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The emergence of the Alpha variant of novel coronavirus 2019 (SARS-CoV-2) is a concerning issue but their clinical implications have not been investigated fully.We conducted a nested case-control study to compare severity and mortality caused by the Alpha variant (B.1.1.7) with the one caused by the wild type as a control from December 2020 to March 2021, using whole-genome sequencing. 28-day mortality and other clinically important outcomes were evaluated.Infections caused by the Alpha variant were associated with an increase in the use of oxygen (43.4% vs 26.3%. p = 0.017), high flow nasal cannula (21.2% vs 4.0%, p = 0.0007), mechanical ventilation (16.2% vs 6.1%, p = 0.049), ICU care (30.3% vs 14.1%, p = 0.01) and the length of hospital stay (17 vs 10 days, p = 0.031). More patients with the Alpha variant received medications such as dexamethasone. However, the duration of each modality did not differ between the 2 groups. Likewise, there was no difference in 28-day mortality between the 2 groups (12% vs 8%, p = 0.48), even after multiple sensitivity analyses, including propensity score analysis.The Alpha variant was associated with a severe form of COVID-19, compared with the non-Alpha wild type, but might not be associated with higher mortality.

Background We experienced a pseudo-outbreak of aspergillosis in a newly constructed COVID-19 ward. Within the first 3 months from the commencement of the ward, six intubated patients of COVID-19 developed probable or possible pulmonary aspergillosis. We suspected an outbreak of pulmonary aspergillosis associated with ward construction and launched air sampling for the investigation of the relationship between these. Methods The samples were collected at 13 locations in the prefabricated ward and three in the general wards, not under construction, as a control. Results The results from samples revealed different species of Aspergillus from those detected by the patients. Aspergillus sp. was detected not only from the air samples in the prefabricated ward but also in the general ward. Discussion In this investigation, we could not find evidence of the outbreak that links the construction of the prefabricated ward with the occurrence of pulmonary aspergillosis. It might suggest that this series of aspergillosis was more likely occurred from fungi that inherently colonized patients, and was associated with patient factors such as severe COVID-19 rather than environmental factors. Once an outbreak originating from building construction is suspected, it is important to conduct an environmental investigation including an air sampling.

Apart from saving the lives of coronavirus disease (COVID-19) patients on mechanical ventilation (MV), recovery from the sequelae of prolonged MV (PMV) is an emerging issue.c METHODS: We conducted a retrospective study among consecutive adult COVID-19 patients admitted to an intensive care unit (ICU) in Kobe, Japan, between March 3, 2020, and January 31, 2021, and received invasive MV. Clinical outcomes included in-hospital mortality and recovery from COVID-19 in survivors regarding organ dysfunction, respiratory symptoms, and functional status at discharge. We compared survivors' outcomes with MV durations of14 days and ≤14 days.We included 85 patients with a median age of 69 years (interquartile range, 64-75 years); 76 (89%) patients had at least 1 comorbidity, 72 (85%) were non-frail, and 79 (93%) were functionally independent before COVID-19 infection. Eighteen patients (21%) died during hospitalization. At discharge, 59/67 survivors (88%) no longer required respiratory support, 50 (75%) complained of dyspnea, and 40 (60%) were functionally independent. Of the survivors, 23 patients receiving MV for14 days had a worse recovery from COVID-19 at discharge compared with those on MV for ≤14 days, as observed using the Barthel index (median: 35 [5-65] vs. 100 [85-100]), ICU mobility scale (8 [5-9] vs. 10 [10-10]), and functional oral intake scale (3 [1-7] vs. 7 [7-7]) (P 0.0001).Although four-fifths of the patients survived and50% of survivors demonstrated clinically important recovery in organ function and functional status during hospitalization, PMV was related to poor recovery from COVID-19 at discharge.

The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients.This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination.A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded.Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

Purpose Coronavirus disease 2019 (COVID-19) has placed a great burden on critical care services worldwide. Data regarding critically ill COVID-19 patients and their demand of critical care services outside of initial COVID-19 epicenters are lacking. This study described clinical characteristics and outcomes of critically ill COVID-19 patients and the capacity of a COVID-19-dedicated intensive care unit (ICU) in Kobe, Japan. Methods This retrospective observational study included critically ill COVID-19 patients admitted to a 14-bed COVID-19-dedicated ICU in Kobe between March 3, 2020 and June 21, 2020. Clinical and daily ICU occupancy data were obtained from electrical medical records. The last follow-up day was June 28, 2020. Results Of 32 patients included, the median hospital follow-up period was 27 (interquartile range 19–50) days. The median age was 68 (57–76) years; 23 (72%) were men and 25 (78%) had at least one comorbidity. Nineteen (59%) patients received invasive mechanical ventilation for a median duration of 14 (8–27) days. Until all patients were discharged from the ICU on June 5, 2020, the median daily ICU occupancy was 50% (36–71%). As of June 28, 2020, six (19%) died during hospitalization. Of 26 (81%) survivors, 23 (72%) were discharged from the hospital and three (9%) remained in the hospital. Conclusion During the first months of the outbreak in Kobe, most critically ill patients were men aged ≥ 60 years with at least one comorbidity and on mechanical ventilation; the ICU capacity was not strained, and the case-fatality rate was 19%. Supplementary Information The online version contains supplementary material available at 10.1007/s00540-021-02897-w.

Activating mutations in the ABCC8 gene cause diabetes and inactivating mutations usually cause hyperinsulinemic hypoglycemia in infancy. Patients with hypoglycemia in infancy due to a heterozygous inactivating mutation have been reported to occasionally progress to diabetes later in life. We explored the gene responsible for diabetes in two brothers, who were suspected to have diabetes at 15 and 18 years‐of‐age, respectively, with whole exome sequencing, and identified a compound heterozygous ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). Although their father and mother were heterozygous carriers of the p.Arg168Cys and the p.Arg1421Cys mutation, respectively, neither parent had diabetes. These mutations have been reported to be responsible for hypoglycemia in infancy and function as an inactivating mutation. Our results suggest that the inactivating ABCC8 gene mutation is also important in the etiology of diabetes., Pedigree of a family with young‐onset diabetes due to a compound heterozygous inactivating ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). These mutations had been reported to be responsible for hypoglycemia in infancy and be functional inactivating mutations.

Neonatal diabetes is a rare disease, often caused by a monogenic abnormality. A male infant patient developed diabetic ketoacidosis at 2 months‐of‐age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. For >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased. The mutation was transmitted in an autosomal‐dominant fashion across three generations of his family, but the severity of diabetes varied among members from neonatal diabetes to mild diabetes. One family member had normal glucose tolerance despite having the mutation. This case presentation could help in the understanding of neonatal diabetes caused by the ABCC8 gene mutation., A male infant developed diabetic ketoacidosis (DKA) at 2 months‐of‐age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. After that, for >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased.

Background Patients with coronavirus disease 2019 (COVID-19) and underlying cardiovascular comorbidities have poor prognoses. Our aim was to identify the impact of serum lactate dehydrogenase (LDH), which is associated with mortality in acute respiratory distress syndrome, on the prognoses of patients with COVID-19 and underlying cardiovascular comorbidities. Methods Among 1518 patients hospitalized with COVID-19 enrolled in the CLAVIS-COVID (Clinical Outcomes of COVID-19 Infection in Hospitalized Patients with Cardiovascular Diseases and/or Risk Factors study), 515 patients with cardiovascular comorbidities were analyzed. Patients were divided into tertiles based on LDH levels at admission [tertile 1 (T1), Graphical abstract Image, graphical abstract

Penicillium marneffei (Talaromyces marneffei) infection sometimes occurs in HIV‐infected patients in South‐East Asia. However, reports on asymptomatic cases are rare. Herein, we report a case of a 27‐year‐old Burmese HIV‐positive woman with pulmonary penicilliosis. Chest radiography showed a lung mass; however, the patient did not have any respiratory symptoms. Cultures of bronchoalveolar lavage and lung tissue grew P marneffei. The patient was diagnosed with penicilliosis and successfully treated with amphotericin B and itraconazole. Our findings suggest that P marneffei infection should be considered in the differential diagnosis of a lung mass in HIV‐infected patients, even when asymptomatic for respiratory symptoms., We report the case of pulmonary penicilliosis, which showed a lung mass on chest radiography but without respiratory symptoms. Reports on asymptomatic cases are rare.

Whole‐exome sequencing is a new technology. We used it to explore the gene responsible for early‐onset diabetes as a result of impaired insulin secretion in a family. In the INS gene, we identified the heterozygous c.188‐31G>A mutation in the proband – a 43‐year‐old woman. The mutation was also identified in her two daughters with diabetes, but not in her son or her parents, all of whom did not have diabetes. The substitution was located 31 bp proximal to exon 3 in intron 2. It was predicted to create an ectopic splice site leading to inserting 29 nucleotides of intron 2 as an exonic sequence in the transcript. The mutation has been reported in White families, and the present case is the first report in an Asian person. The present results would help in understanding the role of the mutation in developing diabetes.

Introduction Autosomal dominant hypocalcemia (ADH) is caused by gain-of-function mutations of the calcium sensing receptor (CaSR). It is characterized by hypercalciuria in spite of hypocalcemia. Vitamin D deficiency increases calcium reabsorption in the distal tubules of the kidneys, resulting in hypocalciuria. Materials and methods A 38-year-old female proband had hypocalcemia, hypocalciuria, and vitamin D deficiency. Her father and brother also had hypocalcemia, but her mother was normocalcemic. We analyzed the CaSR gene abnormality in this family. Polymerase chain reaction (PCR) and sequence analysis were performed to explore the CaSR gene mutation. Mutagenesis, transfection, and functional analysis were performed on the discovered genetic abnormalities. Result PCR and sequence analysis revealed that the proband, her father, and brother had a novel heterozygous mutation of the CaSR genes that causes threonine to asparagine substitution at codon 186 (T186N). Using HEK293 cells transfected with wild-type or T186N CaSR complementary DNA, we assessed the intracellular Ca2+ concentration in response to changes in the extracellular Ca2+ concentration. The cells transfected mutant CaSR gene had higher activity than that of wild-type. Therefore, we determined our patient had ADH with a novel mutation of the CaSR gene and hypocalciuria resulting from a vitamin D deficiency. We administered vitamin D to the proband, which caused elevation of her urinary calcium level, a typical finding of ADH. Conclusion Vitamin D deficiency was suggested to potentially mask hypercalciuria in ADH. Hypocalcemia with vitamin D deficiency should be diagnosed with care.

Background It is clinically emergent to further understand the pathological mechanism to advance therapeutic strategy for endocrine tumors. A high amount of secretory protein with tumorigenic triggers are thought to induce unfolded protein response in endoplasmic reticulum in endocrine tumors, but its evidence is limited. Case presentation A 40-year-old woman had an approximately 10-year history of intermittent headaches. After the incidental detection of a mass in her right adrenal gland by CT scan, she was admitted to our hospital. She had been diagnosed as type 1 Waardenburg syndrome with the symptoms of dystopia canthorum, blue iris, and left sensorineural hearing loss. Urinary catecholamine levels were markedly elevated. 123I-MIBG scintigraphy showed uptake in the mass in her adrenal gland. After the adrenalectomy, her headaches disappeared and urinary catecholamine levels decreased to normal range within 2 weeks. Genome sequencing revealed germline mutation of c.A175T (p.Ile59Phe) in transcription factor PAX3 gene and somatic novel mutation of c.1893_1898del (p. Asp631_Leu633delinsGlu) in proto-oncogene RET in her pheochromocytoma. RNA expression levels of RET were increased 139 times in her pheochromocytoma compared with her normal adrenal gland. Those of unfolded protein response markers, Bip/GRP78, CHOP, ATF4, and ATF6, were also increased in the pheochromocytoma. Conclusion We report a rare case of pheochromocytoma with type 1 Waardenburg syndrome. This is the first case to show the activation of unfolded protein response in the pheochromocytoma with the novel somatic mutation in RET gene. Our findings may support that unfolded protein response is activated in endocrine tumors, which potentially could be a candidate of therapeutic target.

Medullary thyroid carcinoma (MTC) may mimic mixed medullary and follicular thyroid carcinoma (MMFTC). MTC originates from para-follicular cells, while MMFTC is an uncommon tumor characterized by coexistence of follicular and para-follicular cell-derived tumor populations. A 35-year-old woman was diagnosed with MTC but showed a hot nodule in thyroid scintigraphy. The tumor included diffusely-spread follicular lesions within it, which were immunostained with thyroglobulin and calcitonin. Immunofluorescence showed the presence of several tumor cells that were double-stained with thyroglobulin and calcitonin. To clarify whether or not the tumor was MMFTC, we used duplex in situ hybridization (ISH). Thyroglobulin and calcitonin-related polypeptide alpha mRNA were not expressed together in a single cell, so we suspected false-positive staining of tumor cells with thyroglobulin. To make comparisons with other follicular lesions in MTC, we searched our hospital database. Five cases within a ten-year period had been pathologically diagnosed as MTC. All had follicular lesions in the tumor, but unlike the other case, they were peripherally localized. Dual differentiation into follicular or para-follicular tumor cells was not indicated by either immunofluorescence or duplex ISH. Compared with the case suspected to be MMFTC, there was only mild invasion of tumor cells into the follicular epithelium. The extent of follicular lesions and invasiveness of tumor cells may be associated with pseudo-staining of thyroglobulin in MTC. Duplex ISH can distinguish MTC that are stained with thyroglobulin from MMFTC.

Introduction: Mismatch repair (MMR) genes are associated with the MMR mechanism that corrects DNA polymerase misincorporation errors. We analyzed the aggressive pituitary adenomas (PAs) associated with Lynch syndrome due to germline mutation in the MMR gene. Reduced expression of MMR genes mutS homologs 6/2 (MSH6/2) directly promotes PA growth (1, 2). MMR gene expression and programmed cell death 1 ligand 1 (PD-L1) expression are involved in tumor immunity with immune checkpoint inhibitors, but the direct association in PAs is not fully understood. Hypothesis and Objectives: MSH6/2 and PD-L1 expression could affect PA proliferation and invasion by pathological classification of nonfunctioning (NF) PAs because the proliferation and invasiveness differ depending on the PA histological subtype. In this study, we therefore analyzed the correlation between MSH6/2 and PD-L1 mRNA expression levels and clinicopathological factors related to tumor proliferation using human NFPAs. Experimental Design: We performed immunohistochemistry to classify the NFPAs into gonadotroph adenomas (GAs), silent corticotroph adenomas (SCAs), null cell adenomas (NCAs) and pituitary transcription factor 1 (PIT1) lineage PAs according to 2017 WHO classifications. Quantitative analyses were by real-time PCR to detect MSH6/2 and PD-L1 mRNA expressions in NFPAs (n = 89). We also performed statistical analyses of the expressions and clinicopathological factors such as Knosp Grade and histological subtypes. We investigated the effect of MSH6 knockout on cell proliferation and PD-L1 expression in AtT-20ins cells. Major Results: MSH6/2 expression was positively associated with PD-L1 expression. MSH6/2 and PD-L1 expressions are significantly lower in invasive NFPAs with Knosp Grade 3–4 or recurrence than in non-invasive NFPAs with Knosp Grade 1–2. Their expression is significantly lower in SCAs and NCAs than in GAs. Although MSH6/2 expression also tends to be lower, the PD-L1 expression tends to be higher in PIT1 lineage PAs, which is unlike SCAs and NCAs. MSH6 knockout in AtT-20ins significantly decreased PD-L1 expression with cell proliferation promotion. Interpretation of results and Conclusion: MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1 lineage PAs compared to GAs were thought to contribute to their clinically aggressive behaviors. The molecular mechanism of the difference in clinical features of NFPAs was partially elucidated. In particular, reduced expressions of MSH6/2 were thought to be useful for predicting the proliferation and invasiveness of NFPAs. References: (1) Uraki S et al., Endocr J. 2017;64(9):895–906 (2) Uraki S et al., J Clin Endocrinol Metab. 2018;103(3):1171–1179. Declarations of conflicts of Interest: No authors declare any conflicts of interest.

BackgroundCoronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has been affecting many people on earth and our society. Japan is known to have relatively less number of infections as well as deaths among developed nations. However, accurate prevalence of COVID-19 in Japan remains unknown. Therefore, we conducted a cross-sectional study to estimate seroprevalence of SARS-CoV-2 infection.MethodsWe conducted a cross-sectional serologic testing for SARS-CoV-2 antibody using 1,000 samples from patients at outpatient settings who visited the clinic from March 31 to April 7, 2020, stratified by the decade of age and sex.ResultsThere were 33 positive IgG among 1,000 serum samples (3.3%, 95%CI: 2.3-4.6%). By applying this figure to the census of Kobe City (population: 1,518,870), it is estimated that the number of people with positive IgG be 50,123 (95%CI: 34,934-69,868). Age and sex adjusted prevalence of positivity was calculated 2.7% (95%CI: 1.8-3.9%), and the estimated number of people with positive IgG was 40,999 (95%CI: 27,333-59,221). These numbers were 396 to 858 fold more than confirmed cases with PCR testing in Kobe City.ConclusionsOur cross-sectional serological study suggests that the number of people with seropositive for SARS-CoV-2 infection in Kobe, Japan is far more than the confirmed cases by PCR testing.

Thyroid dysfunction and thyroid autoimmunity (TAI) have been reported to be linked to infertility, pregnancy loss and preterm birth. Infertile women undergoing assisted reproductive technology are recommended to maintain thyroid stimulating hormone (TSH) levels below 2.5 μIU/mL. It is unclear, however, whether levothyroxine (L-T4) treatment decreases the effects of TAI on fertility and pregnancy outcome in infertile women. We therefore aimed to clarify the influence of TAI on pregnancy undergoing L-T4 treatment for hypothyroidism. Prospectively recruited to this study were the 595 infertile women who visited the Utsunomiya Ladies Clinic between January 2013 and December 2015. Five patients with Graves' disease were excluded. Clinical profiles of 590 women were as follows: proportion of SCH = 19.6%, thyroid peroxidase antibody (TPOAb) positivity = 10.4%, and thyroglobulin antibody (TgAb) positivity = 15.1%. Fertility was not affected by any thyroid-associated factors. Regarding pregnancy outcomes, TPOAb titers were significantly higher in women who had miscarriage than in those progressed to delivery (46.4 ± 114.1 vs. 18.9 ± 54.6 IU/mL, p = 0.039), notably in those undergoing intrauterine insemination (p = 0.046) and in vitro fertilization (p = 0.023). Multivariate logistic regression analysis revealed that higher age (odds ratio 26.4, p < 0.001) and higher TPOAb titer (odds ratio 11.8, p = 0.043) were risk factors for miscarriage. Higher TPOAb titer should be considered as one of the risk factors for miscarriage in infertile women, even if they have been treated with L-T4 for hypothyroidism.

Highlights • The effectiveness of school closure to mitigate the epidemic of COVID-19 remains unknown. • Time series analyses were conducted using the Bayesian method to evaluate the effectiveness of school closure in Japan. • The intervention of school closure did not appear to decrease the incidence of coronavirus infection., Objectives The Coronavirus disease 2019 (COVID-19) pandemic is causing significant damage to many nations. For mitigating its risk, Japan called on all elementary, junior high, and high schools nationwide to close beginning March 1, 2020. However, its effectiveness in decreasing the disease burden has not been investigated. Methods We used daily data of the COVID-19 and coronavirus infection incidence in Japan until March 31, 2020. Time-series analyses were conducted using the Bayesian method. Local linear trend models with interventional effects were constructed for the number of newly reported cases of COVID-19, including asymptomatic infections. We considered that the effects of the intervention started to appear nine days after the school closure. Results The intervention of school closure did not appear to decrease the incidence of coronavirus infection. If the effectiveness of school closure began on March 9, the mean coefficient α for the effectiveness of the measure was calculated to be 0.08 (95% confidence interval −0.36 to 0.65), and the actual reported cases were more than predicted, yet with a rather wide confidence interval. Sensitivity analyses using different dates also did not demonstrate the effectiveness of the school closure. Discussion School closure carried out in Japan did not show any mitigating effect on the transmission of novel coronavirus infection.

Recently, aromatic amino acids, especially tryptophan were discovered to be the strongest ligands for GPR142, which was previously known as an orphan GPCR. GPR142 is expressed in the digestive tract and pancreas in mice and human. Previously we found that GPR142 is highly expressed in the ghrelin-producing cell line, MGN3-1 cells, and that tryptophan strongly stimulated ghrelin secretion in vitro. In this study, we measured the mRNA expression levels of GPR142 in the gastric samples of 6 morbid obese patients undergone laparoscopic sleeve gastrectomy and compared its level with their clinical parameters. GPR142 expression levels were negatively correlated with plasma desacyl ghrelin levels (p=0.011) and positively correlated with heights (p=0.08). The current results that GPR142 expression levels were correlated with plasma desacyl ghrelin levels may confirm the link between GPR142 signal and regulation of ghrelin secretion demonstrated in our in vitro study. Regarding to the correlation with heights, there are some reports that plasma ghrelin levels were inversely correlated with heights in children[1-3], although, as far as we know, there are no reports demonstrating the relationship between plasma ghrelin levels and heights in adults. Considering that ghrelin strongly stimulates growth hormone secretion, GPR142 signaling may have influence on height through regulating ghrelin-growth hormone axis. Conclusion GPR142 mRNA expression levels were negatively and positively correlated with plasma desacyl ghrelin levels and heights in morbid obese adults undergone bariatric surgery. Current results may help understanding the pathophysiological role of GPR142 in the regulation of ghrelin secretion and heights. References 1. MO Camurdan, et al. Endocrine Journal 2006, 53 (4), 479–484 2. HS Park, et al. Metabolism Clinical and Experimental 2005, 54, 925–929 3. Joy C. Bunt,et al. J Clin Endocrinol Metab 2003, 88(8): 3756-3761

Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

Objectives To assess the effectiveness of short duration antimicrobial therapy for acute cholangitis with bacteraemia. Methods We conducted a retrospective cohort study of patients with acute bacteraemic cholangitis with successful biliary duct drainage at a single centre in Japan. We compared short-course antimicrobial therapy (SCT, ≤7 days) and long-course therapy (LCT, ≥8 days), with a primary outcome of 30-day mortality. We constructed logistic regression models for mortality and a composite outcome, including mortality, recurrence, recrudescence, new bacteraemia, liver abscess or other complications related to cholangitis. We also developed a propensity score for SCT with inverse probability weighting for both the primary outcome and the composite outcome. Results We identified 263 patients in our cohort; 86 (32.7%) patients received SCT and the remaining 177 (67.3%) received LCT. The median durations of SCT and LCT were 6 days (range 2–7 days) and 12 days (range 8–46 days), respectively. The 30-day mortalities of SCT and LCT were 4.7% (4/85) and 5.7% (10/176), respectively (p 1.00). Logistic regression analysis showed that the odds ratio of SCT for 30-day mortality and the composite outcome were 1.07 (95% CI 0.25–4.52, p 0.93) and 1.08 (95% CI 0.48–2.45, p 0.85), respectively. Propensity score analyses for both 30-day mortality and the composite outcome did not demonstrate a difference between SCT and LCT (p 0.65 and p 0.95, respectively). Conclusions SCT with a median duration of 6 days did not have worse outcomes than LCT with a median duration of 12 days. Shortening the duration of antimicrobial therapy may be a reasonable option when treating acute bacteraemic cholangitis following successful biliary drainage.

Background: Antimicrobial therapy with appropriate biliary drainage is considered the standard of care of acute cholangitis, but the optimal duration of antimicrobial therapy remains unknown. Seven to 10 days of antimicrobial therapy is common for the treatment of acute cholangitis, but recent retrospective cohort study suggested shorter duration might be effective enough. Shorter duration of antimicrobial therapy can be beneficial in decreasing the length of hospital stay, improving patients’ quality of life, decreasing adverse effects, and even contributing to decrease in the occurrence of antimicrobial resistance. Methods/design: We will conduct a multi-center, open-label, randomized, non-inferiority trial to compare short course therapy (SCT) with conventional long course therapy (LCT) in treating patients with acute cholangitis. SCT consists of 5-day intravenous antimicrobial therapy if the patients had clinical improvement, while at least 7 days of intravenous antibiotics will be provided to LCT group. The primary outcome is clinical cure at 30 days after their onset. Patients will be randomly assigned with open label fashion. A total sample size of 150 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 10%. Discussion: This trial is expected to reveal whether SCT is non-inferior to conventional LCT or not, and may provide evidence that one can able to shorten the treatment duration for acute cholangitis for the benefit of the patients.

Context Nonislet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome associated with large tumors. The high molecular weight IGF2, known as "big" IGF2, is produced by culprit tumors and leads to severe hypoglycemia. The detailed mechanism of its production in NICTH, however, remains unclear. Objective To clarify the mechanism of production of big IGF2 in light of the processing of pro-IGF2 in patients with solitary fibrous tumor (SFT) and NICTH. Design We enrolled 14 patients with SFT and divided them based on the presence or absence of hypoglycemia. In light of the processing of pro-IGF2 in SFT with hypoglycemia, we, retrospectively, compared the production levels of big IGF2 and the expression levels of IGF2 and proprotein convertase subtilisin/kexin type 4 (PCSK4), a proteolytic enzyme of pro-IGF2. Results In all patients with NICTH, big IGF2 was detected in serum by western immunoblotting analysis. Moreover, we showed that two patients without hypoglycemia also had a small amount of big IGF2 in their serum. By immunohistochemical analysis, the protein expression level of IGF2 was significantly higher in the NICTH group than in the non-NICTH group (P = 0.043). The IGF2/PCSK4 protein expression-level ratio in the NICTH group was significantly higher than that in the non-NICTH group (P = 0.021). Conclusion In patients with SFT and hypoglycemia, an imbalance of IGF2 and PCSK4 expression could lead to increased serum levels of big IGF2.

A 74-year-old Japanese man who was taking antacids presented with profuse diarrhea. Stool culture revealed Vibrio cholerae O1 strain, serogroup Ogawa, biotype El tor. He recalled he had consumed some sashimi but denied any history of travelling abroad, and another cholera case with almost the same strain was reported at the same time in a remote prefecture in the Kanto area. This is a rare case of travel-unrelated cholera in Japan, and it illustrates the importance of suspecting cholera in all patients presenting with large volumes of watery diarrhea in Japan, especially in those who are taking antacids, regardless of their international travel history.

We conducted a study to estimate the seroprevalence of coronavirus disease 2019 (COVID-19) in Kobe, Japan with positive immunoglobulin G (IgG) rate of 3.3% (95% confidence interval [CI] 2.3%-4.6%) in April 2020. Because there were large concerns about the spread of COVID-19 among citizens thereafter, we conduct a follow-up cross-sectional study to estimate the seroprevalence, and we also added a validation study using a different assay.We conducted cross-sectional serologic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody using 1000 samples from patients at outpatient settings who visited the clinic from May 26 to June 7, 2020, stratified by the decade of age and sex. We used both Kurabo and Abbott serology assays to identify IgG against SARS-CoV-2.There were 18 and 2 positive IgG among 1000 serum samples using Kurabo and Abbott serology assays, respectively (1.8%, 95% CI 1.1%-2.8%, and 0.2%, 95% CI 0.02%-0.7% respectively). By applying the latter figure to the census of Kobe City (population: 1,518,870), it is estimated that the number of people with positive IgG is 3038 (95% CI: 304-10,632) while a total of 285 patients were identified by polymerase chain reaction (PCR) testing at the end of the study period. Assuming Abbott assay as the reference, Kurabo assay had calculated sensitivity and specificity of 100% and 98.4% respectively. Age and sex adjusted prevalence of positivity was calculated to be 0.17%.We found a lower seroprevalence than 2 months before in Kobe city although the figures were still higher than those detected by PCR. Kurabo assay showed more false positives than true positives despite reasonable sensitivity and specificity, due to low prevalence in Kobe.

Objectives Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has been affecting many people on earth and our society. Japan is known to have relatively smaller number of its infections as well as deaths among developed nations. However, accurate prevalence of COVID-19 in Japan remains unknown. Therefore, we conducted a cross-sectional study to estimate seroprevalence of SARS-CoV-2 infection. Methods We conducted a cross-sectional serologic testing for SARS-CoV-2 antibody using 1000 samples from patients at outpatient settings who visited the clinic from March 31 to April 7, 2020, stratified by the decade of age and sex. Results There were 33 positive IgG among 1000 serum samples (3.3%, 95%CI: 2.3–4.6%). By applying this figure to the census of Kobe City (population: 1,518,870), it is estimated that the number of people with positive IgG be 50,123 (95%CI: 34,934–69,868). Age and sex adjusted prevalence of positivity was calculated 2.7% (95%CI: 1.8–3.9%), and the estimated number of people with positive IgG was 40,999 (95%CI: 27,333–59,221). These numbers were 396 to 858-fold more than confirmed cases with PCR testing in Kobe City. Conclusions Our cross-sectional serological study suggests that the number of people with seropositive for SARS-CoV-2 infection in Kobe, Japan is far more than the confirmed cases by PCR testing.