Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study).

PURPOSE: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC. PATIENTS AND METHODS: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT. RESULTS: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%. CONCLUSIONS: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.

Repression of latent NF-κB enhancers by PDX1 regulates ß cell functional heterogeneity.

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified ß cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). ß cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in ß cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1ß receptor, an NF-κB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single ß cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy.

Cross-sectional nationwide epidemiologic survey on quality of life and treatment efficacy in Japanese patients with congenital ichthyoses.

BACKGROUND: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate. OBJECTIVE: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments. METHODS: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016-31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants' Dermatitis Quality of Life Index. RESULTS: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS. CONCLUSION: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment.

Impact of Locoregional Therapies for Brain Lesions on Survival in Patients With Non-small Cell Lung Cancer With Multiple Extrathoracic Metastases.

BACKGROUND/AIM: The treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) typically involves surgery, irradiation, and chemotherapy (single or combination therapy). However, the impact of these therapies on the survival of patients with NSCLC with multiple extrathoracic metastases has not yet been determined. Therefore, in the present study, we examined the prognostic effect of multimodal treatment for brain metastases in patients with NSCLC with multiple extrathoracic metastases in the absence of driver mutations. PATIENTS AND METHODS: Patients with NSCLC with multiple extrathoracic metastases (including at least one brain metastasis), who visited Saitama Medical Center, Saitama Medical University from January 1, 2010 to December 31, 2016, were enrolled in this study; follow-up was conducted until December 31, 2021. RESULTS: A total of 56 patients were enrolled, including 12 and 44 patients with single and multiple brain metastases, respectively. The median overall survival (OS) for all patients was 4.9 months, and did not differ significantly between patients with single and multiple brain metastases (3.0 vs. 4.9 months, respectively). The selection of locoregional treatment for brain metastases did not depend on Karnofsky performance status (p=0.0862). Among patients with multiple brain metastases, the OS for those who underwent craniotomy followed by whole brain radiation therapy (WBRT), those who received only WBRT, and those treated without locoregional therapy was 47.7, 3.9, and 15.9 months, respectively (p=0.00382). CONCLUSION: Surgical resection followed by radiation therapy is an effective treatment option for brain metastases in patients with multiple metastases. However, WBRT alone did not improve prognosis.

Community gender norms, mental health, and suicide ideation and attempts among older Japanese adults: a cross-sectional study.

OBJECTIVES: Gender norms embedded in communities may restrict opportunities and harm the mental health of older adults, yet this phenomenon has received little attention. This study investigates the connection between older adults' perceptions of community gender norms and mental health and suicide-related outcomes. DESIGN: Cross-sectional. SETTING: This study analyzed data from the 2019 wave of the Japan Gerontological Evaluation Study. PARTICIPANTS: In total, 25,937 participants aged 65 years or older in 61 municipalities. MEASUREMENTS: Perceptions of community gender norms were assessed by the respondents' perceptions of the gender-differentiating language used by those around them such as "You should/should not do XXX, because you are a man/woman." RESULTS: The prevalence of all mental health outcomes was higher among both men and women who perceived community gender norms as restrictive. These associations remained in fully adjusted multivariable analyses. Prevalence ratios for men were 1.36 [95% confidence interval: 1.13, 1.65] for psychological resistance to obtaining help, 1.85 [1.54, 2.23] for depressive symptoms, 1.99 [1.34, 2.96] for suicidal ideation, and 2.15 [1.21, 3.80] for suicide attempts. The corresponding figures for women were 1.39 [1.17, 1.65], 1.80 [1.55, 2.10], 2.13 [1.65, 2.74], 2.62 [1.78, 3.87]. There was a more pronounced association between perceiving community gender norms as restrictive and depressive symptoms and suicidal behaviors among those with nonconventional gender role attitudes compared to those with conventional attitudes. CONCLUSIONS: Considering the effects of community gender norms, in addition to individual gender role attitudes, may be critical in designing effective public health interventions for improving mental health.

Lifestyle parameters of Japanese agricultural and non-agricultural workers aged 60 years or older and less than 60 years: A cross-sectional observational study.

OBJECTIVES: Improving the lifestyle of occupational workers is essential for extending healthy life expectancy. We investigated various lifestyle-related items in a rural Japanese population and compared them between agricultural and non-agricultural workers. METHODS: This cross-sectional study was conducted as a part of the "Iwaki Health Promotion Project." Lifestyle-related items such as sleep, work hours, nutrition, health-related quality of life, and proportion of time spent performing each daily activity were compared between agricultural and non-agricultural workers in the ≥60 years (n = 251) and <60 years (n = 560) age groups. RESULTS: Agricultural workers had significantly lower Pittsburgh Sleep Quality Index total scores than non-agricultural workers in the <60 years group. The proportion of participants with more than 5 weekly working days was high among agricultural workers in both groups. Additionally, the proportion of people who worked more than 8 h per day was high among agricultural workers in both age groups. Energy intake per day was high among agricultural workers in the <60 years group. In both age groups, agricultural workers slept and woke up approximately 40 min earlier than did non-agricultural workers. CONCLUSIONS: Agricultural workers have better sleep habits but work longer than non-agricultural workers, with some differences in energy intake and proportion of time spent on each daily activity. These differences should be considered when planning lifestyle intervention programs for agricultural workers.

The inter-prefectural regional disparity of healthcare resources and representative surgical procedures in orthopaedics and general surgery: a nationwide study in Japan during 2015-2019.

BACKGROUND: Few reports have examined the localized regional disparity in representative surgical procedures in orthopaedics and general surgery globally. This study aimed to clarify the inter-prefectural regional disparity and relationships between healthcare resources and representative surgical procedures using a nationwide database in Japan. METHODS: The number of medical specialists in orthopaedics, general surgery, and anaesthesiology, as well as the number of hospitals, and the incidence of representative surgical procedures in orthopaedics and general surgery were evaluated annually per 100,000 inhabitants/people by prefecture in Japan during 2015-2019. Medium-sized regional disparities were evaluated using the Gini coefficient. Correlation coefficients were calculated for the defined variables and ageing rate. We also compared the urban and rural regional disparities in all study variables. RESULTS: The annual average number/incidence and Gini coefficients were 110.6 and 0.11 for femur fracture surgery, 106.3 and 0.09 for cholecystectomy, 14.2 and 0.11 for orthopaedic surgeon specialists, 17.6 and 0.09 for general surgeon specialists, 5.9 and 0.13 for anaesthesiology specialists, and 8.1 and 0.21 for hospitals, respectively. The correlation coefficients by the incidence of femur fracture surgery were 0.74 for orthopaedic surgeon specialists (p < 0.001), 0.63 for hospitals (p < 0.001), and 0.62 for the ageing rate (p < 0.001); those by the incidence of cholecystectomy were 0.60 for general surgeon specialists (p < 0.001) and 0.59 for hospitals (p < 0.001). The number/incidence of orthopaedic surgeon specialists, hospitals, femur fracture surgery, and cholecystectomy, as well as the ageing rate, were significantly higher in rural prefectures than in urban prefectures (p < 0.05). CONCLUSIONS: Inter-prefectural regional disparity was small, although certain items were unevenly distributed in the rural prefectures, which is contrary to our expectations. Higher prevalence was recognised in rural prefectures due to the higher ageing rate; however, supply and demand are balanced. This study provides basic data for healthcare policy development in a medium-sized community. LEVEL OF EVIDENCE: III.

Trends and age- and sex-stratified analysis of hallux valgus correction surgery from 2014 to 2019: A nationwide population-based cohort study in Japan.

BACKGROUND: Epidemiological studies on hallux valgus (HV) are challenging owing to differences in sampling and diagnostic criteria across studies. This study aimed to indirectly clarify HV epidemiology using a national database. METHODS: The age- and sex-stratified annual number rate of HV correction (RHVC) per 100,000 people in Japan during 2014-2019 were examined. RESULTS: The average annual RHVC was 3.0. RHVC had unimodal (peak, 65-79 years) and bimodal (peaks, 15-19 and 70-74 years) distributions among males and females, respectively, and increased over time in males aged 50-54 and 75-79 years and females aged 80-84 years. CONCLUSIONS: RHVC increases with increasing age and occurs commonly in female teens. The recent RHVC in Japan was lower than that reported in Europe and the United States, with an increasing trend among elderly people. LEVEL OF EVIDENCE: III.

Antenatal corticosteroids and outcomes of small for gestational age infants born at 24-31 gestational weeks: a population-based propensity score matching analysis.

PURPOSE: To evaluate the effect of antenatal corticosteroid (ACS) treatment on neonatal outcomes in small for gestational age (SGA) infants born at 24-31 gestational weeks compared with non-SGA infants. METHODS: A population-based retrospective study was conducted that analyzed clinical data from the Neonatal Research Network of Japan database, which enrolls neonates born at < 32 gestational weeks and weighing 1500 g or less (n = 22,414). Propensity score matching (with the ratio of ACS to no-ACS groups of 1:1) was performed in SGA (n = 7028) and non-SGA (n = 15,386) infants, respectively. Univariate logistic and interaction analyses were performed to compare the short-term neonatal outcomes of infants with and without ACS treatment in utero. RESULTS: In the SGA and non-SGA infants, ACS treatment significantly reduced in-hospital mortality (odds ratio 0.67 95% confidence interval [0.50-0.88] and 0.62 [0.50-0.78], respectively), respiratory distress syndrome (0.77 [0.69-0.87] and 0.63 [0.58-0.68], respectively), and composite adverse outcomes (0.73 [0.58-0.91] and 0.57 [0.50-0.65], respectively). ACS treatment also significantly reduced intraventricular hemorrhage (grade III/IV), periventricular leukomalacia, and sepsis in the non-SGA infants, but not in the SGA infants. However, interaction analyses revealed no significant differences between the SGA and non-SGA infants in the efficacy of ACS treatment on short-term outcomes except for respiratory distress syndrome. CONCLUSIONS: ACS treatment was associated with beneficial effects on mortality, respiratory distress syndrome, and adverse composite outcomes in extremely and very preterm SGA infants, with similar efficacy on all neonatal outcomes except for respiratory distress syndrome observed in the non-SGA infants.

Time-restricted feeding mitigates obesity through adipocyte thermogenesis.

Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.

A novel behavioral science-based health checkup program and subsequent metabolic risk reductions in a workplace: Checkup championship.

The effectiveness of general health checkups and lifestyle counseling has been questioned. This study examined whether a workplace health promotion program implemented during a health checkup was associated with metabolic syndrome-related indicators. Hakuhodo DY group, one of Japan's largest advertising agencies, implemented a behavioral science-based program called "Checkup Championship" (Kenshin-sen in Japanese) in 2019, in which all employees could voluntarily participate. We studied 3697 employees (2818 men and 879 women, mean age: 40.7 years), consisting of 1509 program participants and 2188 non-participants. The characteristics of participants and non-participants were balanced using inverse probability weighting. We used their data from the health checkups in 2018 and 2019 together with other covariates and performed a difference-in-differences analysis using a linear mixed model. After program implementation, greater reductions were observed among participants compared with non-participants in weight (-0.66 kg, 95% confidence interval: -0.84 to -0.47), body mass index (-0.23 kg/m2, -0.29 to -0.16), waist circumference (-0.67 cm, -0.91 to -0.43), systolic blood pressure (-1.13 mmHg, -2.10 to -0.16), and diastolic blood pressure (-0.84 mmHg, -1.53 to -0.15). In addition, we observed greater reductions in weight, body mass index, waist circumference, and low-density lipoprotein cholesterol among participants who were with two or more risk factors for metabolic syndrome than other participants. We found that participation in a health checkup program based on behavioral science was associated with reduced metabolic syndrome-related indicators. There may be room for improvement in the effectiveness of general health checkups.

Impact of hypertensive disorders of pregnancy on respiratory outcomes in extremely and very preterm infants: A population-based study in Japan.

OBJECTIVES: We aimed to evaluate the impact of hypertensive disorders of pregnancy (HDP) on short- and medium-term respiratory outcomes in extremely and very preterm infants using the Neonatal Research Network of Japan database. STUDY DESIGN: This was a population-based retrospective study of preterm infants weighing ≤ 1500 g born between 22 and 31 weeks of gestation between 2003 and 2017. After 1:1 stratification matching by four factors (maternal age, gestational age, parity, and year of delivery), a total of 5137 infants in each group (HDP and non-HDP groups) were selected. MAIN OUTCOME MEASURES: The association between HDP and various respiratory outcomes was evaluated using univariate and multivariate logistic regression analyses. RESULTS: In the multivariate analyses, HDP was associated with higher odds for respiratory distress syndrome (RDS) (odds ratio 1.83, 95% confidence interval [1.65-2.03]), but reduced odds of persistent pulmonary hypertension of the newborn (PPHN) (0.34 [0.26-0.46]) and inhaled nitric oxide use (0.43 [0.33-0.55]). Although HDP was associated with an increased risk of chronic lung disease (CLD) in the univariate analysis, this association was not significant after adjustment for covariates (0.94 [0.83-1.07]). No significant association was found between HDP and home oxygen therapy (HOT) and medium-term oxygen use. CONCLUSION: The impact of maternal HDP largely differed depending on respiratory disorders and respiratory support. HDP was associated with higher odds of RDS but reduced odds of PPHN. The risks for CLD, HOT, and medium-term respiratory outcomes in the HDP group were comparable to those in the non-HDP group.

Intrauterine exposure to hypertensive disorders of pregnancy and postnatal growth in extremely and very preterm infants.

OBJECTIVES: There is growing evidence regarding the association between rapid growth during infancy and metabolic and cardiovascular diseases later in life. We aimed to evaluate postnatal growth trajectories in extremely and very preterm infants exposed to hypertensive disorders of pregnancy (HDP) in utero. STUDY DESIGN: This multicenter retrospective study used a nationwide database of preterm infants weighing ≤1,500 g born between 22 and 31 weeks of gestation between 2003 and 2015. MAIN OUTCOME MEASURES: The Z-scores for height and weight were evaluated at three time points (at birth, corrected age of 1.5 years, and chronological age of 3 years) in 5,144 infants (HDP, n = 1,188; non-HDP, n = 3,956). Univariate and multivariate regression analyses were performed to investigate the associations between HDP exposure and accelerated postnatal growth. RESULTS: Male and female infants in the HDP group showed increased mean Z-scores for height and weight, whereas those in the non-HDP group showed decreased mean Z-scores. Multivariate analyses showed that HDP were associated with accelerated postnatal growth (Δ Z-scores) in weight in both male and female infants (ß coefficient [95% CI]; male 0.17 [0.05-0.30], female 0.27 [0.14-0.39]), but not in height (male 0.02 [-0.09 to 0.13], female 0.04 [-0.06 to 0.15]). An interaction analysis revealed no significant differences in the effects of HDP on postnatal growth between male and female infants. CONCLUSIONS: Intrauterine exposure to HDP contributes to accelerated postnatal weight growth in extremely and very preterm infants during early childhood. In addition, no sex differences were observed in postnatal growth.

P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian ß-cell failure.

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian ß-cell failure. Our approach was to generate ß-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant ß-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.

Circadian rhythms ­ 'inbuilt' 24-hour cycles ­ control many aspects of behaviour and physiology. In mammals, they operate in nearly all tissues, including those involved in glucose metabolism. Recent studies have shown that mice with faulty genes involved in circadian rhythms, the core clock genes, can develop diabetes. Diabetes arises when the body struggles to regulate blood sugar levels. In healthy individuals, the hormone insulin produced by beta cells in the pancreas regulates the amount of sugar in the blood. But when beta cells are faulty and do not generate sufficient insulin levels, or when insulin lacks the ability to stimulate cells to take up glucose, diabetes can develop. Marcheva, Weidemann, Taguchi et al. wanted to find out if diabetes caused by impaired clock genes could be treated by targeting pathways regulating the secretion of insulin. To do so, they tested over 2,500 potential drugs on genetically modified beta cells with faulty core clock genes. They further screened the drugs on mice with the same defect in their beta cells. Marcheva et al. identified one potential compound, the anti-parasite drug ivermectin, which was able to restore the secretion of insulin. When ivermectin was applied to both healthy mice and mice with faulty beta cells, the drug improved the control over glucose levels by activating a specific protein receptor that senses molecules important for storing and utilizing energy. The findings reveal new drug targets for treating forms of diabetes associated with deregulation of the pancreatic circadian clock. The drug screening strategy used in the study may also be applied to reveal mechanisms underlying other conditions associated with disrupted circadian clocks, including sleep loss and jetlag.

Influence of background characteristics in responders of regenerative therapy by periurethral injection of adipose-derived regenerative cells for male stress urinary incontinence.

OBJECTIVES: To determine if the male responders with post-prostatectomy incontinence in the ADRESU study, which is a clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells, are influenced by any background characteristics. METHODS: Briefly, autologous adipose-derived regenerative cells isolated from abdominal adipose tissue and a mixture of adipose-derived regenerative cells with fat tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Sixteen out of 43 patients (37.2%) responded to treatment (responders) and exhibited improvement in the urine leakage volume, defined as >50% reduction from baseline determined by the 24-hour pad test at 52 weeks of treatment (or last visit within 52 weeks). Background data such as age, body weight, method of prostatectomy, baseline frequency of leaks, number of leaks, number of pad changes, International Consultation on Incontinence Questionnaire-Short Form, King's Health Questionnaire, urodynamic urethral function including functional profile length and maximum urethral closure pressure, and abdominal leak point pressure were collected and compared between responders and nonresponders. RESULTS: None of the background factors influenced improvement in the responders as compared with the nonresponders. However, a significant between-group difference in the rates of decrease in urine leakage volume was noted in patients of younger age (<70 years), compared with those of older age (≥70 years) from 2 to 26 weeks of treatment. CONCLUSION: A greater decrease in urine leakage volume was noted in the younger patient group than in the older patient group.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding.

In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

Initial rapidity of tumor growth as a prognostic factor for the therapeutic effect of immune-checkpoint inhibitors in patients with non-small cell lung cancer: evaluation for linear and non-linear correlation.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs. METHODS: This study is a single-institution retrospective study in Japan. NSCLC patients treated with nivolumab, pembrolizumab, or atezolizumab at Saitama Medical Center from January 1, 2016 to December 31, 2018 were enrolled, and followed until December 31, 2020. We defined and calculated the initial rapidity of tumor progression (IRP) as: the increase in the sum of the diameters of intrathoracic tumors and lymph nodes on two series of chest computed tomography (CT) scans (one obtained at an initial checkup and the other obtained immediately before the first treatment) divided by the number of days between these CT scans. Two coefficients were calculated: the maximal information coefficient (MIC) between IRP and time to treatment failure (TTF) using the Python package with minepy library, and the Spearman's rank correlation coefficient. RESULTS: A total of 55 patients (median age, 70 years; 47 men) were enrolled. The median TTF with ICIs was 126 days, and four patients continued to receive ICI treatment at the end of the follow-up. The MIC between IRP and TTF was 0.302 with weak correlation, and the Spearman's rank correlation coefficient was -0.347 (P=0.00938). CONCLUSIONS: The initial tumor growth rate had a negative linear correlation with the therapeutic effect of ICIs.