Humoral immune response against SARS-CoV-2 and polyethylene glycol elicited by anti-SARS-CoV-2 mRNA vaccine, and effect of pre-existing anti-polyethylene glycol antibody in patients with hematological and autoimmune diseases.

Background: The effects of vaccination are modified by hematological and autoimmune diseases and/or treatment. Anti-SARS-CoV-2 mRNA vaccine contains polyethylene glycol (PEG), it is largely unknown whether PEG influences the effects of vaccination or induces a humoral response. This study examined whether anti-PEG antibodies before vaccination (pre-existing) influenced the acquisition of SARS-CoV-2 antibodies and evaluated the relationship between the development of anti-SARS-CoV-2 antibodies and anti-PEG antibodies after SARS-CoV-2 vaccination in hematological and autoimmune diseases. Methods: Anti-SARS-CoV-2 antibody IgG, anti-PEG IgG, and IgM titers were evaluated in patients with hematological and autoimmune diseases after the second dose of BNT162B2. Anti-PEG IgG and IgM titers were also measured before vaccination to examine changes after vaccination and the relationship with vaccine efficacy. Results: In patients with hematological (n = 182) and autoimmune diseases (n = 96), anti-SARS-CoV-2 and anti-PEG antibody titers were evaluated after a median of 33 days from 2nd vaccination. The median anti-SARS-CoV-2 antibody titers were 1901 AU/mL and 3832 AU/mL in patients with hematological and autoimmune disease, respectively. Multiple regression analysis showed that age and days from 2nd vaccination were negatively associated with anti-SARS-CoV-2 antibody titers. Anti-CD20 antibody treatment was negatively correlated with anti-SARS-CoV-2 antibody titers in hematological disease, and C-reactive protein (CRP) was positively correlated with anti-SARS-CoV-2 antibody titers in autoimmune disease. Baseline anti-PEG antibody titers were significantly higher in patients with autoimmune disease but were not correlated with anti-SARS-CoV-2 antibody titers. Patients with increased anti-PEG IgG acquired higher anti-SARS-CoV-2 antibody titers in patients with autoimmune disease. Conclusions: Anti-SARS-CoV-2 antibody acquisition was suboptimal in patients with hematological disease, but both anti-SARS-CoV-2 antibody and anti-PEG IgG were acquired in patients with autoimmune disease, reflecting robust humoral immune response. Pre-existing anti-PEG antibody titers did not affect anti-SARS-CoV-2 antibody acquisition.

Identification of exhaled volatile organic compounds that characterize asthma phenotypes: A J-VOCSA study.

BACKGROUND: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. METHODS: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). RESULTS: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR. CONCLUSIONS: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified.

Skeletal muscle mass during chemotherapy for haematological malignancies: a retrospective study.

OBJECTIVE: This study investigated whether baseline or alteration in muscle mass affects complications during chemotherapy or overall survival (OS) in haematological malignancies. METHODS: Skeletal Muscle Index (SMI) was evaluated by bioimpedance analysis before and after chemotherapy in patients with haematological malignancies, and the association between muscle mass and clinical data was retrospectively analysed. RESULTS: Exactly 104 patients were enrolled, with a mean age of 62.2 years. SMI was 7.85 and 6.08 in male and female patients under 65 years and 7.10 and 5.92 over 65 years, before chemotherapy, respectively. Lower baseline SMI was not correlated with worse OS in total patients (p=0.915). After a median measurement interval of 30 days after chemotherapy (n=67), body weight and SMI decreased by 2.73% and 2.87% (mean), respectively. The decrease in body weight correlated with the loss of trunk muscle mass (R2=0.2107) but was more strongly associated with the loss of lower limbs muscle mass (R2=0.3985). The muscle mass of lower limbs significantly decreased in lymphoma patients who experienced febrile neutropenia (-0.42% vs -6.04%, p=0.040). OS significantly decreased in lymphoma patients with loss of lower limbs muscle ≥2.8% (p=0.0327). CONCLUSIONS: Muscle loss occurred following anticancer treatments, significantly contributing to worse outcomes. Body composition assessment and relevant multimodal prevention of muscle loss may be vital for patients receiving chemotherapy for haematological malignancies.

Toxoplasmic encephalitis with high 201Tl uptake and retention mimicking malignant lymphoma in a patient with human immunodeficiency virus infection.

Various opportunistic infections develop during immunodeficiency due to human immunodeficiency virus (HIV) infection. The treatment options for malignant lymphoma (ML) and toxoplasmic encephalitis (TE) are completely different; therefore, their discrimination is critical. A 25-year-old female of foreign nationality had been experiencing headaches for several weeks and suddenly developed convulsions. Brain computed tomography revealed multiple intracranial lesions; therefore, the patient was referred to the neurosurgery department. Brain magnetic resonance imaging (MRI) revealed multiple masses with surrounding edema, accompanied by enhanced contrast. The largest mass (2 cm) in the left occipital lobe exhibited ringed contrast enhancement. Her blood test results showed a CD4 count of 40/µL, positive HIV Ag/Ab, HIV-RNA level of 56 × 104 copies/mL, positive anti-Toxoplasma IgG (63 IU/mL), and negative anti-Toxoplasma IgM. 201Tl- single photon emission computed tomography (201Tl-SPECT) revealed abnormal accumulation only in the tumor in the left occipital lobe (early T/N ratio, 3.034; delayed T/N ratio, 2.738; retention index, 0.9), which was suspected to be a ML. Both tumors, with or without high accumulation of 201Tl, were subjected to craniotomy biopsy. Pathological examination revealed infiltration of small lymphocytes with a necrotic background. The patient was diagnosed with TE based on a positive result of a tissue polymerase chain reaction test for Toxoplasma gondii. Two weeks after sulfamethoxazole and trimethoprim combination therapy, MRI imaging showed dramatic improvement in multiple brain tumors. This case is atypical because ML was ruled out despite high 201Tl-SPECT uptake and retention. Careful diagnosis through pathological examination and DNA testing is important.

Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid.

As multiple myeloma (MM) progresses, immune effector cells decrease in number and function and become exhausted. This remains an insurmountable clinical issue that must be addressed by development of novel modalities to revitalize anti-MM immunity. Human Vγ9Vδ2 T (Vδ2+ γδ T) cells serve as the first line of defense against pathogens as well as tumors and can be expanded ex vivo from peripheral blood mononuclear cells (PBMCs) upon treatment with amino-bisphosphonates in combination with IL-2. Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). However, the expansion of Th1-like Vδ2+ γδ T cells by these immunomodulatory drugs was abolished under IL-2 blockade, although IL-2 production was induced in PBMCs. BTN3A1 triggers phosphoantigen presentation to γδ T-cell receptors and is required for γδ T-cell expansion and activation. ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

A Nursing Pre-Transplant Intervention to Reduce Patients' Uncertainty about Allogeneic Hematopoietic Stem Cell Transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) procedures often experience high levels of uncertainty. In this study, we developed and implemented a nursing intervention program to help patients recognize and reduce pre-transplant uncertainty. This study used a pretest-posttest single-group design without a control group. Eighteen patients undergoing HSCT participated in the intervention program-which included informational support, confirmation that the patients understood the information provided, and emotional support. Outpatients received the intervention at their initial outpatient visits after their procedure dates were determined, while inpatients received it at discharge following their procedures. The Universal Uncertainty in Illness Scale (UUIS), which consists of 26 items and six subscales, was used as the primary outcome measure. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Hospital Anxiety and Depression Scale were used as secondary outcome measures. The sample included 18 individuals (13 male and five female participants; median age, 52 years). Most participants had acute lymphoblastic leukemia and had previously undergone bone marrow transplantations. Following our intervention, the total UUIS score significantly decreased, from 80.83 ± 18.42 before the intervention to 63.06 ± 23.53 afterward (t = 4.98, p < .001). Furthermore, significant post-intervention reductions were observed for all six subscales of the UUIS. There were no significant differences in the functional EORTC QLQ-C30 scale scores; however, the symptom scale showed a significant decrease in fatigue (pre = 35.19 ± 19.53, post = 25.93 ± 17.04, Z = -1.99, p < 0.046) and constipation (pre = 20.37 ± 20.26, post = 7.41 ± 14.26, Z = -2.11, p = 0.035). There were no significant differences in anxiety and depression levels pre- and post-intervention. Overall, the intervention effectively reduced both UUIS total and subscale scores related to pre-HSCT uncertainties. Assessing uncertainty prior to HSCT is vital to assisting patients in coping with the procedure. Nurses not only provide information but also tailor the information to the patients' cognitive abilities, thereby simplifying their understanding of the disease and its treatment.

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3'-UTR change as a possible cause.

Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.

A novel zinc-chelating compound has antifungal activity against a wide range of Candida species, including multidrug-resistant Candida auris.

Objectives: In recent years, the incidence of invasive fungal infections has increased, resulting in considerable morbidity and mortality, particularly among immunocompromised individuals. Potential challenges in treating these infections with the few existing antifungal agents highlight the urgency of developing new ones. Here, we evaluated six alkyl polyamine compounds (APCs), not previously reported as antifungal drugs to our knowledge, that could deprive fungi of essential transition metals. Methods: The APC with confirmed antifungal activity against Candida spp. was analysed by using transcriptomics, followed by metal-addition experiments, mass spectrometric analyses and intracellular zinc quantification with a fluorescent probe. Results: A cyclic APC with three pyridylmethyl groups, APC6, had high antifungal activity against a wide range of Candida species, including MDR Candida auris. We conclusively demonstrated that APC6 was able to capture zinc within fungal cells. APC6 not only exhibited activity against C. auris as a single agent but also enhanced the efficacy of an azole antifungal agent, voriconazole, in vitro and in vivo. APC6 disrupted the biofilms formed by Candida species. Conclusions: This zinc-chelating compound has potential as an antifungal agent, and the control of zinc levels in Candida species could be a powerful approach to treating drug-resistant candidiasis.

Chlorobenzene-driven palladium-catalysed lactonisation of benzoic acids.

Herein, we developed a palladium-catalysed C-H cyclisation of benzoic acids in chlorobenzene without additional oxidants. The key to the success of these reactions is the use of chlorobenzene, which serves a dual role as a solvent and an oxidant, thus providing a simple and efficient method for synthesising phthalides.

Acute accumulation of PIM2 and NRF2 and recovery of ß5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of ß5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of ß5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.

Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib.

Hyperthermia is a unique treatment option for cancers. Multiple myeloma (MM) remains incurable and innovative therapeutic options are needed. We investigated the efficacy of hyperthermia and carfilzomib in combination against MM cells. Although MM cell lines exhibited different susceptibilities to pulsatile carfilzomib treatment, mild hyperthermia at 43℃ induced MM cell death in all cell lines in a time-dependent manner. Hyperthermia and carfilzomib cooperatively induced MM cell death even under suboptimal conditions. The pro-survival mediators PIM2 and NRF2 accumulated in MM cells due to inhibition of their proteasomal degradation by carfilzomib; however, hyperthermia acutely suppressed translation in parallel with phosphorylation of eIF2α to reduce these proteins in MM cells. Recovery of ß5 subunit enzymatic activity from its immediate inhibition by carfilzomib was observed at 24 h in carfilzomib-insusceptible KMS-11, OPM-2, and RPMI8226 cells, but not in carfilzomib-sensitive MM.1S cells. However, heat treatment suppressed the recovery of ß5 subunit activity in these carfilzomib-insusceptible cells. Therefore, hyperthermia re-sensitized MM cells to carfilzomib. Our results support the treatment of MM with hyperthermia in combination with carfilzomib. Further research is warranted on hyperthermia for drug-resistant extramedullary plasmacytoma.

Impact of computer-aided characterization for diagnosis of colorectal lesions, including sessile serrated lesions: Multireader, multicase study.

OBJECTIVES: Computer-aided characterization (CADx) may be used to implement optical biopsy strategies into colonoscopy practice; however, its impact on endoscopic diagnosis remains unknown. We aimed to evaluate the additional diagnostic value of CADx when used by endoscopists for assessing colorectal polyps. METHODS: This was a single-center, multicase, multireader, image-reading study using randomly extracted images of pathologically confirmed polyps resected between July 2021 and January 2022. Approved CADx that could predict two-tier classification (neoplastic or nonneoplastic) by analyzing narrow-band images of the polyps was used to obtain a CADx diagnosis. Participating endoscopists determined if the polyps were neoplastic or not and noted their confidence level using a computer-based, image-reading test. The test was conducted twice with a 4-week interval: the first test was conducted without CADx prediction and the second test with CADx prediction. Diagnostic performances for neoplasms were calculated using the pathological diagnosis as reference and performances with and without CADx prediction were compared. RESULTS: Five hundred polyps were randomly extracted from 385 patients and diagnosed by 14 endoscopists (including seven experts). The sensitivity for neoplasia was significantly improved by referring to CADx (89.4% vs. 95.6%). CADx also had incremental effects on the negative predictive value (69.3% vs. 84.3%), overall accuracy (87.2% vs. 91.8%), and high-confidence diagnosis rate (77.4% vs. 85.8%). However, there was no significant difference in specificity (80.1% vs. 78.9%). CONCLUSIONS: Computer-aided characterization has added diagnostic value for differentiating colorectal neoplasms and may improve the high-confidence diagnosis rate.

Deep dermatophytosis caused by Trichophyton rubrum in an elderly patient with CARD9 deficiency: A case report and literature review.

Deep dermatophytosis is an invasive and sometimes life-threatening fungal infection mainly reported in immunocompromised patients. However, a caspase recruitment domain-containing protein 9 (CARD9) deficiency has recently been reported to cause deep dermatophytosis. Herein, we report the first Japanese case of deep dermatophytosis associated with CARD9 deficiency. An 80-year-old Japanese man with tinea corporis presented with subcutaneous nodules on his left sole. Histopathological findings revealed marked epithelioid cell granulomas with filamentous fungal structures in the deep dermis and subcutis, and the patient was diagnosed with deep dermatophytosis. Despite antifungal therapy, the subcutaneous nodule on his left sole gradually enlarged, his left calcaneal bone was invaded, and the patient finally underwent amputation of his left leg. Genetic analysis revealed a homozygous CARD9 c.586 A > G (p. Lys196Glu) variant, suggesting a CARD9 deficiency. Here, we discuss the clinical features of CARD9 deficiency-associated deep dermatophytosis with a case report and review of the literature.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Cross-Sectional and Longitudinal Associations between Skin Autofluorescence and Tubular Injury Defined by Urinary Excretion of Liver-Type Fatty Acid-Binding Protein in People with Type 2 Diabetes.

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.

VDR is an essential regulator of hair follicle regression through the progression of cell death.

Vitamin D receptor (VDR) is essential for hair follicle homeostasis as its deficiency induces hair loss, although the mechanism involved remains unknown. Our research shows that, in Vdr-knockout mice, the hair cycle is halted during the catagen stage, preceding alopecia. In addition, in Vdr-knockout hair follicles, epithelial strands that normally regress during the catagen phase persist as "surviving epithelial strands." Single-cell RNA sequencing analysis suggests that these surviving epithelial strands are formed by cells in the lower part of the hair follicle. These findings emphasize the importance of the regression phase in hair follicle regeneration and establish VDR as a regulator of the catagen stage.

Exophiala dermatitidis coinfection with nontuberculous mycobacteria: A case report and literature review.

Six years ago, a 60-year-old man presented to our hospital with a cough and sputum. Upon suspicion of nontuberculous mycobacterial (NTM) infection, he was followed up at our hospital. Because the abnormal shadows in the bilateral lung fields deteriorated slightly over 6 years, bronchoscopy was performed. Exophiala dermatitidis and Mycobacterium intracellulare were detected in the bronchial lavage fluid. The patient underwent follow-up examinations without drug administration. Currently, the patient's condition remains stable. E. dermatitidis is regulatory found in the lungs of patients with cystic fibrosis, but only rarely is it found in respiratory samples from patients without cystic fibrosis. However, NTM complications have been reported more frequently in recent years. Due to the increasing number of NTM patients, E. dermatitidis pulmonary infections may also increase. Additional research is required to develop strategies for treating this infection.

Lung adenocarcinoma with micropapillary and solid patterns: Recurrence rate and trends.

BACKGROUND: Lung adenocarcinomas with micropapillary pattern (MP) or solid pattern (SP) have poor prognosis with frequent postoperative recurrence. However, treatment strategies for these histological subtypes have not been established. This study examined the recurrence rates and patterns in patients with these histological subtypes. METHODS: Overall, 238 patients with lung adenocarcinoma who underwent radical resection were included. According to the histological subtypes, the patients were classified into three groups: neither MP nor SP (MP-/SP-), MP (MP+), and SP (SP+). The clinical and pathological characteristics and recurrence-free survival (RFS) were examined in each group. In addition, univariate and multivariate analyses were performed to investigate the recurrence factors. The site of recurrence, PD-L1 expression, and driver mutations were examined in patients with postoperative recurrence. RESULTS: The recurrence rates were significantly higher in the MP+ and SP+ groups (p = 0.01). The RFS was significantly shorter in the MP+ and SP+ groups (p < 0.001) than in the MP-/SP- group, especially in pStage 1A (p = 0.001). The relationship between recurrence and pathologic factors was significant for pleural, lymphatic, and vascular invasion, as well as MP in univariate analysis and only for MP in multivariate analysis. Most recurrences were distant metastases in the MP+ and SP+ groups. PD-L1 was highly expressed in recurrent SP+ cases. CONCLUSIONS: Early-stage lung adenocarcinoma with MP or SP frequently has postoperative recurrence. Prevention of distant metastases is important in these patients to improve prognosis, and aggressive postoperative chemotherapy may be considered.