小谷 和彦

BACKGROUND: The oxidized high-density lipoprotein (oxHDL) is a possible marker for cardiovascular diseases. This study investigated the effects of smoking cessation with varenicline (a partial agonist of nicotinic acetylcholine receptors) on the levels of oxHDL in the serum of subjects compared with those of high-density lipoprotein cholesterol (HDL-C). METHODS: Data of 99 nicotine-dependent adult subjects who visited the smoking cessation outpatient services at International University of Health and Welfare Shioya Hospital were reviewed. Each subject was treated with varenicline titrated up to 1.0 mg twice daily for 12 weeks. Serum levels of oxHDL and HDL-C were repeatedly measured by enzyme-linked immunosorbent assay and enzymatic method, respectively. RESULTS: The serum levels of oxHDL were significantly decreased from 163.2 ± 96.6 to 148.3 ± 80.7 U/mL (p = 0.034, n = 99). This effect was more prominent when the data of subjects in whom the treatment was objectively unsuccessful (exhaled carbon monoxide at 3 months ≥ 10 ppm) were omitted (from 166.6 ± 98.4 to 147.4 ± 80.6 U/mL; p = 0.0063, n = 93). In contrast, the serum levels of HDL-C were significantly increased (p = 0.0044, n = 99). There was a close relationship between the baseline levels of oxHDL and HDL-C (R = 0.45, p < 0.0001, n = 99). Changes in the levels of oxHDL were closely associated with changes in the levels of exhaled carbon monoxide in subjects in whom smoking cessation with varenicline was very effective (decrease in exhaled carbon monoxide by ≥ 15 ppm after treatment with varenicline; R = 0.42, p = 0.0052, n = 43). CONCLUSIONS: Although there was a close relationship between the baseline serum concentrations of oxHDL and HDL-C, smoking cessation decreased oxHDL and increased HDL-C. This effect on oxHDL may be associated with the effectiveness of smoking cessation.

BACKGROUND: Difficulties experienced by mothers in raising their children can be resolved using social networking services (SNSs). Being aware of issues associated with SNSs in such situations may be useful for supporting mothers. We herein review the issues associated with using SNSs to support mothers. METHODS: This review was conducted using an electronic search engine to search for articles that described issues associated with using SNSs to support mothers, and which were published up to August 2022. RESULTS: After screening, a total of 19 articles were included. We thematically categorized the contents into three major issues associated with using SNSs for support of mothers: (1) issues on the management side, (2) issues on the user side, and (3) social and environmental issues. The mainly discussed issues were the safety of using SNSs and/or securing and training human resources on the management side, busyness of mothers on the user side, as well as sociocultural and communication environment-related limitations as social and environmental issues. CONCLUSIONS: The issues we detected would aid in developing the use of SNSs as a tool to support mothers. Further research on these issues is needed.

Abstract Weight reduction therapy represents a fundamental strategy to prevent nonalcoholic fatty liver disease (NAFLD) in patients with obesity, which may result in liver fibrosis. Histological findings previously demonstrated that weight reduction therapy attenuated NAFLD. The FIB4 index is widely used to assess the status of NAFLD. The present study investigated whether the FIB4 index improved during weight reduction therapy. We used cohort data of the Japan Obesity and Metabolic syndrome Study and examined the correlation between body weight (BW) loss (BW loss) and changes in the FIB4 index (ΔFIB4 index) in patients who successfully reduced their BW by more than 5% from baseline BW after 3, 6, and 12 months (M) of weight reduction therapy. A negative correlation (r = −0.342, p = 0.029) was observed between BW loss and FIB4 index after 3 M, but not after 6 M, whereas a positive correlation (r = 0.298, p = 0.03) was noted after 12 M. These results revealed changes in the correlation between ΔBW loss and ΔFIB4 index during the therapy, mainly due to time-dependent changes in components of the FIB4 index formula. Thus, we concluded that the FIB4 index is useful and reliable to assess liver fibrosis until 3 M during weight reduction therapy. However, after 3 M, we should recognize that the FIB4 index may not reflect liver status. Therefore, it is important to consider this characteristic of the FIB4 index as a limitation when assessing liver fibrosis in obese patients receiving weight reduction therapy.

INTRODUCTION: Spontaneously hyperlipidemic (SHL) mice, a mouse strain derived from an inbred strain of Japanese wild (original)-type mice (KOR; Mus musculus molossinus), show high plasma cholesterol concentrations with disruption of the apolipoprotein E (Apoe) gene. However, the details of the Apoe gene of SHL mice have yet to be described. MATERIAL AND METHODS: The DNA sequence of the Apoe gene of SHL mice was compared to that of control KOR mice in genomic DNA and cDNA analyses. RESULTS: In the DNA analysis, a 4700-bp fragment was found to be inserted into exon 4 of the Apoe gene of SHL mice. The insertion contained two 365-bp repeats at each terminal and was flanked by a 6-bp target duplication at each side. The inserted fragment produced a frameshift of an early stop codon, resulting in a protein product that consisted of 87 amino acids in SHL mice compared to 311 amino acids in control KOR mice. CONCLUSIONS: These findings provide useful information about the molecular basis of SHL mice and related lipid disorders.

Objective Type 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity. Methods A total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations. Results During the follow-up, HbA_1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA_1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA_1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023). Conclusions Glycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

BACKGROUND: Japan has established comprehensive education-scholarship programs to supply physicians in rural areas. Their entrants now comprise 16% of all medical students, and graduates must work in rural areas for a designated number of years. These programs are now being adopted outside Japan, but their medium-term outcomes and inter-program differences are unknown. METHODS: A nationwide prospective cohort study of newly licensed physicians 2014-2018 (n = 2454) of the four major types of the programs-Jichi Medical University (Jichi); regional quota with scholarship; non-quota with scholarship (scholarship alone); and quota without scholarship (quota alone)-and all Japanese physicians in the same postgraduate year (n = 40,293) was conducted with follow-up workplace information from the Physician Census 2018, Ministry of Health, Labour and Welfare. In addition, annual cross-sectional survey for prefectural governments and medical schools 2014-2019 was conducted to obtain information on the results of National Physician License Examination and retention status for contractual workforce. RESULTS: Passing rate of the National Physician License Examination was highest in Jichi, followed in descending order by quota with scholarship, the other two programs, and all medical graduates. The retention rate for contractual rural service of Jichi graduates 5 years after graduation (n = 683; 98%) was higher than that of quota with scholarship (2868; 90%; P < 0.001) and scholarship alone (2220; 81% < 0.001). Relative risks of working in municipalities with the least population density quintile in Jichi, quota with scholarship, scholarship alone, and quota alone in postgraduate year 5 were 4.0 (95% CI 3.7-4.4; P < 0.001), 3.1 (2.6-3.7; < 0.001), 2.5 (2.1-3.0; < 0.001), and 2.5 (1.9-3.3; < 0.001) as compared with all Japanese physicians. There was no significant difference between each program and all physicians in the proportion of those who specialized in internal medicine or general practice in postgraduate years 3 to 5 CONCLUSIONS: Japan's education policies to produce rural physicians are effective but the degree of effectiveness varies among the programs. Policymakers and medical educators should plan their future rural workforce policies with reference to the effectiveness and variations of these programs.

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio-ankle vascular index (CAVI), based on the blood pressure-independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5-year follow-up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow-up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P<0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global χ2 value increased from 33.8 to 45.2 (P<0.001), and the net reclassification index was 0.254 (P=0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01859897.

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

AIMS: Endothelial cell vascular endothelial growth factor receptor 2 (VEGFR-2) plays a pivotal role in angiogenesis, which induces physiological cardiomyocyte hypertrophy via paracrine signalling between endothelial cells and cardiomyocytes. We investigated whether a decrease in circulating soluble VEGFR-2 (sVEGFR-2) levels is associated with poor prognosis in patients with chronic heart failure (HF). METHODS AND RESULTS: We performed a multicentre prospective cohort study of 1024 consecutive patients with HF, who were admitted to hospitals due to acute decompensated HF and were stabilized after initial management. Serum levels of sVEGFR-2 were measured at discharge. Patients were followed up over 2 years. The outcomes were cardiovascular death, all-cause death, major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death and HF hospitalization, and HF hospitalization. The mean age of the patients was 75.5 (standard deviation, 12.6) years, and 57% were male. Patients with lower sVEGFR-2 levels were older and more likely to be female, and had greater proportions of atrial fibrillation and anaemia, and lower proportions of diabetes, dyslipidaemia, and HF with reduced ejection fraction (<40%). During the follow-up, 113 cardiovascular deaths, 211 all-cause deaths, 350 MACE, and 309 HF hospitalizations occurred. After adjustment for potential clinical confounders and established biomarkers [N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein], a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death [hazard ratio (HR), 1.79; 95% confidence interval (CI), 1.16-2.74] and all-cause death (HR, 1.43; 95% CI, 1.04-1.94), but not with MACE (HR, 1.11; 95% CI, 0.86-1.43) or HF hospitalization (HR, 1.03; 95% CI, 0.78-1.35). The stratified analyses revealed that a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death (HR, 1.76; 95% CI, 1.07-2.85) and all-cause death (HR, 1.49; 95% CI, 1.03-2.15) in the high-NT-proBNP group (above the median), but not in the low-NT-proBNP group. Notably, the patients with high-NT-proBNP and low-sVEGFR-2 (below the 25th percentile) had a 2.96-fold higher risk (95% CI, 1.56-5.85) for cardiovascular death and a 2.40-fold higher risk (95% CI, 1.52-3.83) for all-cause death compared with those with low-NT-proBNP and high-sVEGFR-2. CONCLUSIONS: A low sVEGFR-2 value was independently associated with cardiovascular death and all-cause death in patients with chronic HF. These associations were pronounced in those with high NT-proBNP levels.

Hepcidin-25 is suggested as a surrogate iron status marker in athletes who show exercise-induced anemia; however, the implications of hepcidin concentration in this population remain poorly understood. This study aimed to investigate the relationship between hepcidin and body fat levels in rugby football players. We included 40 male university rugby football players (RUG) and 40 non-athlete controls. All participants underwent an anthropometric analysis and blood testing that included both hepcidin-25 and ferritin levels. The hepcidin-25 level was slightly (11.6%, p = 0.50) higher, and the ferritin level was significantly (35.9%, p < 0.05) lower, in the RUG group than in controls. The hepcidin-25 to-ferritin ratio was significantly higher (62.5%, p < 0.05) in the RUG group. While significant U-shaped correlations were observed between the body fat and ferritin levels in both groups, the correlations between the hepcidin levels and fat mass index were significantly higher in the RUG group (RUG: r = 0.79, controls: r = 0.45). Notably, the RUG with the lower fat mass index group had a higher hepcidin-25 level, lower ferritin level, and then significantly higher hepcidin-25/ferritin ratio. The hepcidin-25/ferritin ratio may serve as a biomarker for iron status in RUG, especially RUG with lower fat mass.

BACKGROUND: Primary care physicians have diverse responsibilities. To collaborate with cancer specialists efficiently, they should prioritise roles desired by other collaborators rather than roles based on their own beliefs. No previous studies have reported the priority of roles such clinic-based general practitioners are expected to fulfil across the cancer care continuum. This study clarified the desired roles of clinic-based general practitioners to maximise person-centred cancer care. METHODS: A web-based multicentre questionnaire in Japan was distributed to physicians in 2019. Physician roles within the cancer care continuum were divided into 12 categories, including prevention, diagnosis, surgery, follow-up with cancer survivors, chemotherapy, and palliative care. Responses were evaluated by the proportion of three high-priority items to determine the expected roles of clinic-based general practitioners according to responding physicians in similarly designated roles. RESULTS: Seventy-eight departments (25% of those recruited) from 49 institutions returned questionnaires. Results revealed that some physicians had lower expectations for clinic-based general practitioners to diagnose cancer, and instead expected them to provide palliative care. However, some physicians expected clinic-based general practitioners to be involved in some treatment and survivorship care, though the clinic-based general practitioners did not report the same priority. CONCLUSION: Clinic-based general practitioners prioritised involvement in prevention, diagnoses, and palliative care across the cancer continuum, although lower expectations were placed on them than they thought. Some additional expectations of their involvement in cancer treatment and survivorship care were unanticipated by them. These gaps represent issues that should be addressed.

BACKGROUND: A survey of IFCC members was conducted to determine current and future perspectives on digital innovations within laboratory medicine and healthcare sectors. METHODS: Questions focused on the relevance of digital diagnostic solutions, implementation and barriers to adopting digital technologies, and supplier roles in supporting innovation. Digital diagnostic market segments were defined by solution recipient (laboratory, clinician, patient/consumer, payor) and proximity to core laboratory operations. RESULTS: Digital solutions were of active interest for >90% of respondents. Although solutions to improve core operations were ranked as the most relevant currently, a future shift to technologies beyond core laboratory expertise is expected. A key area of potential differentiation for laboratory customers was clinical decision support. Currently, laboratories collaborate strongly with suppliers of laboratory integration software and information systems, with high expectations for future collaboration in clinical decision support, disease self-management, and population health management. Asia Pacific countries attributed greater importance to adopting digital solutions than those in other regions. Financial burden was the most commonly cited challenge in implementing digital solutions. CONCLUSIONS: Specialists in laboratory medicine are proactively approaching digital innovations and transformation, and there is high enthusiasm and expectation for further collaboration with suppliers and healthcare professionals beyond current core laboratory expertise.

BACKGROUND: High-dose intravenous immunoglobulin (IVIG) is the mainstay of treatment for Kawasaki disease (KD). Usually, 2 g/kg of IVIG is administered over 10-24 h, depending on the institution or physician, but the association between infusion speed and effectiveness has not been reported. In this study, we evaluated the differences in efficacy and safety between two different IVIG administration speeds. METHODS: This was a multicenter, unblinded, randomized controlled study. Patients newly diagnosed with KD were randomized into two groups: one who received IVIG over 12 h (12H group, double speed), and one that received IVIG over 24 h (24H group, reference speed). The endpoints included the duration of fever, incidence of coronary artery abnormalities (CAAs) and of adverse events. Laboratory data were evaluated before and after IVIG administration. RESULTS: A total of 39 patients were enrolled. There was no difference between groups in fever duration after the initiation of IVIG (21 h vs. 21.5 h, p = 0.325), and no patient experienced CAAs. Two adverse events were observed in the 12H group (elevation of aspartate aminotransferase and vomiting), however no severe adverse events requiring treatments or extension of hospital stay were observed in either group. After initial IVIG administration, the change ratio of inflammatory markers, such as white blood cell counts, neutrophils, C-reactive protein, and albumin, did not show significant differences between the two groups. On the other hand, a greater increase of serum immunoglobulin G from its baseline level was observed in the 24H group compared to the 12H group (3037 ± 648 mg/dl vs. 2414 ± 248 mg/dl, p < 0.01). CONCLUSION: The efficacy and safety of IVIG administered over 12 h (double speed) were similar to those administered over 24 h (reference speed). TRIAL REGISTRATION: University Hospital Medical Information Network ( UMIN000014665 ). Registered 27 July 2014 - Prospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000017058.