decreased from 44.5 to 23.2%, and biguanides (BGs) increased from 19.3 to 50.3%. Dipeptidyl peptidase-4 inhibitors (DPP4is) increased to 56.9% in 2019. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) increased to 23.6% in 2019. About 90% of type 2 diabetes mellitus patients had BMI < 30 kg/m2 . DPP4is were the most used OADs in 2019. When BMI exceeded 30 kg/m2 , use of BGs and sodium-glucose cotransporter 2 inhibitors increased, and use of sulfonylureas and DPP4is decreased. Although DPP4is were the most used OADs for patients with BMI <30 kg/m2 , they were the third most prescribed OADs for patients with BMI >35 kg/m2 after BGs and sodium-glucose cotransporter 2 inhibitors . CONCLUSIONS: DPP4i usage was as high as that of BG in the analysis of Japanese type 2 diabetes mellitus patients with relatively low BMI. This was considered to be a treatment option appropriate for the pathophysiology in Japanese patients.

A Japanese Patient with Hereditary Myopathy with Early Respiratory Failure Due to the p.P31732L Mutation of Titin.

Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be the sole symptom in the disease course. We herein report the first Japanese HMERF patient with a p.P31732L mutation in titin. The patient manifested respiratory failure and mild weakness of the neck flexor muscle at 69 years old and showed fatty replacement of the bilateral semitendinosus muscles on muscle imaging. Our case indicates that HMERF with a heterozygous p.P31732L mutation should be included in the differential diagnosis of muscular diseases presenting with early respiratory failure.

[Atezolizumab-induced Guillain-Barré syndrome-like acute demyelinating polyneuropathy responsive to steroid therapy: a case report].

A 76-year-old man, who received atezolizumab for the treatment for small cell lung cancer, acutely developed limb weakness with sensory disturbance after the third course of the treatment. Nerve conduction studies were consistent with demyelinating polyneuropathy and acute demyelinating polyneuropathy caused by atezolizumab was suggested. Atezolizumab was immediately withdrawn, and intravenous immunoglobulin (IVIg) and methylprednisolone pulse therapies with subsequent oral administration of prednisolone were initiated, after which neurological deficits steadily improved. Although Guillain-Barré syndrome-like neuropathy caused by immune checkpoint inhibitor (ICI) was occasionally reported, this is the first case of acute demyelinating polyneuropathy triggered by atezolizumab, monoclonal antibody targeting programmed death-ligand 1. This case suggests that combined treatments with IVIg and corticosteroids are effective for neuropathy induced by atezolizumab as same as those by other ICI.

[An 18-year-old man of hereditary neuropathy with liability to pressure palsies presenting with bilateral brachial plexopathy during military training].

An 18-year-old man without familial history of neuropathy developed motor and sensory disturbance of bilateral upper limbs after maintaining shoulder abduction/external rotation and elbow flection position of both upper limbs for an hour during military training. Neurological examination and electromyography studies suggested left brachial plexopathy, although a nerve conduction study (NCS) showed mild demyelination of bilateral median nerve and right ulnar nerve. Thoracic outlet syndrome (TOS) was firstly suspected because symptoms were induced by the specific position which narrows, costoclavicular and retropectoralis minor space and cause compression of the brachial plexus; however, no findings suggesting TOS were observed on computed tomography and magnetic resonance imaging. Hence, we suspected a diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) due to having episodes of bilateral acute brachial plexopathy and mild demyelination on NCS. The diagnosis of HNPP was confirmed by the deletion of the PMP22 gene deletion.

[A 81-year old man of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive myopathy associated with lung adenocarcinoma cancer].

An 81-year-old man, who had no history of taking statins, developed progressive muscle weakness of the limbs and dysphagia. Laboratory tests showed a high level of CK and positivity for serum 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Tests for other autoantibodies to ARS and SRP were negative. A pathological analysis of the left biceps muscle revealed numerous necrotic and regenerated fibers with macrophage infiltration and deposition of C5b-9 complement in and around the myofibers. Chest CT showed a nodular shadow, which was suspected to be lung cancer, in the upper left lobe. A pathological analysis of a transbronchial lung biopsy specimen revealed lung adenocarcinoma with high level of HMGCR. He was diagnosed with HMGCR necrotizing myopathy associated with lung cancer, and both his muscle strength and dysphagia improved after three treatments with intravenous immunoglobulin (IVIg). He did not undergo surgery or radiation therapy because of interstitial pneumonia. This case suggests that a paraneoplastic mechanism caused the production of HMGCR antibodies, leading to myositis in this patient. Treatment with IVIg can be effective for patients with HMGCR antibody-positive paraneoplastic necrotizing myopathy that is refractory to corticosteroid therapy.

Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis.

INTRODUCTION: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. METHODS: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. RESULTS: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-µm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. CONCLUSIONS: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.

Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro.

Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood-brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells. Of these, 34 cell-surface proteins were selectively internalized into human brain microvascular endothelial cells, but not into human umbilical vein endothelial cells (HUVECs), a model of human peripheral microvascular endothelial cells. Two cell-surface proteins, intercellular adhesion molecule-1 (ICAM1) and podocalyxin (PODXL), were identified as BBB-localized endocytic cell-surface proteins in humans, using open mRNA and protein databases. Immunohistochemical evaluation confirmed PODXL expression in the plasma membrane of hCMEC/D3 cells and revealed that anti-PODXL antibody-labeled cell-surface PODXL internalized into hCMEC/D3 cells. Immunohistochemistry further revealed that PODXL is localized at the luminal side of human brain microvessels, supporting its potential suitability for translational applications. In conclusion, our findings highlight novel endocytic cell-surface proteins capable of internalizing into human brain microvascular endothelial cells. ICAM1 or PODXL targeted antibody or ligand-labeled biopharmaceuticals and nanocarriers may provide effective targeted delivery to the brain across the BBB for the treatment of central nervous system (CNS) diseases.

Cognitive Impairment Caused by Isolated Adrenocorticotropic Hormone Deficiency without Other Hypo-adrenalism Signs - Autoimmune Encephalopathy Mimics.

Isolated adrenocorticotropic hormone deficiency (IAD) is a cause of adrenal insufficiency (AI), which shows impaired secretion of adrenocorticotropic hormone (ACTH) with the preserved secretion of other anterior pituitary gland hormones. We herein report a case of IAD complicated by chronic thyroiditis presenting with neuropsychiatric symptoms without other signs indicative of AI that showed complete improvement of the cognitive function after the administration of corticosteroids. The clinical features of our case may be confused with autoimmune encephalopathies (AEs); however, IAD should be strictly differentiated from AEs, as it requires permanent hormone replacement without addition of immunosuppressive agents.

Increased IP-10 production by blood-nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy.

OBJECTIVE: Dysfunction of the blood-nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN. METHODS: We determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system. RESULTS: The induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor,vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups. CONCLUSION: The autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN.

Autologous Transplantation of the Internal Limiting Membrane for Refractory Macular Hole following Ruptured Retinal Arterial Macroaneurysm: A Case Report.

PURPOSE: To report a case of macular hole (MH) secondary to a retinal arterial macroaneurysm (RAMA) which was successfully treated with an autologous transplantation of internal limiting membrane (ILM). CASE REPORT: An 87-year-old female presented with a sudden decrease in central vision in the right eye. A fundus examination revealed a RAMA in the superonasal macular region, a subretinal hemorrhage (SRH), involving the macula, and a sub-ILM hemorrhage. A pars plana vitrectomy (PPV) was performed. Intraoperatively, an MH filled with coagulum was detected. We tried to blow off and drain the SRH with a current of BSS and a gentle suction with a 27-gauge vitreous cutter from the MH, but some amount of SRH at the bottom of the MH remained. The ILM was peeled off for 2 disc diameters around the MH. The vitreous cavity was filled with air at the end of the operation. Two weeks after the surgery, the MH was not closed. One month following the initial PPV, a second PPV was performed to achieve closure of the MH. RESULTS: An autologous transplantation of ILM was performed as second PPV. Six months after the final surgery, the MH was successfully closed and the best-corrected decimal visual acuity was 0.6. CONCLUSIONS: Autologous ILM transplantation can be an effective treatment option for MH closure following RAMA rupture.