Stage III Chorioamnionitis is Associated with Reduced Risk of Severe Retinopathy of Prematurity.

OBJECTIVE: To identify whether histologically confirmed chorioamnionitis (hCAM) is associated with development of retinopathy of prematurity (ROP). STUDY DESIGN: We retrospectively analyzed 2 different cohorts. Cohort 1 was the national database of newborns in Japan born at ≤1500g or <32 weeks' gestation (January 2003 through April 2021, n = 38 013). Cohort 2 was babies born at <1500g from a single institution in Tsuchiura, Japan, (April 2015 through March 2018, n = 118). RESULTS: For Cohort1, after adjusting for potential confounders, stage III CAM (n = 5554) was associated with lower odds of severe ROP (stage ≥3 or required peripheral retinal ablation) by 14% (OR: 0.86; 95% CI: 0.78-0.94]. CAM of stage I (n = 3277) and II (n = 4319) was not associated with the risk of ROP. For Cohort 2, the odds of severe ROP were significantly reduced in moderate to severe hCAM groups (stage II, OR: 0.06, 95% CI: 0.05-0.82; stage III, OR: 0.10, 95% CI: 0.01-0.84). Neonates with funisitis, comorbidity of hCAM, and a finding of fetal inflammatory response had lower odds of severe ROP (OR: 0.11; 95% CI: 0.01-0.93). CONCLUSIONS: After adjusting for confounders, severe hCAM with fetal inflammatory response was associated with reduced risk of ROP.

Mixed-methods study of medical students' attitudes toward peer physical examinations in Japan.

BACKGROUND: Most Japanese medical schools likely continue to rely on peer physical examination (PPE) as a tool to for teaching physical examination skills to students. However, the attitudes of medical students in Japan toward PPEs have not be identified. Therefore, we evaluated students' attitudes toward PPE in a Japanese medical school as a preparation for developing a PPE policy tailored to the context of Japanese culture. METHODS: We conducted a mixed-methods study with an explanatory sequential approach, in which qualitative data were used to interpret the quantitative findings. Surveys and interviews were conducted with medical students and junior residents at a Japanese university. A total of 63 medical students and 50 junior residents responded to the questionnaire. We interviewed 16 participants to reach theoretical saturation and investigated the attitudes of medical students toward PPE and the themes emerging from the interview data, providing detailed descriptions of the quantitative findings. RESULTS: Female participants were significantly more likely than male participants to report varying degrees of resistance to being a model patient during PPE (male: 59.7%, female: 87%, p < 0.001). Most of the participants who took on the role of patients that involved undressing were males. The participants expected improvements in issues related to the guarantee of freedom to refuse to be a model patient and measures to protect confidentiality. Approximately 22% of the participants reported that they witnessed incidental findings (including variations within the normal range) in front of other students during PPE. CONCLUSIONS: The findings imply that medical students expect high levels of autonomy and confidentiality when volunteering as model patients during PPE. Thus, developing a PPE policy suitable for Japanese culture may be effective in establishing a student-centered PPE environment.

Association between Grit and depressive symptoms at the timing of job start among medical residents during the COVID-19 pandemic in Japan: a cross-sectional study.

INTRODUCTION: The COVID-19 pandemic had an additional negative impact on the mental health of healthcare workers, including residents. Previous studies revealed that grit, which is an individual trait to achieve long-term goals unrelated to intelligence quotient, is not only positively associated with academic achievement and career success but also negatively correlated with depression. This study aimed to examine the association between grit and depressive symptoms among residents at the time of job start during the coronavirus disease 2019 (COVID-19) pandemic in Japan. MATERIALS AND METHODS: This cross-sectional study used data from all post-graduate year 1 residents from March 2020 to April 2022 at Tokyo Medical and Dental University, Tokyo, Japan. Grit was measured by the Japanese version of Grit-S. The resident's depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. The association of interest was examined using logistic regression analysis. RESULTS: Among 221 residents, 28 (12.7%) have depressive symptoms. One unit increase in Grit-S score after adjusting for age, sex, graduated university, and sleeping hours was associated with lower odds of having depressive symptoms by 63% (odds ratio [OR]: 0.37; 95% confidence interval [CI]: 0.19-0.74). Further, the perseverance of effort subscale score was associated with lower odds of having depressive symptoms after covariate adjustment (OR: 0.43; 95% CI: 0.22-0.84). CONCLUSIONS: Higher grit scores were associated with lower odds of having depressive symptoms among residents at the timing of job start during the COVID-19 pandemic. Regular mental health assessment is particularly important for residents with low grit scores at entry.

Elucidation of the needs for telecritical care services in Japan: a qualitative study.

OBJECTIVE: To clarify the reasons for consultation, advice sought by frontline physicians and relationship between the patient's pathology and the type of advice provided to guide the future development of telecritical care services. DESIGN: Secondary analysis of transcripts of telephone calls originally recorded for quality control purposes was conducted using a thematic content analysis. The calls were conducted between December 2019 and April 2021 (total cases: 70; total time: ~15 hour). SETTINGS: Intensivists provided consultation services to frontline physicians at secondary care institutions in the Kansai and Chubu regions. PARTICIPANTS: Non-intensive care frontline physicians working in five secondary care institutions in the Kansai and Chubu regions and intensivists providing a consultation service (n=26). INTERVENTIONS: Not applicable. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome was the themes emerging from the language used during telephone and video consultations, indicating the gap filled by the telecritical care service. FINDINGS: We analysed 70 cases and approximately 15 hours of anonymised audio data. We identified the following reasons for consultation: 'lack of competence in treatment and diagnostic testing' and 'lack of access to consultation in their own hospital'. Frontline physicians most often sought advice related to 'treatment', followed by 'patient triage and transfer', 'diagnosis' and 'diagnostic testing and evaluation'. Regarding the relationship between the patient's pathology and type of advice provided, the most commonly sought advice by frontline physicians varied based on the patient's pathology. CONCLUSION: This study explored the characteristics of 70 telecritical sessions and identified the reasons for and nature of the consultations. These findings can be used to guide the future provision and scale up of telecritical services.

A novel variant of NR5A1, p.R350W implicates potential interactions with unknown co-factors or ligands.

Introduction: NR5A1 and NR5A2 belong to an orphan nuclear receptor group, and approximately 60% of their amino acid sequences are conserved. Transcriptional regulation of NR5A receptors depends on interactions with co-factors or unidentified ligands. Purpose and methods: We employed in vitro and in silico analysis for elucidating the pathophysiology of a novel variant in the ligand-binding domain of NR5A1, p.R350W which was identified from a 46,XY patient with atypical genitalia. Results: In the study, [1] reporter assays demonstrated that R350 is essential for NR5A1; [2] 3D model analysis predicted that R350 interacted with endogenous ligands or unknown cofactors rather than stabilizing the structure; [3] R350 is not conserved in NR5A2 but is specifically required for NR5A1; and [4] none of the 22 known missense variants of the ligand binding domain satisfied all the previous conditions [1]-[3], suggesting the unique role of R350 in NR5A1. Conclusion: Our data suggest that NR5A1 has unidentified endogenous ligands or co-activators that selectively potentiate the transcriptional function of NR5A1 in vivo.

Facilitators and barriers to physicians' entrepreneurial ventures in major Japanese cities: A qualitative study.

BACKGROUND: The Japanese healthcare system currently faces numerous challenges, including a super-aging society and an excessive burden on medical workers; therefore, the need for innovative solutions from healthcare ventures to tackle these issues has increased. Meanwhile, as physicians play important roles in healthcare ventures, the need for Japanese physician entrepreneurs is more important than ever. Given the lack of research examining barriers to physicians starting ventures and what skills, knowledge, and surrounding environments act as facilitators, this study aimed to identify the facilitators and barriers faced by physicians to start ventures. METHODS: Between September and November 2019 and in May 2021, qualitative interviews were conducted with 33 participants, which included eight physician entrepreneurs; two administrative officers at the Ministry of Health, Labour and Welfare and the Ministry of Economy, Trade and Industry; three faculty members at Tokyo Medical and Dental University (in-depth interviews); and 20 medical students (focus group discussions). The interviews were deductively coded based on the social ecological model. The inductive approach was applied to coding any knowledge necessary to start a business. We conducted member checking with three physician entrepreneurs and seven medical students to improve our results' credibility. RESULTS: The factors influencing a physician's decision to launch a new business include their willingness to contribute to society, the unique environment in which an individual is placed while in medical school and afterward, negative aspects of the lack of diversity in physicians' careers, the financial stability provided by a medical license, and self-efficacy. CONCLUSIONS: Our study revealed facilitators and barriers to physicians' entrepreneurial ventures. Knowledge about these factors might be useful in supporting physicians to launch or become involved in healthcare ventures.

Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: A case report.

BACKGROUND: Spinocerebellar ataxia type 5 (SCA5), a dominant spinocerebellar ataxia is caused by spectrin beta nonerythrocytic 2 gene (SPTBN2) mutation. It typically consists of a slow progressive cerebellar ataxia with an onset principally in adulthood. Here, we report on the first Japanese patient with infantile-onset SCA5 associated with a novel heterozygous SPTBN2 mutation. CASE REPORT: The patient, a 6-year-old girl, developed delayed motor development and unsteady arm movement during infancy. She also showed gaze-evoked nystagmus, saccadic eye pursuit, dysarthria, dysmetria, intention tremor and mild intellectual disability. Brain MRI revealed moderate cerebellar atrophy and mild pontine atrophy. Comprehensive target capture sequencing to identify the causative gene identified a novel missense mutation in SPTBN2 (c.1309C

Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders.

OBJECTIVES: Defects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as "DNA-repair defects" or "DNA damage deficiency", characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis. METHODS: A nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted. RESULTS: Sixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%. CONCLUSION: Comprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects.

Long-Term Evaluation of Low-Dose Betamethasone for Ataxia Telangiectasia.

BACKGROUND: Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. METHODS: Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. RESULTS: Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. CONCLUSIONS: Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency.

We report the case of an 18-year-old man with a phosphoglycerate kinase (PGK) deficiency who had slowly progressive leukodystrophy during adolescence. The patient had a history of severe neonatal jaundice, hemolytic crisis with rhabdomyolysis triggered by febrile viral infections, dysarthria, and intellectual disability during early childhood. Clumsiness in walking and writing became obvious at ∼10years of age. Evaluations performed by us on the 18-year-old patient confirmed the presence of pyramidal tract signs, increased muscle tone, and generalized dystonia. Brain magnetic resonance (MR) imaging revealed leukodystrophy in the periventricular white matter, posterior limbs of the internal capsule, dorsal pons, and middle cerebellar peduncles. Compared to MR images acquired at 9years of age, MR images acquired at 18years of age showed that the white matter atrophy had progressed. The PGK deficiency was diagnosed by identifying a known missense mutation in PGK1 (c.1060G>C) through comprehensive target capture sequencing and by observing low PGK activity in his red blood cells. The patient underwent a ketogenic diet for 2weeks, which we expected would increase adenosine triphosphate levels through sources other than the PGK-associated glycolytic pathway. The diet was not tolerated owing to the unexpected emergence of hemolysis. Hemolytic anemia, neurological dysfunction, and myopathy are often associated with PGK deficiencies. However, leukodystrophy as a symptom of PGK deficiency has not been reported previously. Our case highlights the progressive nature of the neurological complications related to PGK deficiencies. Therefore, long-term follow-up is recommended, even if neurological impairments are not obvious during childhood.

Targeting the enhanced ER stress response in Marinesco-Sjögren syndrome.

BACKGROUND AND OBJECTIVE: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells. METHODS: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined. RESULTS: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis. CONCLUSION: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies.

A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin.

Major facilitator superfamily domain containing 2a (Mfsd2a) is a member of the major facilitator superfamily. Mfsd2a functions as a transporter for docosahexaenoic acid and also plays a role in the unfolded protein response (UPR) upon tunicamycin (TM) exposure. UPR is involved in the pathogenesis of various human diseases. TM and thapsigargin are representative experimental reagents that induce UPR. To elucidate the detailed function of Mfsd2a in UPR in vivo, we generated Mfsd2a-deficient mice and investigated the role of Mfsd2a during UPR induced by TM or thapsigargin. Phenotypically, Mfsd2a-deficient mice were small and short-lived. No gross anatomical abnormalities in Mfsd2a-deficient mice compared with the wild-type mice were exhibited. Embryonic fibroblasts derived from Mfsd2a-null mice failed to show induction of GRP78 and DDIT3 expressions upon TM exposure but not upon Tg exposure. This phenomenon could not be overcome despite the exposure under high TM concentration. Reconstitution of Mfsd2a in Mfsd2a-null MEF showed hypersensitivity to TM. Furthermore, we examined the physiological role of Mfsd2a against TM using an in vivo mouse model. DDIT3 induction by TM was drastically attenuated in both the liver and brain of Mfsd2a-deficient mice. These results reveal that Mfsd2a plays a critical role in UPR upon TM exposure.

Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy.

PURPOSE: The pathomechanism and treatment of PCDH19 female epilepsy (PCDH19-FE) remain unclear. Here, we report that corticosteroids are effective for control of the seizure clusters or other acute symptoms of PCDH19-FE and argue for the possible involvement of a compromised blood-brain barrier (BBB) in its pathogenesis. METHODS: The efficacy of corticosteroids was retrospectively reviewed in five Japanese patients with PCDH19-FE. The results of antibody assays against the N-methyl-d-aspartate-type glutamate receptor (abs-NR) in serum/cerebrospinal fluid were also compiled. RESULTS: Corticosteroid treatments significantly improved the acute symptoms, including seizure clusters, in all cases, most often immediately after the initial administration. However, the effect was transient, and some seizures recurred within a few weeks, especially in association with fever. Serum and/or cerebrospinal fluid abs-NR were detected in all patients. Target sequences of the detected antibodies were multiple, and the titers tended to decrease over time. In one patient, immunohistochemical analysis using rat hippocampal slices also revealed serum antibodies targeting an unknown epitope in neuronal cytoplasm. CONCLUSION: Our findings imply an involvement of inflammatory processes in the pathogenesis of PCDH19-FE and therapeutic utility for corticosteroids as an adjunctive option in acute treatment. PCDH19 is well expressed in brain microvascular endothelial cells and thus its impairment may cause BBB vulnerability, which may be ameliorated by corticosteroids. The abs-NR detected in our patients may not indicate an autoimmune pathomechanism, but may rather represent non-specific sensitization to degraded neuronal components entering the general circulation, the latter process facilitated by the BBB vulnerability.