Long-term clinical observation of patients with heterozygous KIF1A variants.

KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.

The Clinical Course and Treatment of a Case of Refractory Systemic Juvenile Myasthenia Gravis Successfully Treated with Thymectomy.

Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.

Reliability and validity of the Japanese version of the Professional Fulfillment Index among healthcare professionals: A validation study.

OBJECTIVES: Translation of the Professional Fulfillment Index (PFI) into Japanese would be more useful than the currently developed scales for appropriately measuring burnout and professional fulfillment in healthcare professionals. This study aimed to develop the Japanese version of the PFI and examine its internal consistency, structural validity, and convergent validity in healthcare professionals. METHODS: Healthcare professionals in Japan were recruited online. The survey was conducted from October to November 2022. Internal consistency was tested using Cronbach's α. Structural validity was tested using confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Convergent validity was tested using Pearson's correlation coefficients, which were calculated between each score of the PFI scale and burnout (the Japanese Burnout Scale: JBS), depressive symptoms (the Patient Health Questionnaire-9), and QOL (the General Health Questionnaire-12). RESULTS: The Cronbach's alpha was .91 in professional fulfillment, .80 in burnout: work exhaustion, .90 in burnout: interpersonal disengagement, and .89 in burnout: total score. Confirmatory factor analysis demonstrated a modest fit, and EFA yielded a three-factor structure the same as the original PFI. The all three subscales and total score of burnout were significantly correlated with the scores of all the scales (p < .001; e.g., burnout: work exhaustion correlated emotional exhaustion in JBS, r = .71). CONCLUSIONS: The Japanese version of the PFI demonstrated acceptable high internal consistency, structural validity, and convergent validity of the scale with a three-factor structure the same as in the original PFI. The Japanese version of PFI proved to be reliable and valid for use in healthcare professionals.

Association Between Attitudes Toward Trauma Informed Care and Psychological First-Aid Training Experience Among Health Care Professionals in Japan.

OBJECTIVE: Trauma informed care (TIC) is an important approach for people who have experienced trauma. Although psychological first aid (PFA) may be effective training in TIC, no study reported an association between PFA training and TIC. This study aimed to investigate the association between PFA training and attitudes toward TIC among health care professionals in Japan. METHODS: Japanese health care professionals were recruited for a survey conducted from May 21 to June 18, 2021. TIC was assessed by the Attitudes Related to Trauma Informed Care Scale 10-item short form (ARTIC-10). A question about PFA training participation was originally developed through discussion among researchers. Univariate and multiple linear regression analyses were used to examine the association between the PFA experience and ARTIC-10. RESULTS: In total, 484 (3.6%) health care professionals completed all questions. Among them, 77 (15.9%) had experienced PFA training. Univariate and multiple linear regression analyses showed that PFA experience (B = 0.19, 95% CI: 0.02-0.36, P = 0.03; B = 0.17, 95% CI: 0.01-0.34, P = 0.04) was significantly associated with ARTIC-10. CONCLUSIONS: This study was the first to show an association between PFA training and attitudes toward TIC among health care professionals, which was a significant result for future research on PFA training, TIC, and trauma care.

Multiple Cerebral Hemorrhages and White Matter Lesions Developing after Severe hMPV Pneumonia in a Patient with Trisomy 13: A Case Report and Review of the Literature.

Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. A few case reports have described hMPV encephalitis or encephalopathy. Neuroimaging data on patients with hMPV encephalitis are scarce. We report a patient with trisomy 13 who developed severe hMPV pneumonia, multifocal cerebral and cerebellar hemorrhagic infarctions and extensive cerebral white matter demyelination. Although adult respiratory distress syndrome and disseminated intravascular coagulation contributed to the devastating central nervous system (CNS) lesions, endothelial dysfunction of the CNS caused by hMPV infection probably also played a pathophysiological role in this case.

Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2.

Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.

Severe Asthma Where Eosinophilic Granulomatosis with Polyangiitis Became Apparent after the Discontinuation of Dupilumab.

The use of biologic agents has enabled control of severe asthma, but there is a risk that eosinophilic granulomatosis with polyangiitis (EGPA) may be masked in some cases. We herein report a 71-year-old man who was administered dupilumab for 2 years to stabilize his asthma symptoms. A few months after discontinuation of dupilumab administration, an increase in the eosinophil count in peripheral blood, leg pain, and a rash appeared. Based on pathology, he was diagnosed with EGPA. EGPA in this case was considered to have become apparent due to the discontinuation of dupilumab administration.

Longitudinal change in depressive symptoms among healthcare professionals with and without COVID-19 vaccine hesitancy from October 2020 to June 2021 in Japan.

This study aimed to compare the longitudinal change in depressive symptoms among healthcare professionals in Japan who are willing to receive novel coronavirus disease (COVID-19) vaccination and those who are unwilling to receive COVID-19 vaccination. The baseline survey was conducted in October 2020 (Survey time 1: T1); respondents in T1 were invited to participate in May 2021 (Survey time 2: T2). Depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9). Group comparisons of the estimated mean of PHQ-9 score at T1 and T2 were estimated by the analysis of covariance. In T1, 597 participants (response rate: 4.4%) completed all questions. In T2, 211 participants (follow up rate: 35.3%) completed all questions. The group and time interaction effect was significant (F(1, 207)=3.9, p=0.049); depressive symptoms were worse among healthcare professionals who were unwilling to receive vaccination than among those who were willing to receive vaccination. This study showed that depressive symptoms were worse among healthcare professionals who were unwilling to receive COVID-19 vaccination than those who are willing to receive COVID-19 vaccination. This suggests that it is important to take care of healthcare professionals who are unwilling to receive vaccination to prevent mental health deterioration.

Tuberculosis during lung cancer treatment-A case series.

This study aimed to clarify the characteristics of patients with lung cancer undergoing treatment until the onset of tuberculosis. Between 2005 and 2019, patients who were admitted to Tokyo National Hospital due to tuberculosis during lung cancer treatment were examined retrospectively. There were 42 patients, and detailed medical information was obtained in 39 patients. The median age of the 39 patients were 75 years (range: 47-92 years), of which 33 were males and 36 were Japanese Baby Boomers or older. Regarding risk factors for developing tuberculosis, smoking was noted in 34 cases, oral corticosteroid use in 13, and previous tuberculosis in six. Thirty-seven patients had one risk factor and 19 had two or more risk factors, but diagnosis of latent tuberculosis infection (LTBI) was obtained in only one patients, and none had received LTBI treatment. The first-line treatment for lung cancer was resection in 13 cases, chemoradiotherapy in 6, chemotherapy in 10, radiation therapy in 3, laser therapy in 1, and best supportive care (BSC) alone in 6. At tuberculosis onset, BSC accounted for 17 cases, but other situations were considerably existed such as anticancer medication (12 cases), and observation after lung cancer treatment (10 cases). Tuberculosis occurred in various situations in elderly patients with lung cancer. It is critical to actively evaluate the risk of tuberculosis and consider LTBI screening and treatment.

Longitudinal Change of Psychological Distress among Healthcare Professionals with and without Psychological First Aid Training Experience during the COVID-19 Pandemic.

This study aimed to compare longitudinal change of the psychological distress of a group with psychological first aid (PFA) experience and a group without PFA experience among physicians and other healthcare professionals from before the novel coronavirus disease (COVID-19) pandemic to during the pandemic. The baseline survey was conducted in January 2020 (T1). The respondents in T1 were invited to participate in March (T2) and November 2020 (T3). Psychological distress was assessed by the Kessler 6 Scale. Participants were divided into two categories: a group with and a group without PFA experience. Participants were further divided between physicians and healthcare professionals other than physicians, because physicians are more likely to experience morally injurious events. A mixed-model repeated-measures ANOVA was conducted as an indicator of the group differences. In T1, 398 healthcare professionals participated. The longitudinal analysis of healthcare professionals other than physicians showed that psychological distress was significantly greater in the group without PFA experience than in the group with PFA experience (T1 vs. T3). This study showed psychological distress among healthcare professionals other than physicians was significantly greater in the group without PFA experience than in the group with PFA experience during the COVID-19 pandemic, but the results were not consistent among physicians.

Reduced efficacy of perampanel in patients with severe motor and intellectual disabilities syndrome and drug-resistant epilepsy: A single-center analysis from Japan.

People with severe motor and intellectual disabilities syndrome (SMIDS) have multiple comorbidities and high mortality rates. This study examined whether there is a difference in the efficacy and tolerability of perampanel (PER) between patients with drug-resistant epilepsy with or without SMIDS. The study identified 65 patients with drug-resistant epilepsy who underwent PER treatment as adjunctive therapy. The 50 % responder rate was 22 % (14/65) overall and 11 % (5/44) in patients with SMIDS versus 43 % (9/21) in patients without SMIDS (p <0.01). Although the overall 50 % responder rate was similar to those of previous reports, PER was less efficacious in the patients with SMIDS; nevertheless, PER was tolerated in the patients with SMIDS.

Usefulness of Rapid Desensitization Therapy for Severe Rash Caused by Molecularly Targeted Drugs Used in the Treatment of Non-small-cell Lung Cancer.

Molecular-targeted drugs (MTDs), such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors, are used to treat non-small-cell lung cancer (NSCLC). The incidence of rash caused by EGFR-TKIs and discontinuation of MTDs because of rash are issues. Rapid desensitization therapy (RDT) was performed in five patients who developed severe rash after introduction of MTDs and was successful in four, all of whom showed no rash relapse. RDT may thus be useful for treating rash in patients receiving MTDs for NSCLC.

Unexpected Mutations by CRISPR-Cas9 CTG Repeat Excision in Myotonic Dystrophy and Use of CRISPR Interference as an Alternative Approach.

Myotonic dystrophy type 1 is the most common type of adult-onset muscular dystrophy. This is an autosomal dominant disorder and caused by the expansion of the CTG repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Messenger RNAs containing these expanded repeats form aggregates as nuclear RNA foci. Then, RNA binding proteins, including muscleblind-like 1, are sequestered to the RNA foci, leading to systemic abnormal RNA splicing. In this study, we used CRISPR-Cas9 genome editing to excise this CTG repeat. Dual cleavage at the 5' and 3' regions of the repeat using a conventional Cas9 nuclease and a double nicking with Cas9 nickase successfully excised the CTG repeat. Subsequently, the formation of the RNA foci was markedly reduced in patient-derived fibroblasts. However, contrary to expectations, a considerable amount of off-target digestions and on-target genomic rearrangements were observed using high-throughput genome-wide translocation sequencing. Finally, the suppression of DMPK transcripts using CRISPR interference significantly decreased the intensity of RNA foci. Our results indicate that close attention should be paid to the unintended mutations when double-strand breaks are generated by CRISPR-Cas9 for therapeutic purposes. Alternative approaches independent of double-strand breaks, including CRISPR interference, may be considered.

Green Synthesis of (R)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids.

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1.

OBJECTIVE: To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. METHODS: We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca(2+) measurements. RESULTS: A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca(2+) influx is decreased by the mutant STIM1. CONCLUSIONS: The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca(2+) influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca(2+) homeostasis.

A mechanistic investigation of anti-elimination in (Z)-1,2-bis(arylseleno)-1-alkenes and their sulfur analogs.

The oxidation of (Z)-1,2-bis(arylseleno)-1-alkenes is known to afford alkynyl selenoxides via a unique selenoxide anti-elimination mechanism; however, to date, there have been no mechanistic studies of this reaction. During our studies of this transformation, monoselenoxides 6 and 7 were unexpectedly isolated as stable reaction intermediates. In addition, (77)Se NMR studies of the reaction mixture revealed the presence of an intramolecular Se···O interaction and the formation of alkynyl selenoxides. Meanwhile, even at higher temperatures, the reaction of a (Z)-1,2-bis(arylsulfinyl)-1-alkene, the sulfur analog of (Z)-1,2-bis(arylseleninyl)-1-alkenes, did not proceed via sulfoxide elimination but proceeded via isomerization and disproportionation. Therefore, the intramolecular Se···O interaction can be concluded to play a pivotal role in the anti-elimination reaction.

Sense of coherence and personality traits related to depressive state.

Aims. The current study aims to examine the influence of job stress, SOC, and personality traits on depressive state. Methods. A self-reported survey was conducted among 347 female nurses in a general hospital. Job stress was measured using the Japanese version of the Brief-Job Stress Questionnaire scale. Depressive state was assessed by the K6 scale. We used 13-item SOC scale. Personality traits were assessed by the Japanese version of Ten-Item Personality Inventory. Multiple liner regression analyses were conducted to examine predictors that significantly affect depressive state. Results. Job and life satisfaction and SOC negatively related to the depressive state (ß = -0.76, P < 0.01; ß = -0.18, P < 0.001, resp.) while neuroticism was positively correlated (ß = 0.49, P < 0.001). Also, intrinsic rewards tended to negatively relate (ß = -0.80, P < 0.1). Conclusions. From a practical perspective, the possible influence of SOC and neurotic personality on depressive state should be considered for health care professionals.

Relationship between depressive state, job stress, and sense of coherence among female nurses.

BACKGROUND: People with a strong sense of coherence (SOC) have a high ability to cope with stress and maintain good physical and mental health. AIMS: The aim of this study was to investigate the relationship between depressive state, job stress, and SOC among nurses in a Japanese general hospital. MATERIALS AND METHODS: A self-reporting survey was conducted among 348 female nurses in a general hospital. Job stress was measured using the Japanese version of the effort-reward imbalance (ERI) scale. Depressive state was assessed by the K6 scale. SOC was assessed with the SOC scale, which includes 29 items. Stepwise multiple regression analysis was conducted to examine factors that significantly affect depressive state. RESULTS: SOC, over-commitment, effort-esteem ratio, and age were significantly correlated with the depressive state (ß = -0.46, P < 0.001; ß = 0.27, P < 0.001; ß = 0.16, P < 0.001; ß = -0.10, P < 0.001, respectively). CONCLUSIONS: SOC may have a major influence on the depressive state among female nurses in a Japanese general hospital. From a practical perspective, health care professionals should try to enhance the SOC of nurses.