Impact of polypharmacy on 3-year mortality in patients with heart failure: a retrospective study.

BACKGROUND: Guideline-directed medical therapy (GDMT) is important in heart failure management; however, polypharmacy itself may impact heart failure. Although measures against polypharmacy are needed, current discussion on unilateral drug tapering (including the drugs that should be tapered) is insufficient. In this study, we investigated the relationship between the number of prescribed GDMT drugs and prognosis in patients with heart failure. METHODS: In this single-centre retrospective study, 3,146 eligible patients with heart failure were included and divided into four groups based on the median number of prescribed GDMT drugs and the median number of drugs not included in the GDMT (ni-GDMT) at the time of hospital discharge. The definition of GDMT was based on various Japanese guidelines. The primary outcome was all-cause mortality within 3 years of hospital discharge. RESULTS: A total of 252 deaths were observed during the 3-year follow-up period. Kaplan-Meier analysis revealed that groups with GDMT drug count ≥ 5 and ni-GDMT drug count < 4 had the lowest mortality, and those with GDMT drug count < 5 and ni-GDMT drug count ≥ 4 had the highest mortality (log-rank, P < 0.001). Cox regression analysis revealed a significant association between ni-GDMT drug count and all-cause mortality, even after adjustment for number of GDMT medications, age, male, left ventricular ejection function < 40%, hemoglobin, albumin levels, and estimated glomerular filtration rate [HR = 1.06 (95% CI: 1.01-1.11), P = 0.020]. Conversely, the GDMT drug count was not associated with increased mortality rates. CONCLUSIONS: The ni-GDMT drug count was significantly associated with 3-year mortality in patients with heart failure. Conversely, the GDMT drug count did not worsen the prognosis. Polypharmacy measures should consider ni-GDMT drug quantity to improve the prognosis and outcomes in patients with heart failure.

Pathogenic role and diagnostic utility of interferon-α in histiocytic necrotizing lymphadenitis.

PURPOSE: Histiocytic necrotizing lymphadenitis (HNL) is an inflammatory disease of unknown etiology clinically characterized by painful lymphadenopathy. This study aimed to investigate the role of interferon (IFN)-α in the pathogenesis of HNL and the clinical significance of serum IFN-α levels for the diagnosis and monitoring of HNL disease activity. METHODS: This study enrolled 47 patients with HNL and 43 patients with other inflammatory diseases that require HNL differentiation including malignant lymphoma (ML), bacterial lymphadenitis, and Kawasaki disease. Expression of IFN-stimulated genes (ISGs) and MX1 in the lymph nodes was measured by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence staining, respectively. Enzyme-linked immunosorbent assay was used to quantify serum cytokine levels. The results were compared with the clinical features and disease course of HNL. RESULTS: Patients with HNL had a significantly elevated ISG expression in the lymph nodes compared with those with ML. MX1 and CD123, a specific marker of plasmacytoid dendritic cells (pDCs), were colocalized. In patients with HNL, serum IFN-α levels were significantly elevated and positively correlated with disease activity. The serum IFN-α level cutoff value for differentiating HNL from other diseases was 11.5 pg/mL. CONCLUSION: IFN-α overproduction from pDCs may play a critical role in HNL pathogenesis. The serum IFN-α level may be a valuable biomarker for the diagnosis and monitoring of disease activity in patients with HNL.

Association between Stimulation-Site Pain and Clinical Improvement during Repetitive Transcranial Magnetic Stimulation for Patients with Major Depressive Disorders: A Prospective Observational Study at Two Sites.

INTRODUCTION: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) in Japan has not been adequately investigated. Furthermore, the relationship between stimulation-site pain and the antidepressant effects of rTMS has not been thoroughly examined. Therefore, this study aimed to clarify (1) the real-world efficacy and safety of rTMS for TRD in Japan and (2) the relationship between stimulation-site pain and clinical improvement of depressive symptoms. METHODS: We conducted a retrospective observational study involving 50 right-handed patients with TRD. All patients received high-frequency rTMS for up to 6 weeks. Depressive symptoms were assessed using the Montgomery-Åsberg depression rating scale (MADRS). Pain at the stimulation site was reported by the patients using a visual analog scale (VAS) after each session. Remission and response rates at 3 and 6 weeks were calculated based on the MADRS scores. The correlation between changes in the MADRS and VAS scores was examined. RESULTS: Remission and response rates were 36% and 46%, respectively, at the end of 3 weeks, and 60% and 70%, respectively, at 6 weeks. At the end of the treatment, there was significant correlation between the reduction of MADRS and VAS scores (r = 0.42, p = 0.003). CONCLUSION: This study demonstrates the clinical efficacy of rTMS in Japan and the correlation between its antidepressant effects and stimulation-site pain.

Reinforcement of pimobendan with guideline-directed medical therapy may reduce the rehospitalization rates in patients with heart failure: retrospective cohort study.

BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Recombinant mycobacterial DNA-binding protein 1 with post-translational modifications boosts IFN-gamma production from BCG-vaccinated individuals' blood cells in combination with CpG-DNA.

Tuberculosis remains a large health threat, despite the availability of the tuberculosis vaccine, BCG. As BCG efficacy gradually decreases from adolescence, BCG-Prime and antigen-booster may be an efficient strategy to confer vaccine efficacy. Mycobacterial DNA-binding protein 1 (MDP1, namely Rv2986c, hupB or HU) is a major Mycobacterium tuberculosis protein that induces vaccine-efficacy by co-administration with CpG DNA. To produce MDP1 for booster-vaccine use, we have created recombinant MDP1 produced in both Escherichia coli (eMDP1) and Mycolicibacterium smegmatis (mMDP1), an avirulent rapid-growing mycobacteria. We tested their immunogenicity by checking interferon (IFN)-gamma production by stimulated peripheral blood cells derived from BCG-vaccinated individuals. Similar to native M. tuberculosis MDP1, we observed that most lysin resides in the C-terminal half of mMDP1 are highly methylated. In contrast, eMDP1 had less post-translational modifications and IFN-gamma stimulation. mMDP1 stimulated the highest amount of IFN-gamma production among the examined native M. tuberculosis proteins including immunodominant MPT32 and Antigen 85 complex. MDP1-mediated IFN-gamma production was more strongly enhanced when combined with a new type of CpG DNA G9.1 than any other tested CpG DNAs. Taken together, these results suggest that the combination of mMDP1 and G9.1 possess high potential use for human booster vaccine against tuberculosis.

Gut microbiota of one-and-a-half-year-old food-allergic and healthy children.

BACKGROUND: Intestinal bacteria may play a role in the development of food allergies. This study aimed to analyze and compare the gut microbiota of food-allergic children with that of healthy children of the same age. METHODS: Stool samples were collected from one-and-a-half-year-old food-allergic (FA group, n = 29) and healthy controls (HC group, n = 19). A questionnaire was provided to examine the children's birth, dietary, medical, and social histories. The gut microbiota was profiled by 16S rRNA sequencing. Differences in taxonomic composition were assessed using linear discriminant analysis effect size (LEfSe), and microbial functional profiles were predicted with Tax4Fun2. RESULTS: No significant difference in the alpha diversity index between the two groups; however, a negative correlation was observed between the Shannon diversity index and the relative abundance of Bacteroides. A significant difference was observed in beta diversity (permutational multivariate analysis of variance) in the bacterial composition between the FA and HC groups (P < 0.05). The FA group had a higher abundance of Escherichia and Anaeromassilibacillus and a lower abundance of Bacteroides, Oscillibacter, Ruminococcus, Hungateiclostridium and Anaerotaenia than the HC group (LEfSe: linear discriminant analysis score >2). The FA group showed a predicted increase in the expression levels of genes associated with intestinal pathogenicity compared with that in the HC group. CONCLUSIONS: The gut microbiota of food-allergic children has a higher abundance of bacteria involved in intestinal inflammation and a lower abundance of bacteria involved in immune tolerance than that of healthy children. This dysbiosis may also be associated with food allergies.

Differences in Characteristics Between Patients Who Met or Partly Met the Diagnostic Criteria for Food Protein-Induced Enterocolitis Syndrome (FPIES).

BACKGROUND: Some patients with food protein-induced enterocolitis (FPIES)-like allergy do not completely fulfill the diagnostic criteria of the international consensus guideline for FPIES. However, it is unclear whether such FPIES-like patients represent a completely different population from FPIES. OBJECTIVE: This study aimed to clarify differences in characteristics between patients with FPIES who fully met diagnostic criteria and those who partly met them. METHODS: This was a cross-sectional study using data at the time of registration in multicenter, prospective studies of patients with FPIES in Japan. Children who had delayed emesis within 1 to 4 hours and/or diarrhea within 5 to 10 hours after ingestion of food were recruited between March 2020 and February 2022. We examined their compatibility with the diagnostic criteria of the international consensus guideline and their detailed clinical characteristics, including trigger foods, the serving size that elicited symptoms, and antigen-specific IgE antibody titers. RESULTS: Of the 225 patients with FPIES, 140 fully met the diagnostic criteria whereas 79 patients did not fully meet them but demonstrated reproducible symptoms. The frequencies of pallor, lethargy, and diarrhea were significantly higher in those who met the criteria fully, whereas the age at onset, trigger foods, comorbidity, and perinatal information were comparable. Analysis of patients with FPIES to hen's egg revealed significantly higher levels of egg white- and egg yolk-specific IgE in patients who partly met criteria, whereas the serving size eliciting symptoms was comparable. CONCLUSIONS: Patients who partly met the diagnostic criteria may have a milder phenotype of FPIES, but this needs to be validated in further studies using biomarkers reflecting the pathophysiology.

Impact of Red Blood Cell Transfusion on Subsequent Cardiovascular Events in Patients with Acute Heart Failure and Anemia.

Red blood cell (RBC) transfusion therapy is often performed in patients with acute heart failure (AHF) and anemia; however, its impact on subsequent cardiovascular events is unclear. We examined whether RBC transfusion influences major adverse cardiovascular events (MACE) after discharge in patients with AHF and anemia.We classified patients with AHF and anemia (nadir hemoglobin level < 10 g/dL) according to whether they received RBC transfusion during hospitalization. The endpoint was MACE (composite of all-cause death, non-fatal acute coronary syndrome/stroke, or heart failure readmission) 180 days after discharge. For survival analysis, we used propensity score matching analysis with the log-rank test. As sensitivity analysis, we performed inverse probability weighting analysis and multivariable Cox regression analysis.Among 448 patients with AHF and anemia (median age, 81 years; male, 55%), 155 received RBC transfusion and 293 did not. The transfused patients had worse clinical features than the non-transfused patients, with lower levels of nadir hemoglobin and serum albumin and a lower estimated glomerular filtration rate. In the propensity-matched cohort of 87 pairs, there was no significant difference in the MACE-free survival rate between the 2 groups (transfused, 73.8% vs. non-transfused, 65.3%; P = 0.317). This result was consistent in the inverse probability weighting analysis (transfused, 76.0% vs. non-transfused, 68.7%; P = 0.512), and RBC transfusion was not significantly associated with post-discharge MACE in the multivariable Cox regression analysis (adjusted hazard ratio: 1.468, 95% confidence interval: 0.976-2.207; P = 0.065).In conclusion, this study suggests that RBC transfusions for anemia may not improve clinical outcomes in patients with AHF.

Fractional excretion of urea nitrogen can identify true worsening renal function in patients with heart failure.

AIMS: Fractional excretion of urea nitrogen (FEUN), used to differentiate the cause of acute kidney injury, has emerged as a useful fluid index in patients with heart failure (HF). We hypothesized that FEUN could be useful in identifying worsening renal function (WRF) associated with poor outcomes in patients with acute HF (AHF). METHODS AND RESULTS: Overall, 1103 patients with AHF (median age, 78 years; male proportion, 60%) were categorized into six groups according to the presence of WRF and FEUN values (low, ≤32.1%; medium, >32.1% and ≤38.0%; and high, >38.0%) at discharge. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level from admission to discharge. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). The cut-off values for low, medium, and high FEUN were based on a previous study. The primary outcome of this study was HF readmission after hospital discharge. During the 1 year follow-up, 170 HF readmissions occurred. Kaplan-Meier analysis revealed significantly higher HF readmission rates in patients with WRF than in those without WRF (log-rank test, P < 0.001). Additionally, among patients with WRF, HF readmission rates were lowest in those with medium FEUN values, followed by those with low FEUN values and those with high FEUN values. On multivariable analysis, the presence of WRF with low or high FEUN values was independently associated with increased HF readmission, as compared with the absence of WRF with medium FEUN values. Notably, no association was noted between WRF with medium FEUN values and HF readmission. CONCLUSIONS: The prognostic impact of WRF was significantly mediated by the FEUN values and was associated with worse outcomes only when the FEUN values were either low or high. Our study suggests that FEUN can identify prognostically relevant WRF in patients with AHF.

Genetic engineering employing MPB70 and its promoter enables efficient secretion and expression of foreign antigen in bacillus Calmette Guérin (BCG) Tokyo.

Vaccination is an important factor in public health. The recombinant bacillus Calmette Guérin (rBCG) vaccine, which expresses foreign antigens, is expected to be a superior vaccine against infectious diseases. Here, we report a new recombination platform in which the BCG Tokyo strain is transformed with nucleotide sequences encoding foreign protein fused with the MPB70 immunogenic protein precursor. By RNA-sequencing, mpb70 was found to be the most transcribed among all known genes of BCG Tokyo. Small oligopeptide, namely, polyhistidine tag, was able to be expressed in and secreted from rBCG through a process in which polyhistidine tag fused with intact MPB70 were transcribed by an mpb70 promoter. This methodology was applied to develop an rBCG expressing the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2. Immunoblotting images and mass spectrometry data showed that RBD was also secreted from rBCG. Sera from mice vaccinated with the rBCG showed a tendency of weak neutralizing capacity. The secretion was retained even after a freeze-drying process. The freeze-dried rBCG was administered to and recovered from mice. Recovered rBCG kept secreting RBD. Collectively, our recombination platform offers stable secretion of foreign antigens and can be applied to the development of practical rBCGs.

The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.

The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.

Liver remnant volume to body weight ratio of 0.65% as a lower limit in right hepatic trisectionectomy with bile duct resection.

BACKGROUND: Previous studies have suggested the utility of an indocyanine green plasma clearance rate of the future liver remnant (FLR) (ICGK-F) ≥0.05 in hepatobiliary resection to reduce the surgical risk. The present study aimed to verify whether future liver remnant size rather than ICGK-F matters in extended hepatobiliary resection. METHODS: Between 2004 and 2021, patients who underwent right hepatic trisectionectomy with bile duct resection were included. The effect of the FLR volume-to-body weight ratio (FLR/BW) and ICGK-F on posthepatectomy liver failure was evaluated along with other parameters. RESULTS: Among 91 study patients, the median ICGK-F, FLR, and FLR/BW were 0.057 (range, 0.027-0.099), 392 mL (145-705), and 0.78% (0.40-1.37), respectively. Posthepatectomy liver failure occurred in 23 patients. The incidence was 10 (40%) in 25 patients with an ICGK-F <0.05 and 12 (18%) in 65 patients with an ICGK-F ≥0.05 (P = .053); 13 (52%) in 25 patients with a FLR/BW <0.65% and 10 (15%) in 66 patients with a FLR/BW ≥0.65% (P = .001). Multivariate analysis showed that a FLR/BW <0.65% (odds ratio, 11.7; P = .005), age ≥65 years (odds ratio, 31.7; P < .001), and blood loss ≥25 mL/kg (odds ratio, 22.1; P = .004) were independent predictors of posthepatectomy liver failure, but ICGK-F <0.05 was not (P = .499). According to the meeting number of 3 factors, posthepatectomy liver failure incidence was 0 of 22 (0%) in patients with 0 factors, 6 of 43 (14%) in patients with 1, and 17 of 26 (65%) in patients with 2 or 3 (P < .001). CONCLUSION: A FLR/BW ≥0.65% may serve as a volumetric basis to reduce posthepatectomy liver failure after extended hepatobiliary resection.

What Is Food Noise? A Conceptual Model of Food Cue Reactivity.

As GLP-1 receptor agonists, like semaglutide, emerge as effective treatments for weight management, anecdotal reports from patients and clinicians alike point to a reduction in what has been colloquially termed "food noise", as patients report experiencing less rumination and obsessive preoccupation about food. In this narrative review, we discuss concepts used in studies to investigate human eating behavior that can help elucidate and define food noise, particularly food cue reactivity. We propose a conceptual model that summarizes the main factors that have been shown to determine the magnitude of the reactivity elicited by external and internal food cues and how these factors can affect short- and long-term behavioral and clinical outcomes. By integrating key research conducted in this field, the Cue-Influencer-Reactivity-Outcome (CIRO) model of food cue reactivity provides a framework that can be used in future research to design studies and interpret findings related to food noise and food cue reactivity.

Quality of measurement properties of medication adherence instruments in cardiovascular diseases and type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Medication adherence has a major impact on reducing mortality and healthcare costs related to the treatment of cardiovascular diseases and diabetes mellitus. Selecting the best patient-reported outcome measure (PROM) among the many available for this kind of patient is extremely important. This study aims to critically assess, compare and synthesize the quality of the measurement properties of patient-reported outcome measures to assess medication adherence among patients with cardiovascular diseases and/or type 2 diabetes mellitus. METHODS: This review followed the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines and was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). The searches were performed in Web of Science, SCOPUS, PubMed, CINAHL, EMBASE, LILACS, PsycINFO, and ProQuest (gray literature). RESULTS: A total of 110 records encompassing 27 different PROMs were included in the review. The included records were published between 1986 and 2023, most of which reported studies conducted in the United States and were published in English. None of the PROMs were classified in the category "a", thus being recommended for use due to the quality of its measurement properties. The PROMs that should not be recommended for use (category "c") are the MTA, GMAS, DMAS-7, MALMAS, ARMS-D, and 5-item questionnaire. The remaining PROMs, e.g., MMAS-8, SMAQ, MEDS, MNPS, ARMS-12, MGT, MTA-OA, MTA-Insulin, LMAS-14, MARS-5, A-14, ARMS-10, IADMAS, MAQ, MMAS-5, ProMAS, ARMS-7, 3-item questionnaire, AS, 12-item questionnaire, and Mascard were considered as having the potential to be recommended for use (category "b"). CONCLUSION: None of the included PROMs met the criteria for being classified as trusted and recommended for use for patients with cardiovascular diseases and/or type 2 diabetes mellitus. However, 21 PROMs have the potential to be recommended for use, but further studies are needed to ensure their quality based on the COSMIN guideline for systematic reviews of PROMs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019129109.

A genome-wide association study for allergen component sensitizations identifies allergen component-specific and allergen protein group-specific associations.

Background: Allergic diseases are some of the most common diseases worldwide. Genome-wide association studies (GWASs) have been conducted to elucidate the genetic factors of allergic diseases. However, no GWASs for allergen component sensitization have been performed. Objective: We sought to detect genetic variants associated with differences in immune responsiveness against allergen components. Methods: The participants of the present study were recruited from the Tokyo Children's Health, Illness, and Development study, and allergen component-specific IgE level at age 9 years was measured by means of allergen microarray immunoassays. We performed GWASs for allergen component sensitization against each allergen (single allergen component sensitization, number of allergen components analyzed, n = 31), as well as against allergen protein families (allergen protein group sensitization, number of protein groups analyzed, n = 16). Results: We performed GWAS on 564 participants of the Tokyo Children's Health, Illness, and Development study and found associations between Amb a 1 sensitization and the immunoglobulin heavy-chain variable gene on chromosome 14 and between Phl p 1 sensitization and the HLA class II region on chromosome 6 (P < 5.0 × 10-8). A GWAS-significant association was also observed between the HLA class II region and profilin sensitization (P < 5.0 × 10-8). Conclusions: Our data provide the first demonstration of genetic risk for allergen component sensitization and show that this genetic risk is related to immune response genes including immunoglobulin heavy-chain variable gene and HLA.

Psychometric Analysis of the Rapid Eating Assessment for Participants-Short Form to Evaluate Dietary Quality in a Pre-Surgical Bariatric Population.

Dietary quality and eating behaviors are essential to evaluating bariatric surgery candidates. The Rapid Eating Assessment for Participants-Short Form (REAP-S) is a previously validated measure of dietary quality suited for use in primary care. This study aimed to evaluate the psychometric properties of the REAP-S in a pre-surgical bariatric population. This study included data from one academic medical center from August 2020 to August 2022. Variables included socio-demographics, the REAP-S, mental health, and assessments of appetitive traits. Statistical methods included Cronbach's alpha, confirmatory factor analysis (CFA), and multivariable analyses. A total of 587 adult patients were included in this analysis. The mean score for the REAP-S was 28.32 (SD: 4.02), indicative of relatively moderate dietary quality. The internal consistency of the REAP-S was moderate, with a Cronbach's alpha of 0.65. The three-factor CFA model resulted in a comparative fit index of 0.91. Race (p = 0.01), body mass index (p = 0.01), food fussiness (p < 0.0001), food responsiveness (p = 0.005), and socially desirable responses (p = 0.003) were significantly associated with the total REAP-S score. Although the REAP-S's original purpose was to assess dietary quality within a primary care population, it shows promise for application within a bariatric surgery-seeking population.