Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data.

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.

Intracranial aneurysm as a possible complication of osteogenesis imperfecta: a case series and literature review.

Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other complications are poorly understood. We describe three patients with OI with unruptured intracranial aneurysm (IA) detected by magnetic resonance angiography (MRA) screening of 14 patients. Case 1 was a 73-year-old woman with type 1 OI with blue sclera, vertebral compression fractures, and impaired hearing. Lumbar spine bone mineral density (BMD) was preserved (young adult mean (YAM): 86%). MRA revealed an IA in the right internal carotid artery. Case 2 was a 43-year-old man with type 4 OI and leg-length discrepancy due to left femoral neck fracture. Lumbar spine BMD was decreased (YAM: 61%). MRA showed an IA in the left anterior cerebral artery. Case 3 was a 35-year-old woman with type 3 OI with blue sclera, dentinogenesis imperfecta, deformity of the long bones, and severe scoliosis. She had undergone spine surgery and needed wheelchair assistance. The YAM of the femoral neck BMD was 71%. MRA indicated an IA in the right posterior communicating artery. The prevalence of IA in our series of patients with OI was 21%, which is higher than the reported prevalence of unruptured IA in the Japanese general population (2.2%), suggesting that IA may be a complication of OI. Our literature review revealed no cases of OI with unruptured IA, but 11 cases of OI with subarachnoid hemorrhage. IA seems unrelated to OI type, sex, or age. We recommend MRA of adults with OI.

Early Detection of Worsening Heart Failure in Patients at Home Using a New Telemonitoring System of Respiratory Stability.

BACKGROUND: Early detection of worsening heart failure (HF) with a telemonitoring system crucially depends on monitoring parameters. The present study aimed to examine whether a serial follow up of all-night respiratory stability time (RST) built into a telemonitoring system could faithfully reflect ongoing deterioration in HF patients at home and detect early signs of worsening HF in a multicenter, prospective study.Methods and Results: Seventeen subjects with New York Heart Association class II or III were followed up for a mean of 9 months using a newly developed telemonitoring system equipped with non-attached sensor technologies and automatic RST analysis. Signals from the home sensor were transferred to a cloud server, where all-night RSTs were calculated every morning and traced by the monitoring center. During the follow up, 9 episodes of admission due to worsening HF and 1 episode of sudden death were preceded by progressive declines of RST. The receiver operating characteristic curve demonstrated that the progressive or sustained reduction of RST below 20 s during 28 days before hospital admission achieved the highest sensitivity of 90.0% and specificity of 81.7% to subsequent hospitalization, with an area under the curve of 0.85. CONCLUSIONS: RST could serve as a sensitive and specific indicator of worsening HF and allow the detection of an early sign of clinical deterioration in the telemedical management of HF.

Naive Bayes Prediction of the Development of Cardiac Events in Heart Failure With Preserved Ejection Fraction in an Outpatient Clinic　- Beyond B-Type Natriuretic Peptide.

BACKGROUND: The heterogeneity of B-type natriuretic peptide (BNP) levels among individuals with heart failure and preserved ejection fraction (HFpEF) makes predicting the development of cardiac events difficult. This study aimed at creating high-performance Naive Bayes (NB) classifiers, beyond BNP, to predict the development of cardiac events over a 3-year period in individual outpatients with HFpEF.Methods and Results:We retrospectively enrolled 234 outpatients with HFpEF who were followed up for 3 years. Parameters with a coefficient of association ≥0.1 for cardiac events were applied as features of classifiers. We used the step forward method to find a high-performance model with the maximum area under the receiver operating characteristics curve (AUC). A 10-fold cross-validation method was used to validate the generalization performance of the classifiers. The mean kappa statistics, AUC, sensitivity, specificity, and accuracy were evaluated and compared between classifiers learning multiple factors and only the BNP. Kappa statistics, AUC, and sensitivity were significantly higher for NB classifiers learning 13 features than for those learning only BNP (0.69±0.14 vs. 0.54±0.12 P=0.024, 0.94±0.03 vs. 0.84±0.05 P<0.001, 85±8% vs. 64±20% P=0.006, respectively). The specificity and accuracy were similar. CONCLUSIONS: We created high-performance NB classifiers for predicting the development of cardiac events in individual outpatients with HFpEF. Our NB classifiers may be useful for providing precision medicine for these patients.

Influence of Glucose Dosage in Parenteral Nutrition on Body Thiamine Levels in Rats.

The objective of this study was to determine the relationship between glucose dosage in parenteral nutrition and reductions in levels of body thiamine in rats. Vitamin-free infusions with differing amounts of glucose were administered to normal or thiamine-deficient rats for 5 days, after which urinary thiamine excretion and the amounts of thiamine in the blood, liver, brain, and skeletal muscles were measured. The total energy dosage was set at three levels (98, 140, and 196 kcal/kg), and the dose of amino acids was constant among all groups. Urinary thiamine excretions on Day 5 decreased with increasing glucose dosage in the infusions. In normal rats, the amount of thiamine in the blood and all organs decreased compared with the diet group; however, no significant differences were found among the infusion groups. In thiamine-deficient rats, on the other hand, the amount of thiamine in the liver and skeletal muscles did not differ significantly among infusion groups; however, the amount of thiamine in the brain and blood decreased with increasing glucose dosage. An organ-specific correlation was found between glucose dosage in infusions and reductions in levels of thiamine. To prevent thiamine deficiencies from affecting the central nervous system, greater caution must be exercised during high-caloric parenteral nutrition. However, a constant supply of thiamine seemed to be essential, irrespective of the amount of energy supplied via parenteral nutrition, to maintain a sufficient level of thiamine in the body.

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension.

BACKGROUND: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. METHODS: Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry, confirmed by enzyme-linked immunosorbent assay, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next-generation sequencing, functional studies in cultured monocytes and endothelial cells, and hemodynamic and lung studies in a rat. RESULTS: SAM domain and HD domain-containing protein 1 (SAMHD1), an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH versus 12 control lungs. Elevated SAMHD1 was localized to endothelial cells, perivascular dendritic cells, and macrophages, and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH versus control lungs (n=4). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase mRNAs were elevated in PAH versus control lungs (n=10), and proteins were localized to macrophages. HERV-K deoxyuridine triphosphate nucleotidohydrolase induced SAMHD1 and proinflammatory cytokines (eg, interleukin 6, interleukin 1ß, and tumor necrosis factor α) in circulating monocytes, pulmonary arterial endothelial cells, and also activated B cells. Vulnerability of pulmonary arterial endothelial cells (PAEC) to apoptosis was increased by HERV-K deoxyuridine triphosphate nucleotidohydrolase in an interleukin 6-independent manner. Furthermore, 3 weekly injections of HERV-K deoxyuridine triphosphate nucleotidohydrolase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8) and elevated interleukin 6. CONCLUSIONS: Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

Pyridoxal 5'-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy.

OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

Impact of right ventricular distensibility on congestive heart failure with preserved left ventricular ejection fraction in the elderly.

To elucidate involvement of age-related impairments of right ventricular (RV) distensibility in the elderly congestive heart failure (CHF), we examined the prevalence of less-distensible right ventricle in patients with preserved left ventricular ejection fraction (LVEF) over a wide range of ages. In 893 patients aged from 40 to 102 years, we simultaneously recorded electrocardiogram, phonocardiogram, and jugular venous pulse wave. Using signal-processing techniques, the prominent 'Y' descent of jugular pulse waveform was detected as a hemodynamic sign of a less-distensible right ventricle. Prevalence of less-distensible right ventricle and elevated RV systolic pressure increased along with aging from the 50s to the 90s in an exponential fashion from 3.3 and 12% up to 33 and 61%, respectively (p < 0.001 for each). This age-dependent deterioration of ventricular distensibility was not observed for the left ventricle. Higher age and higher RV systolic pressure were independently associated with less-distensible right ventricle (Odds ratio, 1.05 per 1 year, p = 0.003; and 1.03 per 1 mmHg, p = 0.026, respectively). The elderly CHF was associated with high prevalence of the less-distensible right ventricle and higher RV systolic pressure, both of which were independent risk factors for CHF (Odds ratio, 5.27, p = 0.001, and 1.08 per 1 mmHg, p < 0.001, respectively). In elderly patients with preserved LVEF, the combination of a less-distensible right ventricle and a high RV systolic pressure seems to be related to developing CHF. The less-distensible right ventricle and elevated RV systolic pressure are closely associated with CHF with preserved LVEF in the elderly patients.

Final adult height in long-term growth hormone-treated achondroplasia patients.

The objective of this study was to evaluate the gain in final height of achondroplasia (ACH) patients with long-term growth hormone (GH) treatment. We analyzed medical data of 22 adult patients (8 males and 14 females) treated with GH at a dose of 0.05 mg/kg/day. Optionally, tibial lengthening (TL) was performed with the Ilizalov method in 15 patients and TL as well as femoral lengthening (FL) in 6 patients. Concomitant gonadal suppression therapy with buserelin acetate was applied in 13 patients. The mean treatment periods with GH were 10.7 ± 4.0 and 9.3 ± 2.5 years for males and females, respectively. GH treatment augmented the final height +0.60 ± 0.52 SD (+3.5 cm) and +0.51 ± 1.29 SD (+2.8 cm) in males and females compared to non-treated ACH patients, respectively. Final height of ACH patients that underwent GH and TL increased +1.72 ± 0.72 SD (+10.0 cm) and +1.95 ± 1.34 SD (+9.8 cm) in males and females, respectively. GH, TL, and FL increased their final height +2.97 SD (+17.2 cm) and +3.41 ± 1.63 SD (+17.3 cm) in males and females, respectively. Gonadal suppression therapy had no impact on final height. CONCLUSIONS: Long-term GH treatment contributes to 2.6 and 2.1% of final adult height in male and female ACH patients, respectively.

MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.

Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1(-/-) embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1(-/-) mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.

[FGF23 related hypophosphatemic rickets:current therapy and unresolved issues].

FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment.

Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels.

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C-C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4 N][Ph3 SnF2 ], which directly constructs the crucial C-C bond at the C11 position in SEA. The NaV Ch-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

Slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with chronic heart failure: from modeling to clinical application.

Influences of slow and deep respiration on steady-state sympathetic nerve activity remain controversial in humans and could vary depending on disease conditions and basal sympathetic nerve activity. To elucidate the respiratory modulation of steady-state sympathetic nerve activity, we modeled the dynamic nature of the relationship between lung inflation and muscle sympathetic nerve activity (MSNA) in 11 heart failure patients with exaggerated sympathetic outflow at rest. An autoregressive exogenous input model was utilized to simulate entire responses of MSNA to variable respiratory patterns. In another 18 patients, we determined the influence of increasing tidal volume and slowing respiratory frequency on MSNA; 10 patients underwent a 15-min device-guided slow respiration and the remaining 8 had no respiratory modification. The model predicted that a 1-liter, step increase of lung volume decreased MSNA dynamically; its nadir (-33 ± 22%) occurred at 2.4 s; and steady-state decrease (-15 ± 5%), at 6 s. Actually, in patients with the device-guided slow and deep respiration, respiratory frequency effectively fell from 16.4 ± 3.9 to 6.7 ± 2.8/min (P < 0.0001) with a concomitant increase in tidal volume from 499 ± 206 to 1,177 ± 497 ml (P < 0.001). Consequently, steady-state MSNA was decreased by 31% (P < 0.005). In patients without respiratory modulation, there were no significant changes in respiratory frequency, tidal volume, and steady-state MSNA. Thus slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with high levels of resting sympathetic tone as in heart failure.

Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model.

Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.

[Neonatal Fc receptor (FcRn)-A Novel Therapeutic Approach for Autoimmune Disease].

Neonatal Fc receptor (FcRn) is involved in recycling of IgG. Recycling begins with IgG-uptake into the cell through pinocytosis. Subsequently, IgG binds to FcRn in acidic vesicles, which results in the recycling of the FcRn-IgG complex to cell surface, and the release of IgG in blood with neutral pH. Whereas IgG unbound to FcRn is not recycled and thus degraded in lysosomes. Therefore, FcRn plays a critical role in maintaining IgG levels in the blood. Recently, FcRn has been considered a therapeutic target for autoimmune diseases caused by IgG autoantibodies, and FcRn inhibitors are developed as therapeutic agents for the diseases. As one example, the administration of an FcRn inhibitor, efgartigimod, reduced IgG and anti-acetylcholine receptor antibody levels in patients with generalized myasthenia gravis (gMG), and improved Myasthenia Gravis Activities of Daily Living score in the phase III trial. In 2022, Efgartigimod Alfa was approved for the treatment of gMG (only when treatment with steroids or non-steroidal immunosuppressive drugs do not lead to sufficient response), regardless of antibody status in Japan. Since FcRn inhibitors have just begun to be used in clinical practice, it is important to accumulate real-world data regarding their efficacy and safety. (Received August 21, 2023; Accepted October 6, 2023; Published February 1, 2024).

Multifaced risk factors and clinical impact of a deep Y descent in patients with heart failure irrespective of RV-PA coupling.

Background: A deep Y descent in the jugular venous pulse (JVP) is associated with diseases such as a decrease in right ventricular (RV) preload reserve. The present study investigated the relationship between RV-pulmonary arterial (PA) coupling and a deep Y descent, examined risk factors for a deep Y descent and clarified whether a deep Y descent was an independent risk factor for cardiac events irrespective of RV-PA coupling in patients with heart failure (HF). Methods: We enrolled 350 patients with HF who underwent echocardiography and JVP examination. A deep Y descent was identified by a deeper 'Y' descent than 'X' descent in the JVP waveform. We defined cardiac events of HF as follows: sudden death, death from HF, the emergent infusion of loop diuretics, or hospitalization for decompensated HF. Results and Conclusions: A deep Y descent and cardiac events were observed in 129 and 83 patients, respectively. The prevalence of a deep Y descent increased with decreases in the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary arterial pressure (SPAP) ratio. Not only the TAPSE/SPAP ratio (odds ratio,0.756 per0.1 mm/mmHg, 95 %confidence interval [CI], 0.660-0.866, p < 0.001), but also age, atrial fibrillation, and the use of beta-blockers were independent factors for a deep Y descent in multivariate logistic model. Multivariate Cox hazard model demonstrated that a deep Y descent was for cardiac events in patients with HF (Hazard ratio,2.682, 95 %CI, 1.599-4.497, p < 0.001) irrespective of the TAPSE/SPAP ratio. The development of therapeutic strategies based on central venous waveform may be needed for patients with HF.

Myasthenia Gravis Disease Burden and Its Impact on Satisfaction with Life: A Qualitative Survey of Patients' Perspectives in Japan.

INTRODUCTION: Myasthenia gravis (MG) has a negative impact on patients' health-related quality of life; however, many clinicians do not fully understand their patients' lived experience of the disease. To understand the actual conditions of patients with MG and clarify the problems they perceive, we conducted a survey to evaluate the effects of the disease on patients' daily life and work. METHODS: A questionnaire-based, qualitative, cross-sectional, non-interventional survey was conducted in Japan between April and May 2022 in patients with MG who were receiving regular outpatient treatment. The questionnaire included items regarding the patients' disease characteristics and experience, satisfaction with life, current treatment status, and treatment satisfaction. RESULTS: In total, 452 patients were included in the survey population (66.6% aged ≥ 60 years; 64.6% with MG disease duration ≥ 10 years; 76.6% acetylcholine receptor [AChR] autoantibody positive). The symptoms of MG had a significant impact on the patients' daily lives, with the most common symptoms being fatigability (74.8%), ptosis (59.7%), diplopia (54.2%), and weakness in the arms and/or legs (50.9%). Patients commonly identified exercise (73.7%), work 68.0%), hobbies (60.4%), travel (60.0%), and socializing with friends (59.7%) as being difficult to perform, with approximately 50% of patients reporting that hospitalization sometimes interfered with their ability to work. In total, 27.2% of patients were dissatisfied with life, with the highest rates of dissatisfaction among patients who were either positive for muscle-specific kinase (MuSK) autoantibodies or seronegative for both AChR and MuSK autoantibodies. CONCLUSION: In Japanese patients with MG, over 25% are dissatisfied with life, indicating several unmet needs in this population.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.

A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation.

Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO.

Right ventricular diastolic dysfunction worsens clinical outcomes in Japanese patients with heart failure.

Background: Heart failure (HF) is a rapidly growing public health issue in super aging societies, such as Japan. Right HF is common in older patients. Therefore, the present study investigated the relationship between right ventricular diastolic function and poor clinical outcomes in patients with HF. Methods: We retrospectively enrolled 387 Japanese HF patients. All data were obtained from our echocardiographic and jugular venous pulse (JVP) databases and medical records. A less-distensible right ventricle (RV) was identified by a deeper 'Y' descent than 'X' descent in the JVP waveform. We defined cardiac events of HF as follows: sudden death, death from HF, emergent infusion of loop diuretics, or hospitalization for deterioration of HF. Comparisons between patients with and without cardiac events and a multivariate analysis of cardiac events were performed. Results: Eighty-five patients had cardiac events. Left ventricular ejection fraction (LVEF) was lower, average mitral E/e' and the prevalence of a less-distensible RV were higher, and tricuspid annular plane systolic excursion was shorter in patients with than in those without cardiac events (median55vs65, p < 0.001; median15vs11, p < 0.001; 64 %vs27%, p < 0.001; median17vs20, p < 0.001, respectively). In a multivariate Cox proportional hazard model, LVEF and a less-distensible RV were independent risk factors for cardiac events (hazard ratio [HR]:0.983 per 1 % increase, p = 0.048; HR:3.150, p < 0.001, respectively). The event-free rate was the lowest for patients with LVEF < 50 % and a less-distensible RV (p for trend < 0.001). Conclusions: When right ventricular diastolic function is impaired and irreversible, Japanese patients with HF may become intractable regardless of LVEF.