Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

Designing Molecularly Imprinted Polymer-Modified Boron-Doped Diamond Electrodes for Highly Selective Electrochemical Drug Sensors.

Drug detection in biological solutions is essential in studying the pharmacokinetics of the body. Electrochemical detection is an accurate and rapid method, but measuring multiple drugs that react at similar potentials is challenging. Herein, we developed an electrochemical sensor using a boron-doped diamond (BDD) electrode modified with a molecularly imprinted polymer (MIP) to provide specificity in drug sensing. The MIP is a polymer material designed to recognize and capture template molecules, enabling the selective detection of target molecules. In this study, we selected the anticancer drug doxorubicin (DOX) as the template molecule. In the electrochemical measurements using an unmodified BDD, the DOX reduction was observed at approximately -0.5 V (vs Ag/AgCl). Other drugs, i.e., mitomycin C or clonazepam (CZP), also underwent a reduction reaction at a similar potential to that of DOX, when using the unmodified BDD, which rendered the accurate quantification of DOX in a mixture challenging. Similar measurements conducted in PBS using the MIP-BDD only resulted in a DOX reduction current, with no reduction reaction observed in the presence of mitomycin C and CZP. These results suggest that the MIP, whose template molecule is DOX, inhibits the reduction of other drugs on the electrode surface. Selective DOX measurement using the MIP-BDD was also possible in human plasma, and the respective limits of detection of DOX in PBS and human plasma were 32.10 and 16.61 nM. The MIP-BDD was durable for use in six repeated measurements, and MIP-BDD may be applicable as an electrochemical sensor for application in therapeutic drug monitoring.

Real-World Discontinuation and Switching Patterns for Interleukin-Inhibitor Treatments in Patients with Moderate-to-Severe Psoriasis in Japan.

INTRODUCTION: Patients with moderate-to-severe psoriasis (PsO) treated with interleukin (IL)-inhibitors may require treatment modification to achieve disease control. This study evaluated discontinuation and switching of IL-inhibitors for PsO patients in Japan. METHODS: Japan Medical Data Center claims (1/2005-5/2022) were used to identify patients with PsO diagnosis preceding a first IL-inhibitor claim (index date) with ≥ 6 months of eligibility prior. Treatment switch (claim for another biologic) and discontinuation (gap in care ≥ 150% of the days' supply of the preceding prescription) were assessed up to 24 months following initiation. Censored Kaplan-Meier time-to-event analyses calculated rates, and Cox proportional hazards models estimated hazard ratios (HRs) adjusting for baseline characteristics. RESULTS: The study included 1481 unique patients treated with brodalumab (BRO; n = 159), guselkumab (GUS; n = 360), ixekizumab (IXE; n = 279), risankizumab (RIS; n = 327), secukinumab (SEC; n = 366), tildrakizumab (n = 40; excluded due to limited data), and ustekinumab (UST; n = 262). At 12/24 months, 25.9%/38.6% of patients overall had discontinued their index IL-inhibitor and 13.5%/21.2% had switched to another biologic. Discontinuation at 12/24 months was lowest for RIS (11.2%/17.4%), followed by UST (17.9%/32.2%), IXE (27.0%/37.0%), GUS (29.8%/43.0%), SEC (35.6%/53.8%), and BRO (37.2%/47.2%). Switching showed a similar trend: RIS (5.7%/10.7%), UST (11.2%/19.9%), SEC (14.7%/25.7%), IXE (14.8%/21.5%), GUS (16.9%/23.2%), and BRO (19.7%/26.8%). HRs of discontinuation relative to RIS were 2.07 for UST, 2.59 for IXE, 2.70 for GUS, 3.65 for BRO, and 3.69 for SEC (all P ≤ 0.001). HRs of switching relative to RIS were 2.05 for IXE, 2.45 for GUS, 2.67 for SEC, 2.73 for UST, and 2.77 for BRO (all P ≤ 0.01). CONCLUSION: Treatment modification of IL-inhibitors for PsO was commonly observed and could indicate insufficient disease control and/or incremental economic burden. Discontinuation and switching rates were lowest for RIS regardless of time point and adjustment for patient characteristics.

Discovery of diphenyl ether-degrading Streptomyces strains by direct screening based on ether bond-cleaving activity.

Diphenyl ethers (DEs), which are widely used in the agricultural and chemical industries, have become hazardous contaminants in the environment. Although several DE-degrading bacteria have been reported, discovering new types of such microorganisms could enhance understanding of the degradation mechanism in the environment. In this study, we used a direct screening method based on detection of ether bond-cleaving activity to screen for microorganisms that degrade 4,4'-dihydroxydiphenyl ether (DHDE) as a model DE. Microorganisms isolated from soil samples were incubated with DHDE, and strains producing hydroquinone via ether bond cleavage were selected using hydroquinone-sensitive Rhodanine reagent. This screening procedure resulted in the isolation of 3 bacteria and 2 fungi that transform DHDE. Interestingly, all of the isolated bacteria belonged to one genus, Streptomyces. To our knowledge, these are the first microorganisms of the genus Streptomyces shown to degrade a DE. Streptomyces sp. TUS-ST3 exhibited high and stable DHDE-degrading activity. HPLC, LC-MS, and GC-MS analyses revealed that strain TUS-ST3 converts DHDE to its hydroxylated analogue and generates hydroquinone as an ether bond-cleavage product. Strain TUS-ST3 also transformed DEs other than DHDE. In addition, glucose-grown TUS-ST3 cells began to transform DHDE after incubation with this compound for 12 h, and produced 75 µM hydroquinone in 72 h. These activities of streptomycetes may play an important role in DE degradation in the environment. We also report the whole genome sequence of strain TUS-ST3.

Trends in socioeconomic inequalities in cervical, breast, and colorectal cancer screening participation among women in Japan, 2010-2019.

BACKGROUND: It is known that socioeconomic status (SES) influences the outcome of cancer treatment and this could partly be explained by decreased use of cancer screening services by people of lower SES. Many studies have indicated that low SES, including low educational attainment or unstable employment, was related to nonparticipation in cancer screening. However, studies investigating trends in SES inequalities within cancer screening participation are limited. Our objective was to examine trends in SES inequalities in cervical, breast, and colorectal cancer screening participation among women in Japan between 2010 and 2019. METHODS: We analyzed 189,442, 168,571, 163,341, and 150,828 women in 2010, 2013, 2016, and 2019 respectively, using nationally representative cross-sectional surveys. The main outcome variables are participation in each cancer screening. We used educational attainment and employment status as measures for SES. Multivariable logistic regression analysis, adjusted for age, marital status, educational attainment, and employment status was performed to evaluate the associations between SES and nonparticipation in each cancer screening. RESULTS: Overall participation rates in each cancer screening increased between 2010 and 2019. Low educational attainment and non-permanent employment status were related to nonparticipation in each cancer screening and inequality according to employment status increased within each screening participation during the study period. For example, dispatched workers were more likely to not participate in cervical cancer screening than permanent workers: in 2010, [aOR 1.11 95 %CI: 1.01 -1.21], and in 2019, [aOR 1.46 95 %CI: 1.34-1.60]. The inequality was greatest in colorectal cancer screening nonparticipation, followed by breast and cervical screening. CONCLUSIONS: Although the participation rates in each cancer screening have increased, inequality in participation in terms of employment status widened among women in Japan between 2010 and 2019. Reducing inequalities in cancer screening participation is essential for cancer screening intervention policies.

Individual experiences and issues in predictive genetic testing for untreatable hereditary neuromuscular diseases in Japan.

Predictive genetic testing (PT) for hereditary diseases that do not have effective treatment or prevention strategies places a psychological burden on parties and their families. There has been little research on the psychosocial aspects of PT in Japan, nor are there any guidelines. To address this gap, we conducted a questionnaire survey of parties at genetic risk for untreatable hereditary neuromuscular diseases, and the National Liaison Conference of Genetic Medicine Departments (GMDs). Of the 63 parties who responded to the survey, 10 (15.9%) had undergone PT. Of the 67 GMDs, only 18 facilities (26.9%) were conducting PT with written procedures. At least two of the six parties with such results felt that some follow-up would be helpful. One party had taken PT for preimplantation genetic testing for monogenic (PGT-M); four, who had no experience, provided free text responses indicating that PGT-M or prenatal genetic testing was chosen as a motivation. Eight were unaware of PT, and six were unaware of their blood relatives' diseases being "hereditary." The results highlighted the need to: 1) develop guidelines for PT in untreatable hereditary diseases; 2) provide access to PT information; and 3) share the "heritability" of diseases with family and relatives.

Impact of stage 1 hypertension in the first and second trimesters on adverse pregnancy outcomes: The Japan Environment and Children's study (JECS).

OBJECTIVES: To investigate the association between stage 1 hypertension, defined as systolic blood pressure (BP) of 130-139 mmHg or diastolic BP of 80-89 mmHg, in the first and second trimesters and the risk of adverse pregnancy outcomes. STUDY DESIGN: We analyzed 79,249 singleton pregnancies from a nationwide birth cohort study. BP in the first and second trimesters was classified into normal, elevated, stage1 hypertension, and stage 2 hypertension. We examined the risk of adverse pregnancy outcomes in each group using multivariable logistic regression analysis. We also investigated the influence of BP changes between the first and second trimesters on adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Overall preterm birth (PTB < 37 weeks), early PTB (<34 weeks), and small for gestational age (SGA). RESULTS: Stage 1 hypertension in the first trimester was associated with increased risks of overall PTB (aOR, 1.23; 95 %CI, 1.08-1.39), early PTB (aOR, 1.38; 95 %CI, 1.07-1.79), and SGA (aOR, 1.19; 95 %CI, 1.04-1.36) compared to normal BP. These risks were more evident in the second trimester; overall PTB (aOR, 1.87; 95 %CI, 1.64-2.14), early PTB (aOR, 2.21; 95 %CI, 1.69-2.87), and SGA (aOR, 1.38; 95 %CI, 1.18-1.62). The risk of PTB was higher among women with an upward BP trajectory between the first and second trimesters. CONCLUSIONS: Stage 1 hypertension in the first and second trimesters was associated with increased risks of overall PTB, early PTB, and SGA. Monitoring the BP trajectory for stage 1 hypertension may be useful for identifying high-risk groups.

The earliest enzyme replacement for infantile-onset Pompe disease in Japan.

BACKGROUND: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. METHODS: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. RESULTS: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. CONCLUSIONS: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.

Electrochemical detection of triamterene in human urine using boron-doped diamond electrodes.

Urine is one of the most used biological fluids for screening drug delivery and the resultant metabolites. In sports, the use of diuretics such as triamterene is considered a violation of anti-doping rules and is stipulated to be present at less than 79 nM in urine by the World Anti-Doping Agency (WADA). It is therefore important to develop effective rapid and low-cost tests for this diuretic. Here we apply electrochemical analysis using boron-doped diamond (BDD) electrodes, which have superior properties such as low background current, a wide potential window, and high resistance to deactivation. Since real urine samples show clear oxidation current peaks in the potential range more positive than 0.5 V (vs. Ag/AgCl) due to the presence of bio-components such as protein, uric acid, and ascorbic acid, to detect triamterene effectively, the electrochemical protocol was optimized towards a potential range where the other components have limited effect. Our results show that reduced triamterene exhibits an oxidation peak at 0.1 V (vs. Ag/AgCl) in 0.1 M phosphate buffer (PB) and at 0.2 V (vs. Ag/AgCl) in pooled human urine. The peak current value increased according to the triamterene concentration. The limit of detection (LOD) was 3.15 nM in the PB and 7.80 nM in pooled human urine. Finally, triamterene detection was attempted in individual urine samples. Triamterene was electrochemically detectable in individual urine samples, excluding urine samples containing an excess amount of ascorbic acid. The limit of detection (LOD) in individual urine samples was determined to be 20.8 nM.

Case Report: Juvenile Myelomonocytic Leukemia Underlying Ornithine Transcarbamylase Deficiency Safely Treated Using Hematopoietic Stem Cell Transplantation.

Background: Juvenile myelomonocytic leukemia (JMML), which is predominantly found in infants, is a clonal abnormality of pluripotent hematopoietic stem cells and presents with the symptoms of both myeloproliferative tumors and myelodysplastic syndromes. Estimates have shown that ~20 cases of JMML occur annually in Japan. Ornithine transcarbamylase deficiency (OTCD), the most common among all urea cycle disorders (UCDs), occurs in 1 of 80,000 people in Japan. Case Presentation: A 10-month-old infant who had fever, vomiting, and diarrhea for 2 days was referred to our hospital for the following abnormalities in blood tests: white blood cell count, 48,200/µL; hemoglobin, 9.0 g/dL; and platelet count, 135,000/µL. Bone marrow examination showed a nucleated cell count of 396,000/mm3 and blast cell count of 5.0%, as well as decreased mature granulocyte count and slightly myeloperoxidase stain-negative blasts but no monoclonal cell proliferation on May-Giemsa staining. Colony assay showed the proliferation of spontaneous colony and high sensitivity to granulocyte-macrophage colony-stimulating factor. Genetic analysis of peripheral blood mononuclear cells showed that the patient was positive for neuroblastoma RAS (NRAS) mutation. The patient was ultimately diagnosed with JMML. Approximately 170 days after his first hematopoietic stem cell transplantation (HSCT), the patient's JMML relapsed. Shortly after the recurrence, nausea, vomiting, hyperventilation, and decreased vitality were observed, followed by a decrease in the level of consciousness. The patient's ammonia level was 472 µmol/L. A test for seven different genetic mutations for the UCD showed the presence of c. 119G>A (amino acid change p. Arg40His). As such, late-onset OTCD was added to his diagnosis. Administration of sodium phenylacetate, l-arginine hydrochloride, and carnitine was continued following the diagnosis of OTCD, after which hyperammonemia was not observed. Regarding JMML relapse, HSCT was performed on day 405 after the first transplantation. Conclusion: Hyperammonemia should be considered a differential diagnosis when unexplained and non-specific symptoms occur during the treatment of hematologic malignancies. Patients should be tested for UCD as a cause of hyperammonemia, and treatment for hyperammonemia should be continued until the cause is identified. The patient shows normal developmental progress, has an intact neurological status, and has not experienced another hyperammonemia attack. His JMML has remained in remission for over 3 years.

Clinical manifestation and long-term outcome of citrin deficiency: Report from a nationwide study in Japan.

Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long-term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long-term outcome.

An economic evaluation of risankizumab versus other biologic treatments of moderate to severe plaque psoriasis in Japan.

OBJECTIVE: To evaluate the cost-effectiveness of risankizumab versus other biologic treatments (adalimumab, infliximab, ustekinumab, secukinumab, brodalumab, ixekizumab, and guselkumab) of moderate-to-severe psoriasis in Japan. METHODS: A Markov cohort-level model was constructed to estimate quality-adjusted life years (QALYs) and costs for each treatment over a lifetime horizon. The model simulated patients' transition through one line of active biologic therapy followed by best supportive care and death. Transition probabilities were informed by network meta-analyses of Psoriasis Activity and Severity Index responses and adverse event-related discontinuation in clinical trials, as well as published real-world evidence and national mortality rates. Costs were evaluated from the health system, societal, and patient out-of-pocket perspectives. RESULTS: Risankizumab was expected to provide 0.30-0.89 additional QALYs versus comparator biologics. Under the health system perspective, incremental cost-effectiveness ratios (ICERs) of risankizumab ranged from ¥2,545,812/QALY versus ustekinumab to ¥6,077,134/QALY versus adalimumab. Societal ICERs were lower, ranging from ¥921,770/QALY to ¥4,350,879/QALY. From the patient perspective, risankizumab was estimated to be cost-saving versus four comparators and was associated with ICERs of <¥500,000/QALY versus the remaining comparators. CONCLUSION: Risankizumab was associated with higher QALYs and, based on typical willingness-to-pay benchmarks (¥5-6.7 million/QALY), considered cost-effective versus other biologics for the treatment of psoriasis in Japan.

Current status of newborn screening for Pompe disease in Japan.

BACKGROUND: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease. RESULTS: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. CONCLUSIONS: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

Evaluating the burden of pruritus due to atopic dermatitis in Japan by patient-reported outcomes.

AIMS: Although pruritus is a hallmark feature of atopic dermatitis, no study has investigated the associated impact of pruritus, due to atopic dermatitis in Japan. The study aimed to evaluate the real-life burden of atopic dermatitis by pruritus severity in adult Japanese patients. The primary objective was to assess the correlation between pruritus severity and work productivity and activity impairment. A secondary objective was to characterize the impact of pruritus on quality of life and to evaluate the burden of symptoms severity and frequency. MATERIALS AND METHODS: A cross-sectional internet-based survey was conducted. Eligible patients were currently employed and working adults with atopic dermatitis for at least 6 months. Stratification on pruritus severity assessed by the Worst Pruritus Numerical Rating Scale at the screening was performed to ensure that different severity groups are represented. Correlations were assessed using Spearman's rank-order correlation coefficient. Multivariate regression analyses were performed to assess the impact of pruritus severity on work productivity and quality of life. RESULTS: The study analyzed 370 patients. Pruritus severity significantly correlated with work impairment (Rho = 0.622, P value (H0: Rho > 0.5) <.001). A greater pruritus severity was associated with greater work productivity and activity impairment and a greater impact on quality of life, sleep, emotional state, and everyday activities. Patients with a greater pruritus severity carried a higher economic burden of treatment and were more often not satisfied with the received therapy. LIMITATIONS: All data were self-reported by patients via an online survey, which is associated with the risk of misclassification for diagnosis, recall bias, and limited participation of patients. CONCLUSIONS: The study provides evidence that pruritus is associated with the overall disease burden and impacts many important life aspects of patients with atopic dermatitis in Japan.

A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

Negative impact of the COVID-19 state of emergency on breast cancer screening participation in Japan.

BACKGROUND: In response to the Coronavirus-19 (COVID-19) pandemic, the Japanese government declared a state of emergency in Saitama, Chiba, Tokyo, Kanagawa, Osaka, Hyogo and Fukuoka prefectures on April 7, 2020; this was extended to the remaining prefectures on April 16, 2020. The state of emergency was lifted on May 25, 2020. Although it was known that breast cancer screening was postponed or canceled during this period, the actual extent of postponement or cancellation has not been clarified. METHODS: We investigated postponement or cancellation of breast cancer screening between April and May 2020 using a cross-sectional, web-based, self-reported questionnaire survey. In addition, we examined the association between socioeconomic and health-related factors and postponement or cancellation by multivariable log-binominal regression. RESULTS: Among 1874 women aged 30-79 years who had scheduled breast cancer screening during the study period, 493 women (26.3%) postponed or canceled screening. While women aged 30-39 years and 70-79 years postponed or canceled less frequently than women aged 40-49 years (prevalence ratio = 0.62 and 0.56, respectively), there was no significant difference between age groups in the women aged 40-69 years. Postponement or cancellation was more frequent in five prefectures, where the state of emergency was declared early (prevalence ratio = 1.25). Employment status, annual household income, family structure, academic background, smoking status, and fear of COVID-19 were not associated with postponement or cancellation. CONCLUSION: Although care should be taken with the interpretation of these findings due to possible biases, they suggest that the postponement or cancellation of breast cancer screening might be due more to facility suspension than to individual factors. It is necessary to explore the ideal way of encouraging breast cancer screening uptake, in an environment of coexistence with COVID-19.

Combined patterns of participation in cervical, breast, and colorectal cancer screenings and factors for non-participation in each screening among women in Japan.

Finding effective strategies to increase participation in cervical cancer screening (CCS), breast cancer screening (BCS) and colorectal cancer screening (CRCS) for women is an important public health issue. Our objective was to examine combined patterns of participation in these three screenings and investigate the factors associated with non-participation in each. We analyzed 115,254 women aged 40-69 who were age-eligible for all three screenings from a 2016 nationally representative cross-sectional survey in Japan. Eight screening patterns were defined as full-participation (CCS + BCS + CRCS), partial-participation (CCS + BCS, CCS + CRCS, BCS + CRCS, CCS, BCS, CRCS), and non-participation (none). Multinomial logistic regression analysis adjusted for age, marital status, educational attainment, employment status, self-rated health, current hospital visits, and smoking status was performed to evaluate the factors associated with each screening pattern, using full-participation as the reference category. Screening rates for cervical, breast, and colorectal cancer were 45.0%, 46.2%, and 40.4%, respectively. Although only 26.9% of women participated in all three screenings, more than 60% participated in at least one screening. Unstable employment, low educational attainment, low self-rated health, and current smoker were associated with both non-participation and partial-participation, especially single-participation in cervical and breast cancer screening. For example, self-employed women were more likely to be non-participants [aOR 2.80 95%CI: 2.65-2.96], single-participants for CCS [aOR 2.87 95%CI: 2.57-3.20], and BCS [aOR 2.07 95%CI: 1.85-2.33] than permanent workers. It may be useful to consider related factors for non-participation patterns to encourage partial-participants to have other cancer screenings by utilizing one cancer screening as an opportunity to provide information about other screenings.

Physical, cognitive, and social status of patients with urea cycle disorders in Japan.

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.