A retrospective study of pulse steroid therapy for acute respiratory failure associated with tuberculosis.

BACKGROUND: Tuberculosis can cause acute respiratory failure, which is associated with a high mortality rate, even in patients receiving effective anti-tuberculosis therapy. We retrospectively analyzed patients with acute respiratory failure associated with tuberculosis who underwent pulse steroid therapy to describe the clinical characteristics and effectiveness of pulse steroid therapy in this condition. METHODS: The medical records of patients admitted to our hospital for culture-proven tuberculosis treatment from April 1, 2017, to March 31, 2022, who received pulse steroid therapy for acute respiratory failure associated with tuberculosis were reviewed. RESULTS: In total, 10 patients were included in this study. Chest computed tomography (CT) revealed diffuse ground-glass opacities and consolidation in these patients. Overall, 70% of the patients (7/10) showed an adjudicated response to pulse steroid therapy, with improved respiratory condition and radiological findings. Three patients died without response to pulse steroid therapy. One patient died of pancreatic cancer after recovering from respiratory failure. The remaining six patients were discharged without supplemental oxygen and completed anti-tuberculosis therapy. CONCLUSIONS: Pulse steroid therapy can lead to dramatic improvements in some patients with acute respiratory failure associated with tuberculosis.

Pre-pandemic social isolation as a predictor of the adverse impact of the pandemic on self-rated health: A longitudinal COVID-19 study in Japan.

Many studies have found adverse effects of the coronavirus disease pandemic on health. Irrespective of being infected by the coronavirus, lockdowns and other measures to restrict mobility have worsened an individual's subjective health assessment. Unlike previous studies, this study examined how pre-pandemic social isolation (in the form of no interaction with others and having no social support) affected the impact of the pandemic on self-rated health in Japan. To this end, we estimated fixed-effects models using 4172 observations of 2086 individuals obtained from a three-wave Internet nationwide survey conducted in January/February 2019 and February 2020 (before the pandemic), in March 2021 (when the pandemic-related state of emergency was effective in four prefectures and just after it was lifted in six prefectures), and in October/November (a full month after the state of emergency was lifted in all prefectures). The state of emergency raised the probability of reporting poor health by 17.8 (95% confidence interval [CI]:1.9-33.8) percentage points among the participants who had not interacted with others before the pandemic, compared with only 0.7 (95% CI: -3.1-4.5) percentage points among other participants. Similar results were obtained in the absence of social support prior to the pandemic. In conclusion, pre-pandemic social isolation was detrimental to health, suggesting that policy measures are needed to avoid social isolation to increase the resilience of public health to external shocks.

How does area-level deprivation depress an individual's self-rated health and life satisfaction? Evidence from a nationwide population-based survey in Japan.

BACKGROUND: Area-level deprivation is well known to have an adverse impact on mortality, morbidity, or other specific health outcomes. This study examined how area-level deprivation may affect self-rated health (SRH) and life satisfaction (LS), an issue that is largely understudied. METHODS: We used individual-level data obtained from a nationwide population-based internet survey conducted between 2019 and 2020, as well as municipality-level data obtained from a Japanese government database (N = 12,461 living in 366 municipalities). We developed multilevel regression models to explain an individual's SRH and LS scores using four alternative measures of municipality-level deprivation, controlling for individual-level deprivation and covariates. We also examined how health behavior and interactions with others mediated the impact of area-level deprivation on SRH and LS. RESULTS: Participants in highly deprived municipalities tended to report poorer SRH and lower LS. For example, when living in municipalities falling in the highest tertile of municipality-level deprivation as measured by the z-scoring method, SRH and LS scores worsened by a standard deviation of 0.05 (p < 0.05) when compared with those living in municipalities falling in the lowest tertile of deprivation. In addition, health behavior mediated between 17.6 and 33.1% of the impact of municipality-level deprivation on SRH and LS, depending on model specifications. CONCLUSION: Results showed that area-level deprivation modestly decreased an individual's general health conditions and subjective well-being, underscoring the need for public health policies to improve area-level socioeconomic conditions.

Carbon Isotope Fractionation during the Formation of CO2 Hydrate and Equilibrium Pressures of 12CO2 and 13CO2 Hydrates.

Knowledge of carbon isotope fractionation is needed in order to discuss the formation and dissociation of naturally occurring CO2 hydrates. We investigated carbon isotope fractionation during CO2 hydrate formation and measured the three-phase equilibria of 12CO2-H2O and 13CO2-H2O systems. From a crystal structure viewpoint, the difference in the Raman spectra of hydrate-bound 12CO2 and 13CO2 was revealed, although their unit cell size was similar. The δ13C of hydrate-bound CO2 was lower than that of the residual CO2 (1.0-1.5‰) in a formation temperature ranging between 226 K and 278 K. The results show that the small difference between equilibrium pressures of ~0.01 MPa in 12CO2 and 13CO2 hydrates causes carbon isotope fractionation of ~1‰. However, the difference between equilibrium pressures in the 12CO2-H2O and 13CO2-H2O systems was smaller than the standard uncertainties of measurement; more accurate pressure measurement is required for quantitative discussion.

The mediating effect of resilience between family functioning and mental well-being in hemodialysis patients in Japan: a cross-sectional design.

BACKGROUND: End-stage kidney disease is highly prevalent worldwide. Currently, one of the most effective treatment modalities is dialysis therapy, which leads to serious side effects. Furthermore, psychiatric illnesses are prevalent among dialysis patients. Recently, researchers asserted that psychological resilience and family support could be helpful to maintain or improve patients' mental well-being. Therefore, the purpose of this study was to examine the mediating effects of resilience on the relationship between family functioning and mental well-being in these patients. METHODS: To investigate the aim of this study, a cross-sectional design was employed. A total of 110 hemodialysis patients, who were receiving outpatient treatment from dialysis units at the University of Fukuoka and St. Maria Health Care Center in Japan, participated. Only the patients who met the criteria and who were willing to participate in this 30-min study were given The General Health Questionnaire-12, Conner-Davidson Resilience Scale, and Family Assessment Device. Structural Equation Modeling (SEM) was performed to test the hypothesis that resilience would mediate the relationship between each subscale of family functioning, namely, cohesion, adaptability, communication, and mental well-being. Then Sobel's test was employed to examine the indirect effect. RESULTS: The results of the SEM showed that the model had an acceptable fit (RMSEA = .077; CFI = .93; and IFI = .94). According to the results, resilience fully mediated the relationship between family functioning, specifically family adaptability and communication, and mental health well-being of the dialysis patients. However, family cohesion was not associated with resilience. CONCLUSIONS: The present study revealed that higher family adaptability and communication resulted in greater resilience, thus associated with better mental health. Given that poor mental health among dialysis patients is significantly associated with a decreased likelihood to adhere to treatment plans, it may lead to a significant risk to therapeutic compliance. As such, patients may experience detrimental consequences, such as death. This study showed that in order to maintain healthy mental well-being, developing resilience is a vital factor for hemodialysis patients.

Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study).

BACKGROUND: Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS: Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS: Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS: Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.

High-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model.

BACKGROUND AND AIMS: Extensive excision of the esophageal mucosa by endoscopic submucosal dissection (ESD) frequently evokes a luminal stricture. This study aimed to determine the efficacy of a high-density collagen patch for the prevention of esophageal stricture in extensive ESD. METHODS: Six pigs underwent circumferential esophageal ESD under general anesthesia. In 3 pigs, artificial ulcers were covered by 2 collagen patches. The other 3 pigs underwent circumferential ESD only. RESULTS: The 2 collagen patches were settled onto the ulcer surface using a general endoscope and instruments. The collagen patch-treated group showed significantly better patency rates on both the oral and anal sides of the wound area compared with the control group at day 14. The mucosal re-epithelization ratio was significantly promoted, and the extent of mucosal inflammation and fibrosis was significantly decreased with the collagen patch treatment in the wound area. The frequency of cells positive α-smooth muscle actin was significantly reduced in the collagen patch-treated group compared with the control group. CONCLUSIONS: We have established a high-density collagen device that can reduce the esophageal stricture associated with extensive ESD. This easy-to-handle device would be useful during superficial esophageal cancer treatment by ESD.

Large-cell neuroendocrine carcinoma of the skin: ultrastructural and immunohistochemical findings.

Large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive neuroendocrine tumor, found mainly in the lung. Although LCNEC has been reported in various organs, LCNEC of the skin is extremely rare, poorly recognized and probably underestimated. Here we report a case of LCNEC of the skin, focusing on the histopathological and ultrastructural findings in detail. The patient was an 85-year-old Japanese woman presented with a mass on her right upper eyelid. Biopsy specimen showed an infiltrative mass with extension into the subcutis. Tumor cells were arranged in organoid and trabecular patterns with sheets, nests and trabecular cords. Extensive necrotic areas were observed. Most of the tumor cells were characterized by large cell size, polygonal shape, low nuclear-cytoplasmic ratio, coarse nuclear chromatin and frequent nucleoli. They were positive for CD56, NSE, AE1/AE3, CK7, and negative for CK20, TTF-1, synaptophysin and chromogranin A. A systematic radiographic examination revealed no additional neoplastic lesions other than the right upper eyelid mass. These findings suggest that the present case is a LCNEC of the skin. The existence of LCNEC in the skin should be recognized, as it is a rare variant of carcinoma that can potentially be misconstrued as a metastasis or as Merkel cell carcinoma.

A Common Mutation of Long QT Syndrome Type 1 in Japan.

BACKGROUND: Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots in KCNQ1 mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients. METHODS AND RESULTS: We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations. In the Japanese cohort, the most common mutation was p. A344spl (c.1032 G>A), comprising a substitution of a guanine for an adenine at the last base of exon 7, and it was found in 17 probands (8.9%). Regarding the clinical characteristics of A344spl carriers, the mean age-of-onset was 10±4 years, >40% were symptomatic, and the mean corrected QT interval was 461±30 ms. The prognosis for carriers of the A344spl mutation (n=31) was intermediate between that for the A341V mutation reported to be associated with severe phenotypes (n=24) and other mutations (n=290). CONCLUSIONS: The A344spl mutation was a frequent LQTS genotype in Japan, which indicates that the influence of country-specific hot spots should be considered when studying LQT1 clinical phenotypes.

[Safe treatment of lung squamous cell carcinoma with nanoparticle albumin-bound Paclitaxel in a patient with a previous hypersensitivity reaction after docetaxel administration].

A 61-year-old man was diagnosed with lung squamous cell carcinoma in the lower lobe of the right lung. He had received first-line chemotherapy consisting of cisplatin and docetaxel (DTX); however, an allergic/hypersensitivity reaction occurred shortly after administration of the second course of DTX. Thirty-nine months later, he received nanoparticle albumin-bound paclitaxel (nab-PTX) as sixth-line chemotherapy, which did not produce a hypersensitivity reaction. Hypersensitivity after DTX administration may have been due to the DTX vehicle. Therefore, nab-PTX administered under close supervision is a valid therapeutic option in similar cases.

Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench.

BACKGROUND: Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. METHODS AND RESULTS: Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na(+) currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function. CONCLUSION: Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.

Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes.

AIMS: CACNA1C mutations have been reported to cause LQTS type 8 (LQT8; Timothy syndrome), which exhibits severe phenotypes, although the frequency of patients with LQT8 exhibiting only QT prolongation is unknown. This study aimed to elucidate the frequency of CACNA1C mutations in patients with long QT syndrome (LQTS), except those with Timothy syndrome and investigate phenotypic variants. METHODS AND RESULTS: CACNA1C gene screening was performed in 278 probands negative for LQTS-related gene mutations. Functional analysis of mutant channels using a whole-cell patch-clamp technique was also performed. Using genetic screening, we identified five novel CACNA1C mutations: P381S, M456I, A582D, R858H, and G1783C in seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay of CACNA1C mutations revealed that the peak calcium currents were significantly larger in R858H mutant channels than those of wild-type (WT). In contrast, A582D mutant channels displayed significantly slower inactivation compared with WT. The two mutant channels exerted different gain-of-function effects on calcium currents. CONCLUSION: In patients with LQTS, the frequency of CACNA1C mutations was higher than reported. Even without typical phenotypes of Timothy syndrome, CACNA1C mutations may cause QT prolongation and/or fatal arrhythmia attacks.

Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction.

AIMS: Ryanodine receptor gene (RYR2) mutations are well known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, RYR2 exon 3 deletion has been identified in patients with dilated cardiomyopathy (DCM) and/or CPVT. This study aimed to screen for the RYR2 exon 3 deletion in CPVT probands, characterize its clinical pathology, and confirm the genomic rearrangement. METHODS AND RESULTS: Our cohort consisted of 24 CPVT probands. Polymerase chain reaction (PCR)-based conventional genetic analysis did not identify any mutations in coding exons of RYR2 in these probands. They were screened using multiplex ligation-dependent probe amplification (MLPA). In probands identified with RYR2 exon 3 deletion, the precise location of the deletion was identified by quantitative PCR and direct sequencing methods. We identified two CPVT probands from unrelated families who harboured a large deletion including exon 3. The probands were 9- and 17-year-old girls. Both probands had a history of syncope related to emotional stress or exercise, exhibited bradycardia, and were diagnosed with left ventricular non-compaction (LVNC). We examined 10 family members and identified six more RYR2 exon 3 deletion carriers. In total, there were eight carriers, of which seven were diagnosed with LVNC (87.5%). Two carriers under the age of 4 years remained asymptomatic, although they were diagnosed with LVNC. Using quantitative PCR and direct sequencing, we confirmed that the deletions were 1.1 and 37.7 kb in length. CONCLUSION: RYR2 exon 3 deletion is frequently associated with LVNC. Therefore, detection of the deletion offers a new modality for predicting the prognosis of patients with LVNC with ventricular/atrial arrhythmias, particularly in children.

A novel HCN4 mutation, G1097W, is associated with atrioventricular block.

BACKGROUND: Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation. METHODS AND RESULTS: Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents. CONCLUSIONS: The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.

Care needs of caregivers of the elderly with early-stage dementia.

Objective: This study aimed to identify the care needs of family caregivers of elderly patients with early-stage dementia and examine support measures. Materials and Methods: We conducted a self-administered questionnaire survey with 115 primary caregivers of outpatients who visited A City Community General Support Center or B University Hospital Department of Neurology for memory loss consultation. The questionnaire content included demographic characteristics, the care needs scale for caregivers of the elderly with early-stage dementia (Care Needs Scale), and the Japanese short version of the Zarit Burden Interview. The Medical Ethics Committee of Fukuoka University approved this study (approval number: M047). Of the 115 participants, 104 were included in the analysis after excluding 11 respondents with missing data. We divided the participants into a young group (under 65 years of age) and an old group (65 years of age or older) and compared the variables and each scale score using the Mann-Whitney U test. We also compared the correlations between the total score and subscale scores of the Care Needs Scale and each variable, in addition, we performed multiple regression analyses using the total score of the Care Needs Scale as the dependent variable. Results: The young caregivers wanted to know how to take care, prevent deterioration, and deal with symptoms of early-stage dementia. They were trying to balance caregiving with work and housekeeping and reduce the stress and burden of long-term care. Older caregivers were confused about caregiving and wanted someone to talk about their situations. Conclusion: Both groups shared that the family's lack of understanding about caregiving and personal and role strains were associated with the care needs of caregivers of the elderly with early-stage dementia.

Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30-40s, the age-dependent clinical and genetic differences remain unknown. METHODS AND RESULTS: A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers. CONCLUSIONS: The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.