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Abstract Estimated glomerular filtration rate (eGFR) variation is associated with end-stage kidney disease (ESKD) development in patients with chronic kidney disease; whether annual variations in eGFR at health check-ups is associated with ESKD risk in the general population is unclear. We conducted a retrospective cohort study using Japanese national medical insurance claims from 2013 to 2020. Individuals who had their eGFR levels measured three times in annual health check-ups were included (N = 115,191), and the coefficient of variation of eGFR (CVeGFR) was calculated from 3-point eGFR. The end-point was ESKD as reported in the claims data. We analyzed the association between CVeGFR and ESKD incidence after adjusting for conventional ESKD risk factors. The CVeGFR median distribution was 5.7% (interquartile range: 3.5–8.5%). During a median follow-up period of 3.74 years, 164 patients progressed to ESKD. ESKD incidence was significantly higher in the highest quartile group (CVeGFR ≥ 8.5%) than in the other groups (P

Summary: Background & aim: Although weight loss programs including diet and exercise targeting patients with obesity are essential, the percentage of patients who successfully achieve weight loss is less than 10%. One cause of failure to achieve weight loss is a strong sense of hunger, which is difficult to sustain. Additionally, it is important to prevent a decrease in muscle mass. Various protein supplements have been used to overcome these problems. However, there is insufficient evidence to support this theory. This study aimed to evaluate the effect of soy or whey protein beverages in conjunction with general dietary and exercise therapies on weight loss. Methods: This placebo-controlled, double-blind, randomized clinical trial was conducted at Kobe University Hospital. Patients with obesity and at least one obesity-related complication were enrolled. Three arms of soy, whey protein, or a placebo were supplemented once a day for 12 weeks, in addition to the general guidance on dietary and exercise therapies in a weight loss program. Energy intake during the trial was calculated using the Food Frequency Questionnaire. The primary outcome was percentage change in body weight from baseline to 12 weeks. Results: Between March 2021 and April 2022, 44 patients were enrolled. No significant differences were observed in body weight, waist circumference, body composition parameters, resting energy expenditure, blood pressure, or metabolic indicators. However, the energy, protein, and lipid intakes calculated from the prescribed nutritional intake in the weight loss program were significantly lower in the soy protein group (control group vs. soy group; total energy [kcal] −121.0 ± 416.6 vs. −340.0 ± 487.0, respectively P = 0.016; protein [g] 8.5 ± 11.9 vs. −5.1 ± 14.7, P = 0.023; lipid [g] −5.1 ± 16.1 vs. −19.8 ± 18.2, P = 0.018). Conclusions: No significant weight loss was observed in the soy or whey protein group. However, in the soy protein group, it was possible to maintain a lower energy intake, and protein and lipid intakes decreased in post-hoc analysis. Although further investigation is necessary, extending the administration period may result in significant weight loss. Clinical trial registration: Japan Registry of Clinical Trials (identifier: jRCTs051200103).

Abstract Background Obesity is associated with various complications and decreased life expectancy, and substantial heterogeneity in complications and outcomes has been observed. However, the subgroups of obesity have not yet been clearly defined. This study aimed to identify the subgroups of obesity especially those for target of interventions by cluster analysis. Methods In this study, an unsupervised, data-driven cluster analysis of 9,494 individuals with obesity (body mass index ≥ 35 kg/m2) was performed using the data of ICD-10, drug, and medical procedure from the healthcare claims database. The prevalence and clinical characteristics of the complications such as diabetes in each cluster were evaluated using the prescription records. Additionally, renal and life prognoses were compared among the clusters. Results We identified seven clusters characterised by different combinations of complications and several complications were observed exclusively in each cluster. Notably, the poorest prognosis was observed in individuals who rarely visited a hospital after being diagnosed with obesity, followed by those with cardiovascular complications and diabetes. Conclusions In this study, we identified seven subgroups of individuals with obesity using population-based data-driven cluster analysis. We clearly demonstrated important target subgroups for intervention as well as a metabolically healthy obesity group.

Abstract Although antithyroid drug (ATD)-induced agranulocytosis is a significant concern, its risks associated with long-term use and re-administration are not fully elucidated. Therefore, we performed this study to determine the incidence of ATD-induced leukopenia and G-CSF administration using administrative claims database. Retrospective cohort study. This study was performed using the DeSC Japanese administrative claims database. A total of 12,491 patients with newly diagnosed Graves’ disease (GD) who received methimazole or propylthiouracil between April 2014, and February 2021 among 3.44 million patients in the database were included in the study. We measured the six-year incidence of leukopenia and granulocyte colony-stimulating factor (G-CSF) administration. The incidence of leukopenia and G-CSF administration was 1.34% (168 patients) and 0.30% (38 patients), respectively. Leukopenia had a dose-dependent and biphasic incidence. The incidence of leukopenia and G-CSF administration was 37.2 (0.7%) and 8.0 (0.2%) per 1000 person-years during the first 72 days of ATD initiation, whereas it was 3.1 and 0.7 per 1000 person-years during the subsequent 6 years, respectively. The incidence of both outcomes was comparable between first administration and re-administration of ATD. The incidence of ATD-induced leukopenia and G-CSF administration was high in the first 72 days, with a reduced risk for at least 6 years thereafter. The incidence was similar between first administration and re-administration. ATD, a standard therapy, is often administered for a long period; therefore, our findings can guide the treatment of GD.

Histologic transformation is one of the mechanisms of resistance to EGFR tyrosine kinase inhibitor in patients with NSCLC with EGFR mutation. The transformation from adenocarcinoma to squamous cell carcinoma (SCC) has been recently recognized as a mechanism of resistance to osimertinib. The prognosis after transformation to SCC is considered to be poor, and the therapeutic strategy for these patients is unclear. Herein, we report a case of long-term response to pembrolizumab monotherapy for an SCC-transformed lesion in a patient with EGFR-mutated adenocarcinoma after osimertinib treatment. A 68-year-old man underwent right upper lobectomy and was diagnosed with lung adenocarcinoma, pathologic stage IIA, with EGFR L858R. Five years after the surgery, he was diagnosed with recurrence and administered osimertinib. Ten months after, biopsy for an enlarged subpleural lesion revealed SCC with EGFR L858R, leading to a diagnosis of histologic transformation. Notably, the programmed death-ligand 1 expression level of the transformed lesion was higher than that of the adenocarcinoma (90% versus

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains.

Abstract In patients with unresectable non-small cell lung cancer, histological diagnosis is frequently based on small biopsy specimens unsuitable for histological diagnosis when they are severely crushed and do not retain their morphology. Therefore, establishing a novel diagnostic method independent of tissue morphology or conventional immunohistochemistry (IHC) markers is required. We analyzed the lipid profiles of resected primary lung adenocarcinoma (ADC) and squamous cell carcinoma (SQCC) specimens using liquid chromatography-tandem mass spectrometry. The specimens of 26 ADC and 18 SQCC cases were evenly assigned to the discovery and validation cohorts. Non-target screening on the discovery cohort identified 96 and 13 lipid peaks abundant in ADC and SQCC, respectively. Among these 109 lipid peaks, six and six lipid peaks in ADC and SQCC showed reproducibility in target screening on the validation cohort. Finally, we selected three and four positive lipid markers for ADC and SQCC, demonstrating high discrimination abilities. In cases difficult to diagnose by IHC staining, [cardiolipin(18:2_18:2_18:2_18:2)-H]− and [triglyceride(18:1_17:1_18:1) + NH4]+ showed the excellent diagnostic ability for ADC (sensitivity: 1.00, specificity: 0.89, accuracy: 0.93) and SQCC (sensitivity: 0.89, specificity: 0.83, accuracy: 0.87), respectively. These novel candidate lipid markers may contribute to a more accurate diagnosis and subsequent treatment strategy for unresectable NSCLC.

Knowledge of gender-specific drug distributions in different organs are of great importance for personalized medicine and reducing toxicity. However, such drug distributions have not been well studied. In this study, we investigated potential differences in the distribution of imipramine and chloroquine, as well as their metabolites, between male and female kidneys. Kidneys were collected from mice treated with imipramine or chloroquine and then subjected to atmospheric pressure matrix-assisted laser desorption ionization-mass spectrometry imaging (AP-MALDI-MSI). We observed differential distributions of the drugs and their metabolites between male and female kidneys. Imipramine showed prominent distributions in the cortex and medulla in male and female kidneys, respectively. Desipramine, one of the metabolites of imipramine, showed significantly higher (*** p < 0.001) distributions in the medulla of the male kidney compared to that of the female kidney. Chloroquine and its metabolites were accumulated in the pelvis of both male and female kidneys. Interestingly, they showed a characteristic distribution in the medulla of the female kidney, while almost no distributions were observed in the same areas of the male kidney. For the first time, our study revealed that the distributions of imipramine, chloroquine, and their metabolites were different in male and female kidneys.

Abstract Background The risk of postoperative recurrence is higher in lung cancer patients who smoke than non-smokers. However, objective evaluation of the postoperative recurrence risk is difficult using conventional pathological prognostic factors because of their lack of reproducibility. Consequently, novel objective biomarkers that reflect postoperative risk in lung cancer patients who smoke must be identified. Because cigarette smoking and oncogenesis alter lipid metabolism in lung tissue, we hypothesized that the lipid profiles in lung cancer tissues are influenced by cigarette smoking and can reflect the postoperative recurrence risk in smoking lung cancer patients. This study aimed to identify lipid biomarkers that reflect the smoking status and the postoperative recurrence risk. Methods Primary tumor tissues of lung adenocarcinoma (ADC) (n = 26) and squamous cell carcinoma (SQCC) (n = 18) obtained from surgery were assigned to subgroups according to the patient’s smoking status. The ADC cohort was divided into never smoker and smoker groups, while the SQCC cohort was divided into moderate smoker and heavy smoker groups. Extracted lipids from the tumor tissues were subjected to liquid chromatography-tandem mass spectrometry analysis. Lipids that were influenced by smoking status and reflected postoperative recurrence and pathological prognostic factors were screened. Results Two and 12 lipid peaks in the ADC and SQCC cohorts showed a significant positive correlation with the Brinkman index, respectively. Among them, in the ADC cohort, a higher lipid level consisted of three phosphatidylcholine (PC) isomers, PC (14:0_18:2), PC (16:1_16:1), and PC (16:0_16:2), was associated with a shorter recurrence free period (RFP) and a greater likelihoods of progressed T-factor (≥ pT2) and pleural invasion. In the SQCC cohort, a lower m/z 736.5276 level was associated with shorter RFP and greater likelihood of recurrence. Conclusions From our data, we propose three PC isomers, PC (14:0_18:2), PC (16:1_16:1), and PC (16:0_16:2), and a lipid peak of m/z 736.5276 as novel candidate biomarkers for postoperative recurrence risk in lung ADC and SQCC patients who are smokers.

Epicutaneous exposure to protein allergens, such as papain, house dust mite (HDM), and ovalbumin (OVA), represents an important mode of sensitization for skin diseases including protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. These diseases are inducible by re-exposure to an allergen at both original skin sensitization and distant skin sites. In this study, we examined the serum IgE/IgG1 response, differentiation of T-helper (TH) cells, and epicutaneous TH recall response in mice pre-sensitized with protein allergens through the back skin and subsequently challenged on the ear skin. Repeated epicutaneous sensitization with allergenic proteins including papain, HDM, OVA, and protease inhibitor-treated papain, but not bovine serum albumin, induced serum allergen-specific antibody production, passive cutaneous anaphylaxis responses, and TH2 differentiation in the skin draining lymph node (DLN) cells. Sensitization with papain or HDM, which have protease activity, resulted in the differentiation of TH17 as well as TH2. In papain- or HDM-sensitized mice, a subsequent single challenge on the ear skin induced the expression of TH2 and TH17/TH22 cytokines. These results suggest that allergenic proteins induce the differentiation of TH2 in skin DLN cells and an antibody response. These findings may be useful for identifying proteins of high and low allergenic potential. Moreover, allergenic proteins containing protease activity may also differentiate TH17 and induce TH2 and TH17/TH22 recall responses at epicutaneous challenge sites. This suggests that allergen protease activity accelerates the onset of skin diseases caused by protein allergens.

Abstract Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

Abstract Aims/Introduction The bone mineral density in patients with type 1 diabetes mellitus is reduced due to impaired insulin secretion. However, it is unclear whether the rate of bone mineral density reduction is affected by the type 1 diabetes mellitus subtype. This study aimed to clarify the difference in bone mineral density across type 1 diabetes mellitus subtypes: slowly progressive (SP), acute‐onset (AO), and fulminant (F). Methods This was a retrospective, single‐center, cross‐sectional study conducted on 98 adult type 1 diabetes mellitus patients. The main outcome included the bone mineral density Z‐score (BMD‐Z) measured at the lumbar spine and femoral neck. Results The lumbar spine BMD‐Z was lower in the acute‐onset than in the slowly progressive subtype (P = 0.03). No differences were observed when compared with the fulminant subtype. The femoral neck BMD‐Z tended to be higher in the slowly progressive than in the acute‐onset and fulminant subtypes. Multiple regression analyses showed that the lumbar spine BMD‐Z was associated with subtypes (AO vs SP) (P = 0.01), but not subtypes (F vs SP), adjusted for sex, duration, retinopathy, and C‐peptide immunoreactivity (CPR). When the patients were divided into disease duration tertiles, in the first and second tertiles, the CPR levels were lower in the acute‐onset or fulminant than in the slowly progressive subtype. In contrast, the lumbar spine and femoral neck BMD‐Z differed between the acute‐onset and slowly progressive only in the second tertiles (both P

ABSTRACT This study clarified the age of death in patients with or without diabetes using the largest health insurance database in Japan. This population‐based retrospective cohort study was performed using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) data. The ages of death between people with and without diabetes were compared. A total of 142,277,986 patients (74,488,962 women and 67,789,024 men) over 6 years, including 4,647,016 females, and 6,507,817 males with diabetes, were included. 2,786,071 females and 2,975,876 males died over 6 years, including 652,699 females and 954,655 males with diabetes. The average age of death in patients with diabetes was 2.6 years less than that of patients without diabetes. This descriptive epidemiological study illustrated the difference in age at death of patients with and without diabetes.

Abstract Photoisomerization of lipids has been well studied. As for the eyes, photoisomerization from 11-cis isomer to all-trans-retinal is well-known as the first step of the visual transduction in the photoreceptors. In addition to that, there would be other ocular lipids that undergo photoisomerization, which may be involved in ocular health and function. To explore any photoisomerizable lipids in the eyes, the nonirradiated and sunlight-irradiated eyeball extracts were subjected to liquid chromatography-mass spectrometry analysis, followed by the identification of the decreased lipid species in the irradiated extracts. Surprisingly, more than nine hundred lipid species were decreased in the irradiated extracts. Three lipid species, coenzyme Q10 (CoQ10), triglyceride(58:4), and coenzyme Q9, were decreased both significantly (p

Abstract Aims/Introduction We assessed the association between dipeptidyl peptidase‐4 inhibitors (DPP‐4is) and bullous pemphigoid (BP) and time‐dependent changes in the risk for developing BP after DPP‐4i initiation. Materials and Methods The present population‐based, real‐world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP‐4is and the development of BP, the self‐controlled case series method was used. Results Among the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person‐years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person‐years, whereas that in patients with type 2 diabetes who did and did not use DPP‐4is was 40.7 and 30.0/100,000 person‐years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP‐4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75–2.63), 1.70 (95% CI 1.37–2.11), 1.44 (95% CI 1.15–1.82), 1.25 (95% CI 0.98–1.59), 0.84 (95% CI 0.63–1.10), 0.84 (95% CI 0.64–1.11) and 1.05 (95% CI 0.92–1.20), for the risk period of ≤30, 31–60, 61–90, 91–120, 121–150, 151–180 and 181–365 days, respectively. Conclusions Although DPP‐4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.

Abstract Background Pulmonary pleomorphic carcinoma (PPC) is a relatively rare and poorly differentiated non-small cell carcinoma. This study aimed to investigate the clinicopathological features including programmed cell death ligand 1 (PD-L1) expression status in patients with PPC who underwent curative resection. Methods We retrospectively studied 29 consecutive patients who had undergone anatomical lung resections for PPC. Perioperative and pathological variables, including radiological findings, were investigated to define prognostic factors. Results Overall survival (OS) rates were 71.8% at 1 year and 60.0% at 5 years. Disease-free survival (DFS) rates were 54.8% at 1 year and 43.6% at 5 years. Univariate analysis revealed that ringed fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) (p = 0.003), a cavity in the tumor on CT (p = 0.004), and tumor size (> 40 mm) (p = 0.014) were poor prognostic factors for OS. Regarding DFS, ringed FDG uptake (p = 0.002), a cavity on CT (p

Abstract Aims/Introduction The purpose of the present study was to quantify errors in the diagnosis of diabetes for use in the national database, using a sufficient population size. Materials and methods A claims database constructed by the JMDC (Tokyo, Japan), using standardized disease classifications and anonymous record linkage, was used in this validation study. We included patients with health insurance claims data from April 2005 to March 2019 in the JMDC claims database. We excluded patients without a record of specific health checkups in Japan. Sample size calculation was based on a 5% prevalence of diabetes and 0.4% absolute accuracy (i.e., 1,250,000 individuals), to calculate the sensitivity, specificity, positive predictive value and negative predictive value. Results In total, 2,999,152 patients were included in this study, of which 165,515 were classified as having diabetes based on specific health checkups (validation cohort prevalence of 5.5%). The newly devised algorithm had three elements – the diagnosis‐related codes for diabetes without suspected flag, the medication codes for diabetes and then these two codes on the same record – and yielded a sensitivity of 74.6%, positive predictive value of 88.4% and Kappa Index of 0.80 (the highest values). Conclusions In future claims database studies, our validated algorithms will be useful as diagnostic criteria for diabetes.

Mass spectrometry imaging (MSI) allows us to visualize the spatial distribution of molecular components in a sample. A large amount of mass spectrometry data comprehensively provides molecular distributions. In this study, we focus on the information in the obtained data and use the Shannon entropy as a quantity to analyze MSI data. By calculating the Shannon entropy at each pixel on a sample, the spatial distribution of the Shannon entropy is obtained from MSI data. We found that low-entropy pixels in entropy heat maps for kidneys of mice had different structures between two ages (3 months and 31 months). Such changes cannot be visualized by conventional imaging techniques. We further propose a method to find informative molecules. As a demonstration of the proposed scheme, we identified two molecules by setting a region of interest which contained low-entropy pixels and by exploring changes of peaks in the region.

BackgroundBarotrauma frequently occurs in coronavirus disease 2019. Previous studies have reported barotrauma to be a mortality-risk factor; however, its time-dependent nature and pathophysiology are not elucidated. To investigate the time-dependent characteristics and the etiology of coronavirus disease 2019-related-barotrauma.Methods and findingsWe retrospectively reviewed intubated patients with coronavirus disease 2019 from March 2020 to May 2021. We compared the 90-day survival between the barotrauma and non-barotrauma groups and performed landmark analyses on days 7, 14, 21, and 28. Barotrauma within seven days before the landmark was defined as the exposure. Additionally, we evaluated surgically treated cases of coronavirus disease 2019-related pneumothorax. We included 192 patients. Barotrauma developed in 44 patients (22.9%). The barotrauma group's 90-day survival rate was significantly worse (47.7% vs. 82.4%, p < 0.001). In the 7-day landmark analysis, there was no significant difference (75.0% vs. 75.7%, p = 0.79). Contrastingly, in the 14-, 21-, and 28-day landmark analyses, the barotrauma group's survival rates were significantly worse (14-day: 41.7% vs. 69.1%, p = 0.044; 21-day: 16.7% vs. 62.5%, p = 0.014; 28-day: 20.0% vs. 66.7%, p = 0.018). Pathological examination revealed a subpleural hematoma and pulmonary cyst with heterogenous lung inflammation.ConclusionsBarotrauma was a poor prognostic factor for coronavirus disease 2019, especially in the late phase. Heterogenous inflammation may be a key finding in its mechanism. Barotrauma is a potentially important sign of lung destruction.

Abstract Background To reduce disease recurrence after radical surgery for lung squamous cell carcinomas (SQCCs), accurate prediction of recurrent high-risk patients is required for efficient patient selection for adjuvant chemotherapy. Because treatment modalities for recurrent lung SQCCs are scarce compared to lung adenocarcinomas (ADCs), accurately selecting lung SQCC patients for adjuvant chemotherapy after radical surgery is highly important. Predicting lung cancer recurrence with high objectivity is difficult with conventional histopathological prognostic factors; therefore, identification of a novel predictor is expected to be highly beneficial. Lipid metabolism alterations in cancers are known to contribute to cancer progression. Previously, we found that increased sphingomyelin (SM)(d35:1) in lung ADCs is a candidate for an objective recurrence predictor. However, no lipid predictors for lung SQCC recurrence have been identified to date. This study aims to identify candidate lipid predictors for lung SQCC recurrence after radical surgery. Methods Recurrent (n = 5) and non-recurrent (n = 6) cases of lung SQCC patients who underwent radical surgery were assigned to recurrent and non-recurrent groups, respectively. Extracted lipids from frozen tissue samples of primary lung SQCC were analyzed by liquid chromatography-tandem mass spectrometry. Candidate lipid predictors were screened by comparing the relative expression levels between the recurrent and non-recurrent groups. To compare lipidomic characteristics associated with recurrent SQCCs and ADCs, a meta-analysis combining SQCC (n = 11) and ADC (n = 20) cohorts was conducted. Results Among 1745 screened lipid species, five species were decreased (≤ 0.5 fold change; P

Adult growth hormone deficiency (AGHD) is a rare endocrine disorder characterized by an abnormal body composition, metabolic abnormalities associated with increased cardiovascular diseases, bone loss, and impaired quality of life. Daily subcutaneous injections with recombinant growth hormone (GH) can alleviate the abnormalities associated with AGHD. Several long-acting GH (LAGH) preparations are currently in development that aim to reduce treatment burden for patients receiving daily GH injections. Somapacitan (Sogroya®; Novo Nordisk, Denmark) is the first LAGH preparation that has been approved for treatment of AGHD in the United States, Europe, and Japan. The recent approval of somapacitan and anticipated approval of other LAGH molecules presents new questions for physicians planning to treat AGHD with LAGH in the future. Differences in the technologies used to prolong the half-life of recombinant GH are expected to result in variations in pharmacokinetic and pharmacodynamic profiles between preparations. Therefore, it is essential that physicians understand and consider such variations when treating patients with these novel GH replacement therapies. Here, we present a set of treatment recommendations that have been created to guide physicians initiating therapy with somapacitan in patients with AGHD who are eligible for GH replacement. Furthermore, we will review the published data that underlie these recommendations to explain the rationale for the treatment and monitoring advice provided.

Light, an inevitable factor for human life, can have negative effects such as cellular inflammation and thus be toxic to cells. Lipids are important biomolecules that are involved in cellular inflammatory responses. Our research revealed the impact of light on cellular lipids. We discovered that blue light irradiation altered cellular lipidome based on non-targeted lipidomic analysis. Inflammation-related lysophospholipids, arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid, in particular, were significantly increased. We created opto-PiC, an optolipidomic tool based on the optogenetically engineered cPLA2 enzyme. Light-induced lipidomic changes were reversed by opto-PiC. Furthermore, the results showed that opto-PiC reduced cell death rate under blue light. Overall, our research provided lipidomic insights and optolipidomics approach into light toxicity. This could help the therapy development in the future for inflammation-related disease.

This article presents a case report of a 17-year-old boy with Kikuchi-Fujimoto disease (KFD), a condition characterized by fever and swollen lymph nodes in the neck. The boy experienced low body temperature, slow heart rate, and low blood pressure while being treated with glucocorticoids or cyclosporine A. These side effects resolved after stopping the medications and providing fluids. The article suggests that using a low dose of cyclosporine A may be a viable alternative for KFD patients who experience these adverse effects. It also mentions that caution should be exercised when using nonsteroidal anti-inflammatory drugs (NSAIDs) alongside this treatment. [Extracted from the article]

This article discusses a case of chronic nonbacterial osteomyelitis (CNO) complicated by recurrent erythema nodosum (EN) and its successful treatment with salazosulfapyridine (SASP). CNO is a condition characterized by bone lesions and can also present with mucocutaneous symptoms. EN is a skin condition associated with inflammation of the subcutaneous tissue. The patient initially received naproxen for treatment but experienced persistent symptoms. SASP was then introduced and led to remission of both CNO and EN. The use of SASP as a second-line treatment for refractory CNO and EN is suggested. [Extracted from the article]

Purpose To evaluate the antitumor efficacy in local and distant tumors induced by local hyperthermia with CTLA-4 blockade Methods A mouse breast cancer cell line was inoculated into both sides of the legs of mice. The mice were treated with three administrations of CTLA-4 blockade, a single application of local hyperthermia (42.5 °C for 20 min) to the tumor on one side of the leg, or the combination of the two. Tumor growth in locally heated tumors (HT tumors) and unheated distant tumors (UnHT tumors) and overall survival were evaluated. Results In the combination group, tumor volume significantly decreased for both HT and UnHT tumors compared with the tumors in the untreated and local hyperthermia monotherapy groups. Remarkable efficacy was only observed in the combination therapy group, in which 7 of 18 mice responded to HT and UnHT tumors, with significant prolonged overall survival. Conclusions Combination therapy enhanced the antitumor response not only in HT tumors but also in UnHT tumors and prolonged overall survival.

Epicutaneous exposure to allergenic proteins is an important sensitization route for skin diseases like protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. Environmental allergen sources such as house dust mites contain proteases, which are frequent allergens themselves. Here, the dependency of T-helper (TH) cell recall responses on allergen protease activity in the elicitation phase in mice pre-sensitized via distant skin was investigated. Repeated epicutaneous administration of a model protease allergen, i.e. papain, to the back skin of hairless mice induced skin inflammation, serum papain-specific IgE and TH2 and TH17 cytokine responses in the sensitization sites, and antigen-restimulated draining lymph node cells. In the papain-sensitized but not vehicle-treated mice, subsequent single challenge on the ear skin with papain, but not with protease inhibitor-treated papain, up-regulated the gene expression of TH2 and TH17/TH22 cytokines along with cytokines promoting these TH cytokine responses (TSLP, IL-33, IL-17C, and IL-23p19). Up-regulation of IL-17A gene expression and cells expressing RORγt occurred in the ear skin of the presensitized mice even before the challenge. In a reconstructed epidermal model with a three-dimensional culture of human keratinocytes, papain but not protease inhibitor-treated papain exhibited increasing transdermal permeability and stimulating the gene expression of TSLP, IL-17C, and IL-23p19. This study demonstrated that allergen protease activity contributed to the onset of cutaneous TH2 and TH17/TH22 recall responses on allergen re-encounter at sites distant from the original epicutaneous sensitization exposures. This finding suggested the contribution of protease-dependent barrier disruption and induction of keratinocyte-derived cytokines to the recall responses.

ContextWith the increasing number of older patients with acromegaly, it is important to understand the effects of aging on the quality of life (QoL) in acromegaly.ObjectiveTo investigate the factors associated with the QoL of older acromegaly patients.DesignThis was a single-center, retrospective, cross-sectional study conducted between 2014 and 2019.MethodsAmong 90 acromegaly patients at Kobe University Hospital, 74 who had completed the QoL evaluation under treatment were enrolled (age = 62.0 [50.7–70.0], female 52%). SF-36 and the AcroQoL questionnaire were used to quantify QoL. The patients were divided into two groups: the young and middle-aged group, aged

Abstract Background Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of β-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing’s syndrome (SCS) and non-functioning adrenal adenoma (NFA). Methods In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n = 18), SCS (n = 18), and NFA (n = 31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled. Results PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3 ~ 2.8) vs. 0.7 (0.5 ~ 1.8) and 0.9 (0.6 ~ 1.4) ng/mL/h; p = 0.018 and p = 0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5 ~ 79.5) vs. 156.0 (92.9 ~ 194.5) and 114.9 (90.1 ~ 153.4); p = 0.001 and p 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR

Abstract Background To improve the postoperative prognosis of patients with lung cancer, predicting the recurrence high-risk patients is needed for the efficient application of adjuvant chemotherapy. However, predicting lung cancer recurrence after a radical surgery is difficult even with conventional histopathological prognostic factors, thereby a novel predictor should be identified. As lipid metabolism alterations are known to contribute to cancer progression, we hypothesized that lung adenocarcinomas with high recurrence risk contain candidate lipid predictors. This study aimed to identify candidate lipid predictors for the recurrence of lung adenocarcinoma after a radical surgery. Methods Frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent a radical surgery were retrospectively reviewed. Recurrent and non-recurrent cases were assigned to recurrent (n = 10) and non-recurrent (n = 10) groups, respectively. Extracted lipids from frozen tissue samples were subjected to liquid chromatography-tandem mass spectrometry analysis. The average total lipid levels of the non-recurrent and recurrent groups were compared. Candidate predictors were screened by comparing the folding change and P-value of t-test in each lipid species between the recurrent and non-recurrent groups. Results The average total lipid level of the recurrent group was 1.65 times higher than that of the non-recurrent group (P

Abstract Background Ring calcification in hepatocellular carcinoma is extremely rare. Untreated hepatocellular carcinoma occasionally includes calcified lesions. Here, we report a case of ring-calcified hepatocellular carcinoma. Case presentation A 60-year-old man with a hepatic tumor was referred to Tokyo Women’s Medical University Hospital. He had a history of chronic hepatitis C. Computed tomography showed a liver tumor 20 mm in diameter in segment 6 of the Couinaud classification, with ring calcification. Based on this uncommon imaging presentation and the patient’s past exposure to the definitive hosts of Echinococcus multilocularis, he was preoperatively diagnosed with echinococcosis. Partial hepatectomy was performed as a radical treatment for echinococcosis. A final diagnosis of hepatocellular carcinoma was confirmed based on pathological findings. The patient was discharged uneventfully. Conclusion The presentation of an extremely rare hepatocellular carcinoma with ring calcification may be disguised as hydatid disease.

A decrease in nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of aging in multiple organisms, including humans. We report a human clinical trial designed to assess the efficacy of single-dose supplementation of nicotinamide, a form of vitamin B3, on increasing NAD+ levels. Nicotinamide intake within the daily tolerable upper level (200 mg) led to the maximal whole blood concentration by a 30-fold increase at 0.5 h with a consistent decrease until 6 h in all 6 healthy male volunteers. The increase in blood nicotinamide amounted to 17%, whereas renal clearance accounted for 1.8% of the ingested dose. NAD+ levels reached a maximum concentration at 12 h, with all time points showing a trend of increase. Blood metabolome assay indicates that the metabolomic changes with NAM supplementation lasted 24 h and then returned to baseline by 48 h. The basal levels of whole blood NAD+ varied among individuals with a negative correlation with body height as well as nicotinamide mononucleotide (NMN) levels. These data warrant consideration for further clinical evaluation with repeated doses of nicotinamide within the safety dose range for the potency to increase NAD+ levels and potential accompanying benefits for healthy longevity.

Background Mass spectrometry (MS) analysis using direct infusion of biological fluids is often problematic due to high salts/buffers. Iodinated contrast media (ICM) are frequently used for diagnostic imaging purposes, sometimes inducing acute kidney injury (AKI) in patients with reduced kidney function. Therefore, detection of ICM in spent hemodialysates is important for AKI patients who require urgent continuous hemodiafiltration (CHDF) because it allows noninvasive assessment of the patient’s treatment. In this study, we used a novel desalination tube before MS to inject the sample directly and detect ICM. Methods Firstly, spent hemodialysates of one patient were injected directly into the electrospray ionization (ESI) source equipped with a quadrupole time-of-flight mass spectrometer (Q-TOF MS) coupled to an online desalination tube for the detection of ICM and other metabolites. Thereafter, spent hemodialysates of two patients were injected directly into the ESI source equipped with a triple quadrupole mass spectrometer (TQ-MS) connected to that online desalination tube to confirm the detection of ICM. Results We detected iohexol (an ICM) from untreated spent hemodialysates of the patient-administered iohexol for computed tomography using Q-TOF MS. Using MRM profile analysis, we have confirmed the detection of ICM in the untreated spent hemodialysates of the patients administered for coronary angiography before starting CHDF. Using the desalination tube, we observed approximately 178 times higher signal intensity and 8 times improved signal-to-noise ratio for ioversol (an ICM) compared to data obtained without the desalination tube. This system was capable of tracking the changes of ioversol in spent hemodialysates of AKI patients by measuring spent hemodialysates. Conclusion The online desalination tube coupled with MS showed the capability of detecting iohexol and ioversol in spent hemodialysates without additional sample preparation or chromatographic separation. This approach also demonstrated the capacity to monitor the ioversol changes in patients’ spent hemodialysates.

Recent studies demonstrate that immune checkpoint blockade (ICB) increases the chances of the abscopal effect, an anti-tumor effect outside the radiation field in radiation therapy. However, the optimal sequence between radiation and ICB remains unclear. To investigate the impact of sequence of radiation in anti-PD-L1 antibody (P1) therapy on immune microenvironments and antitumor efficacies in local and abscopal tumors, metastatic LM8 osteosarcoma cells were inoculated into both legs of C3H mice. For irradiation, only one side leg was irradiated at 10 Gy. Then mice were divided into four groups: administrated anti-PD-L1 antibody three times (P1 monotherapy), receiving radiation 3 days prior to P1 therapy (P1+pre-Rad), and receiving concurrent radiation with P1 therapy (P1+conc-Rad). Thereafter, tumor immune microenvironment and tumor volume changes were analyzed in irradiated and unirradiated tumors. The P1+pre-Rad regimen increased the proportion of CD8+ programmed cell death 1 (PD-1)+ granzyme B (GzmB)+ reinvigorated T cells and decreased the proportion of CD8+ PD-1+ GzmB- exhausted T cells than P1+conc-Rad regimen in unirradiated tumors. Combination regimens suppressed tumor growth in irradiated tumors compared with that in P1 monotherapy. In both irradiated and unirradiated tumors, significant tumor growth suppression and prolonged overall survival were observed under both combination treatment regimens compared with P1 monotherapy. However, no distinct differences in unirradiated tumor volume and survival were observed between P1+pre-Rad and P1+conc-Rad groups. These results suggest that local irradiation is necessary to improve systemic treatment efficacy in P1 therapy regardless of sequence of local irradiation.

Endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated in habituation to stress, and its augmentation reduces stress-induced anxiety-like behavior. Chronic restraint stress (CRS) changes the 2-AG levels in some gross brain areas, such as the forebrain. However, the detailed spatial distribution of 2-AG and its changes by CRS in stress processing-related anatomical structures such as the anterior cingulate cortex (ACC), caudate putamen (CP), nucleus accumbens (NAc), and piriform cortex (PIR) are still unclear. In this study, mice were restrained for 30 min in a 50 mL-centrifuge tube for eight consecutive days, followed by imaging of the coronal brain sections of control and stressed mice using desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The results showed that from the forebrain to the cerebellum, 2-AG levels were highest in the hypothalamus and lowest in the hippocampal region. 2-AG levels were significantly (p < 0.05) upregulated and 2-AG precursors levels were significantly (p < 0.05) downregulated in the ACC, CP, NAc, and PIR of stressed mice compared with control mice. This study provided direct evidence of 2-AG expression and changes, suggesting that 2-AG levels are increased in the ACC CP, NAc, and PIR when individuals are under chronic stress.

The plasma membrane (PM) serves multiple functions to support cell activities with its heterogeneous molecular distribution. Fatty acids (FAs) are hydrophobic components of the PM whose saturation and length determine the membrane’s physical properties. The FA distribution contributes to the PM’s lateral heterogeneity. However, the distribution of PM FAs is poorly understood. Here, we proposed the FA cluster hypothesis, which suggested that FAs on the PM exist as clusters. By the optogenetic tool translocating the endoplasmic reticulum (ER), we were able to manipulate the distribution of PM FAs. We used time-of-flight combined secondary ion mass spectrometry (TOF-SIMS) to image PM FAs and discovered that PM FAs were presented and distributed as clusters and are also manipulated as clusters. We also found the existence of multi-FA clusters formed by the colocalization of more than one FA. Our optogenetic tool also decreased the clustering degree of FA clusters and the formation probability of multi-FA clusters. This research opens up new avenues and perspectives to study PM heterogeneity from an FA perspective. This research also suggests a possible treatment for diseases caused by PM lipid aggregation and furnished a convenient tool for therapeutic development.

Abstract Background Non-tuberculous mycobacterial (NTM) infections are increasing worldwide, making them an international public health problem. Surgical management is often indicated for localized infectious disease; however, most surgeons are unaware of the potential risks of transmission during surgery. Case presentation An 88-year-old Asian female was referred to our hospital for a tumor in the right lateral thoracic region. One month prior, she had a feeling of fullness and complained of localized pain and warmth in the right lateral thoracic wall. Pain and warmth gradually resolved without intervention; however, the fullness was getting worse. Computed tomography (CT) scan showed a mass of approximately 65 × 30 mm with an osteolytic change, involving the right 8th rib. Based on the rapid growth rate and CT findings, we strongly suspected a malignant chest wall tumor, and en bloc tumor resection with the 8th rib was performed. When the specimen was cut, a large amount of viscous pus was drained and its culture showed growth of Mycobacterium avium. Microscopically, the non-caseating epithelioid cell granuloma extended into the rib, infiltrating the bone cortex. On follow-up 1 month after discharge, there were no signs of infection or other adverse events associated with the surgery. Conclusions Herein, we report about a patient with a mass diagnosed as an NTM abscess involving the rib cage, which was confused with a malignant tumor and eventually diagnosed following surgical excision. This report emphasizes the need to be aware of the possibility of NTM infection and take appropriate precautions if the patient has a rapidly growing mass in the chest wall.

Introduction This study was conducted to investigate the incidence and time trend of lower limb amputation (LLA) among people with and without diabetes.Research design and methods This retrospective population-based cohort study was based on the national claims data in Japan, comprising a total population of 150 million. Data of all individuals who had LLA from April 2013 to March 2018 were obtained. We analysed the sex-adjusted and age-adjusted annual LLA rate (every fiscal year) in people with and without diabetes for major and minor amputation. To test for time trend, Poisson regression models were fitted.Results In the 5-year period, 30 187 major and 29 299 minor LLAs were performed in Japan. The sex-adjusted and age-adjusted incidence of major and minor LLAs was 9.5 (people with diabetes, 21.8 vs people without diabetes, 2.3, per 100 000 person-years) and 14.9 (people with diabetes, 28.4 vs people without diabetes, 1.9, per 100 000 person-years) times higher, respectively, in people with diabetes compared with those without. A significant decline in the annual major amputation rate was observed (p

Mass spectrometry imaging (MSI) is well-known for the non-labeling visualization of analytes, including drugs and their metabolites in biological samples. In this study, we applied three different tools of MSI, desorption electrospray ionization (DESI)-MSI, matrix-assisted laser desorption ionization (MALDI)-MSI, and a newly developed atmospheric pressure (AP)-MALDI-MSI known as iMScopeTM QT for rapid mapping of imipramine, chloroquine, and their metabolites in C57BL/6 male wild-type mice. Among three MSI tools, better detection capability for targeted drugs at higher speed (up to 32 pixels/s) was observed in iMScope QT. It revealed that imipramine and its metabolites were significantly accumulated in the renal cortex of mice, but chloroquine and its metabolites were highly accumulated in the renal pelvis and renal medulla of mice. Additionally, a higher accumulation of imipramine was noted in the thalamus, hypothalamus, septum, and hindbrain of mice brains. However, chloroquine and its metabolites showed notable accumulation in the lateral ventricle, fourth ventricle, and fornix of the mice brains. These findings of our study can be helpful in understanding clinically relevant properties, efficacy, and potential side effects of these drugs. Our study also showed the potentiality of iMScope QT for rapid mapping of small drugs and their metabolites in biological samples.

ObjectiveHeterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies.Design and MethodsWe analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies.ResultsImmunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high.ConclusionsPatients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.