Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

The use of video games, smartphones, and PCs/tablet PCs based on a survey of students' lifestyles: necessary actions.

OBJECTIVES: Addictions to video gaming, smartphones, and Personal Computer (PCs)/tablets have become serious public health problems worldwide. METHODS: We distributed a lifestyle survey to sixth-grade students (aged 11-12 years) during the 10-year period 2008-2017 and compared their responses in the first 5-year period (2008-2012) with those during the second 5-year period (2013-2017). The survey asked whether the student was (1) in a good mood upon waking, (2) the time that the student woke up, (3) the time that he/she went to bed, (4) the hours of TV watched per day, (5) the hours of video games played per day, (6) the hours of smartphone use per day, (7) the hours of PC or tablet PC use per day, (8) whether the student had a positive sense of self, (9) the number of times the student ate breakfast each week, and (10) how often the student turned off the TV during meals. RESULTS: Compared with the first 5-year period, during the second period significantly more students reported waking up before 6:30 a.m. (P < 0.01), going to bed before 10:00 p.m. (P < 0.05), and watching TV for <1 h (P < 0.001), and significantly fewer students reported playing video games for <1 h (P < 0.05), using a smartphone for <1 h (P < 0.001), and using a PC or tablet PC for <1 h (P < 0.001). CONCLUSIONS: Educational campaigns should specifically address the use of addictive technologies among adolescents.

Insulinoma induces a hyperinsulinemia-mediated decrease of GLUT2 and GLP1 receptor in normal pancreatic ß-cells.

There have been several clinical reports of transient postoperative hyperglycemia in patients with insulinoma, but the effect of insulinoma on normal ß-cells has not been investigated. We examined the glucose transporter 2 (GLUT2) and glucagon-like peptide 1 receptor (GLP1R) expression in normal pancreatic ß-cells of five patients with insulinoma and five patients with normal glucose tolerance (NGT) as controls. The positive rate of GLUT2-or GLP1R-positive islets in the nontumor area was calculated by the ratio with the analyzed islets. For functional in vitro analyses, q-PCR and Western blotting were performed after insulin loading on MIN6 cells. The expression rates of both GLUT2 and GLP1R were significantly lower in nontumor area islets of insulinoma patients than in patients with NGT (GLUT2: 31.6 ± 15.3% vs 95.9 ± 6.7%, p < 0.01, GLP1R: 66.8 ± 15.0% vs 96.7 ± 5.0%, p < 0.01). Exposure of MIN6 cells to high concentrations of insulin resulted in a significant decrease in GLUT2 protein for 12 h and GLP1R protein for 24 h (GLUT2; 1.00 ± 0.079 vs 0.81 ± 0.04. p = 0.02, GLP1R; 1.00 ± 0.10 vs 0.50 ± 0.24, p = 0.03) but not in those mRNAs. Our findings show that insulinoma is associated with the downregulation of GLUT2 and GLP1R expression in nontumor area islets. These phenomena may be caused by high levels of insulin.

An infantile late-onset case Group of B Streptococcus meningitis diagnosed with a rapid latex kit.

Globally, vaccination has reduced the prevalence of meningitis caused by Streptococcus pneumoniae Neisseria meningitidis, and Haemophilus influenzae. However, neonatal Group B Streptococcus (GBS) meningitis continues to remain a problematic infection of the central nervous system. Here, we report a case of bacterial meningitis in a 34-day old male baby who presented with fever. A cerebrospinal fluid (CSF) test on the day of admission showed an increase in cell count with decreased glucose level. A rapid latex test of the CSF using a commercial kit diagnosed the causative pathogen as GBS. We administered the antibiotics ampicillin, cefotaxime, gentamicin and panipenem/betamipron to the patient for over 14 days. Partial seizures were frequently observed during the course and were well-controlled with midazolam and phenobarbital. Brain magnetic resonance imaging on day 17 showed subdural hygroma in the frontal region, and 99mTc ethyl-cysteinate dimer-single photon emission computed tomography confirmed a decreased cerebral blood flow predominantly in the left frontal region. After three years of follow-up, the condition of the patient improved without any neurological sequelae. Our report highlights that rapid identification of the causative organism is essential in infantile late-onset meningitis. In addition, we consider that the latex kit-based rapid testing of CSF is beneficial for identifying the causative agent of bacterial meningitis.

Cerebral Blood Oxygenation Changes in Juvenile Patients with Delayed Orthostatic Hypotension During an Active Standing Test.

Delayed orthostatic hypotension (OH) is a minor subset of orthostatic dysregulation (OD). Cerebral blood oxygenation in juvenile patients with delayed OH has not been studied. We investigated the bilateral changes in cerebral oxygenation in the prefrontal cortex during an active standing test in 23 juvenile patients with delayed OH using near-infrared spectroscopy (NIRS). We measured the oxy-Hb, deoxy-Hb, and total-Hb during the active standing test. Four observations were made during the test: t1 in a resting supine position, t2 when maintaining blood pressure, and the remaining two (t3, t4) during hypotension. The concentration of oxy-Hb significantly decreased prior to satisfying the diagnostic criteria of delayed OH after standing and did not change thereafter. The concentration of deoxy-Hb increased gradually during the measurement periods. In addition, total-Hb increased from t2 to t3. There was no significant difference in the change in each Hb parameter between the left and right cerebral hemispheres. Our results indicate that NIRS parameters are more sensitive than blood pressure for the interpretation of cerebral autoregulation in juvenile patients with delayed OH.

Incident fracture associated with increased risk of mortality even after adjusting for frailty status in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study.

Frail elderly individuals have elevated risks of both fracture and mortality. We found that incident fractures were associated with an increased risk of death even after adjusting for pre-fracture frailty status as represented by physical performance tests and laboratory tests for common geriatric diseases in community-dwelling elderly Japanese men. INTRODUCTION: While fractures reportedly increase the risk of mortality, frailty may complicate this association, generating a false-positive result. We evaluated this association after adjusting for pre-fracture levels of frailty. METHODS: We examined 1998 community-dwelling ambulatory men aged ≥65 years at baseline in the Fujiwara-kyo Osteoporosis Risk in Men Study for frailty status as represented by activities of daily living (ADL), physical performance tests (grip strength, one-foot standing balance with eyes open, timed 10-m walk), and laboratory sera tests. Participants were then followed for 5 years for incident clinical fractures and death. Effects of incident fracture on death were determined by Cox proportional hazards model with the first fracture during follow-up as a time-dependent predictor and with frailty status indices as covariates. RESULTS: We identified 111 fractures in 99 men and 138 deaths during the follow-up period (median follow-up, 4.5 years). Participants with incident fractures did not have significantly worse frailty statuses, but did show a significantly higher cumulative mortality rate than those without fractures (p = 0.0047). Age-adjusted hazard ratio (HR) of death for incident fracture was 3.57 (95 % confidence interval: 2.05, 6.24). When adjusted for physical performance, this decreased to 2.77 (1.51, 5.06), but remained significant. The HR showed no significant change when adjusted for laboratory test results (3.96 (2.26, 6.94)). Exclusion of deaths within the first 24 months of follow-up did not alter these results. CONCLUSION: Incident clinical fracture was associated with an elevated risk of death independently of pre-fracture levels of frailty in community-dwelling elderly men.

Test of the Brink-Axel Hypothesis for the Pygmy Dipole Resonance.

The gamma strength function and level density of 1^{-} states in ^{96}Mo have been extracted from a high-resolution study of the (p[over →], p[over →]^{'}) reaction at 295 MeV and extreme forward angles. By comparison with compound nucleus γ decay experiments, this allows a test of the generalized Brink-Axel hypothesis in the energy region of the pygmy dipole resonance. The Brink-Axel hypothesis is commonly assumed in astrophysical reaction network calculations and states that the gamma strength function in nuclei is independent of the structure of the initial and final state. The present results validate the Brink-Axel hypothesis for ^{96}Mo and provide independent confirmation of the methods used to separate gamma strength function and level density in γ decay experiments.

Blood identification and discrimination between human and nonhuman blood using portable Raman spectroscopy.

Raman spectroscopy is commonly used in chemistry to identify molecular structure. This technique is a nondestructive analysis and needs no sample preparation. Recently, Raman spectroscopy has been shown to be effective as a multipurpose analytical method for forensic applications. In the present study, blood identification and discrimination between human and nonhuman blood were performed by a portable Raman spectrometer, which can be used at a crime scene. To identify the blood and to discriminate between human and nonhuman blood, Raman spectra of bloodstains from 11 species (human, rat, mouse, cow, horse, sheep, pig, rabbit, cat, dog, and chicken) were taken using a portable Raman spectrometer. Raman peaks for blood (742, 1001, 1123, 1247, 1341, 1368, 1446, 1576, and 1619 cm-1) could be observed by the portable Raman spectrometer in all 11 species, and the human bloodstain could be distinguished from the nonhuman ones by using a principal component analysis. This analysis can be performed on a bloodstain sample of at least 3 months old. The portable Raman spectrometer can be used at a crime scene, and this analysis is useful for forensic examination.

Eosinophilic annular erythema is clinically characterized by central pigmentation reflecting basal melanosis: a clinicopathological study of 10 cases.

BACKGROUND: Eosinophilic annular erythema (EAE) has been proposed as a clinical entity to describe annular skin lesions associated with tissue eosinophilia. However, systematic investigations on the histopathology of EAE have not been performed, and useful histopathological findings for diagnosis of EAE remain unknown. OBJECTIVE: The aim of this study was to investigate the clinicopathological features of EAE. METHODS: We retrospectively studied 10 patients at our hospital during a 5-year span who clinically showed annular or figurate lesions and histopathologically exhibited eosinophilic infiltration in the dermis. RESULTS: Nine of the 10 cases had annular lesions with pigmentation on the interior side. Blood eosinophilia was found in only one patient. Histopathologically, basal melanosis was observed in nine cases. Infiltration of eosinophils was confined to the dermis in nine cases. Patients treated with systemic corticosteroid tended to show less recurrence than those treated with topical corticosteroid. LIMITATIONS: The main limitation of our study is the small number of patients. CONCLUSION: Skin biopsy should be performed when EAE is suspected, even in cases without blood eosinophilia. Basal melanosis and tissue eosinophilia confined to the dermis suggest the diagnosis of EAE. We recommend topical corticosteroids as the initial treatment for EAE.

Two-Proton Radioactivity of

In an experiment with the BigRIPS separator at the RIKEN Nishina Center, we observed two-proton (2p) emission from ^{67}Kr. At the same time, no evidence for 2p emission of ^{59}Ge and ^{63}Se, two other potential candidates for this exotic radioactivity, could be observed. This observation is in line with Q value predictions which pointed to ^{67}Kr as being the best new candidate among the three for two-proton radioactivity. ^{67}Kr is only the fourth 2p ground-state emitter to be observed with a half-life of the order of a few milliseconds. The decay energy was determined to be 1690(17) keV, the 2p emission branching ratio is 37(14)%, and the half-life of ^{67}Kr is 7.4(30) ms.

Tetramethylbenzidine method for monitoring the free available chlorine and microbicidal activity of chlorite-based sanitizers under organic-matter-rich environments.

UNLABELLED: Chlorine is a principal disinfectant for food and environmental sanitation. Monitoring of free available chlorine (FAC) is essential for ensuring the efficacy of food disinfection processes that rely on chlorine. N,N-diethyl-p-phenylenediamine (DPD) is commonly used for FAC monitoring. However, here, we show that upon contact with bovine serum albumin (BSA) or broiler carcasses, chlorite (HClO2 )-based sanitizers acquire a pink colour, which can interfere with measurement of oxidized DPD absorbance at 513-550 nm. Alternatively, the pink colour did not interfere with 3,3',5,5'-tetramethylbenzidine (TMB)-based FAC monitoring. The FAC levels of NaClO and weakly acidified chlorous acid water (WACAW) were first adjusted by the TMB method and the killing activity of these sanitizers towards methicillin-resistant Staphylococcus aureus (MRSA) and feline calicivirus (FCV) was compared in the presence or absence of 0·5% BSA. At 200 ppm FAC, NaClO lost its bactericidal activity against MRSA after 10-min incubation with 0·5% BSA. Meanwhile, under the same conditions WACAW reduced the number of bacteria to below the detection limit. Similar results were obtained with FCV, indicating that the chlorite-based WACAW sanitizer is relatively stable under organic-matter-rich conditions. Moreover, TMB is suitable for in situ FAC monitoring of chlorite-based sanitizers in food and environmental disinfection processes. SIGNIFICANCE AND IMPACT OF THE STUDY: For practical applications of chlorine in food processing, monitoring of FAC is critical to validate disinfection efficacy. In this study we found that chlorite-based sanitizers acquired a pink colour upon contact with BSA or broiler carcasses. This pink colour interfered with FAC monitoring by methods that measure oxidized N,N-diethyl-p-phenylenediamine absorbance between 513-550 nm. Alternatively, FAC levels of chlorite-based sanitizers could be monitored using the absorbance of 3,3',5,5'-tetramethylbenzidine at 650 nm, which does not overlap with the acquired pink colour. These data provide valuable information for safety management of disinfection processes that use chlorite-based sanitizers.

CNTFR Genotype and Sprint/power Performance: Case-control Association and Functional Studies.

The aim of this study was to investigate whether rs41274853 in the 3'-untranslated region of the ciliary neurotrophic factor receptor gene (CNTFR) is associated with elite sprint/power athletic status and assess its functional significance. A total of 211 Japanese sprint/power track and field athletes (62 international, 72 national, and 77 regional athletes) and 814 Japanese controls were genotyped at rs41274853. Luciferase reporter assay was conducted to investigate whether this C-to-T polymorphism affects binding of microRNA miR-675-5p to this region. The TT genotype was significantly more frequent among international sprint/power athletes (19.4%) than in the controls after Bonferroni correction (7.9%, P=0.036, OR=2.81 [95% CI: 1.43-5.55]). Furthermore, in non-athletic young/middle-aged men (n=132), TT genotype carriers exhibited significantly greater leg extension power (26.6±5.4 vs. 24.0±5.4 W/kg BW, P=0.019) and vertical jump performance (50.1±6.9 vs. 47.9±7.5 cm, P=0.047) than the CC+CT genotype carriers. Reporter assays revealed that the miR-675-5p binds to this polymorphic region within the CNTFR mRNA, irrespective of the rs41274853 allele present. Although the functional significance of the rs41274853 polymorphism remains unclear, the CNTFR is one of the candidate genes contributing to sprint/power performance.

Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.

BACKGROUND: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. PATIENTS AND METHODS: Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. RESULTS: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). CONCLUSION: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).

Trabecular bone score may improve FRAX® prediction accuracy for major osteoporotic fractures in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study.

UNLABELLED: FRAX® is widely used to evaluate fracture risk of individuals in clinical settings. However, FRAX® prediction accuracy is not sufficient, and improvement is desired. Trabecular bone score, a bone microarchitecture index, may improve FRAX® prediction accuracy for major osteoporotic fractures in community-dwelling elderly Japanese men. INTRODUCTION: To improve fracture risk assessment in clinical settings, we evaluated whether the combination of FRAX® and Trabecular Bone Score (TBS) improves the prediction accuracy of major osteoporotic fractures (MOFs) in elderly Japanese men compared to FRAX® alone. METHODS: Two thousand and twelve community-dwelling men aged ≥65 years completed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Baseline Study comprising lumbar spine (LS) and femoral neck areal bone mineral density (aBMD) measurements, and interviews regarding clinical risk factors required to estimate 10-year risk of MOF (hip, spine, distal forearm, and proximal humerus) using the Japanese version of FRAX® (v.3.8). TBS was calculated for the same vertebrae used for LS-aBMD with TBS iNsight software (v.2.1). MOFs that occurred during the follow-up period were identified by interviews or mail and telephone surveys. Prediction accuracy of a logistic model combining FRAX® score and TBS compared to FRAX® alone was evaluated by area under receiver-operating characteristic curves (AUCs), as well as category-free integrated discrimination improvement (IDI) and net reclassification improvement (NRI). RESULTS: We identified 22 men with MOFs during 8140 person-years (PY) of follow-up among 1872 men; 67 men who suffered from fractures other than MOFs were excluded. Participants with MOFs had significantly lower TBS (p = 0.0015) and higher FRAX® scores (p = 0.0089) than those without. IDI and NRI showed significant improvements in reclassification accuracy using FRAX® plus TBS compared to FRAX® alone (IDI 0.006 (p = 0.0362), NRI 0.452 (p = 0.0351)), although no difference was observed in AUCs between the two. CONCLUSIONS: TBS may improve MOF prediction accuracy of FRAX® for community-dwelling elderly Japanese men.