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.

Assessment of Heating on Titanium Alloy Cerebral Aneurysm Clips during 7T MRI.

BACKGROUND AND PURPOSE: Patients with cerebral aneurysms often undergo MR imaging after microsurgical clipping. Ultra-high-field MR imaging at 7T may provide high diagnostic capability in such clinical situations. However, titanium alloy clips have safety issues such as adverse interactions with static magnetic fields and radiofrequency-induced heating during 7T MR imaging. The purpose of this study was to quantitatively assess temperature increases on various types of titanium alloy aneurysm clips during 7T MR imaging. MATERIALS AND METHODS: Five types of titanium alloy aneurysm clips were tested, including combinations of short, long, straight, angled, and fenestrated types. Each clip was set in a phantom filled with gelled saline mixed with polyacrylic acid and underwent 7T MR imaging with 3D T1WI with a spoiled gradient recalled acquisition in the steady-state technique. Temperature was chronologically measured at the tips of the clip blade and head, angled part of the clip, and 5 mm from the tip of the clip head using MR imaging-compatible fiber-optic thermometers. RESULTS: Temperature increases at all locations for right-angled and short straight clips were <1°C. Temperature increases at the angled part for the 45° angled clip and the tip of the clip head for the straight fenestrated clip were >1°C. Temperature increases at all locations for the long straight clip were >2°C. CONCLUSIONS: Temperature increases on the right-angled and short straight clips remained below the regulatory limit during 7T MR imaging, but temperature increases on the 45° angled, straight fenestrated, and long straight clips exceeded this limit.

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)).

Diagnostic Accuracy of Screening Arterial Spin-Labeling MRI Using Hadamard Encoding for the Detection of Reduced CBF in Adult Patients with Ischemic Moyamoya Disease.

BACKGROUND AND PURPOSE: Adult patients with ischemic Moyamoya disease are advised to undergo selective revascularization surgery based on cerebral hemodynamics. The purpose of this study was to determine the diagnostic accuracy of arterial spin-labeling MR imaging using Hadamard-encoded multiple postlabeling delays for the detection of reduced CBF in such patients. MATERIALS AND METHODS: Thirty-seven patients underwent brain perfusion SPECT and pseudocontinuous arterial spin-labeling MR imaging using standard postlabeling delay (1525 ms) and Hadamard-encoded multiple postlabeling delays. For Hadamard-encoded multiple postlabeling delays, based on data obtained from the 7 sub-boluses with combinations of different labeling durations and postlabeling delays, CBF corrected by the arterial transit time was calculated on a voxel-by-voxel basis. Using a 3D stereotaxic template, we automatically placed ROIs in the ipsilateral cerebellar hemisphere and 5 MCA territories in the symptomatic cerebral hemisphere; then, the ratio of the MCA to cerebellar ROI was calculated. RESULTS: The area under the receiver operating characteristic curve for detecting reduced SPECT-CBF ratios (<0.686) was significantly greater for the Hadamard-encoded multiple postlabeling delays-CBF ratios (0.885) than for the standard postlabeling delay-CBF ratios (0.786) (P = .001). The sensitivity and negative predictive value for the Hadamard-encoded multiple postlabeling delays-CBF ratios were 100% (95% confidence interval, 100%-100%) and significantly higher than the sensitivity (95% CI, 44%-80%) and negative predictive value (95% CI, 88%-97%) for the standard postlabeling delay-CBF ratio, respectively. CONCLUSIONS: ASL MR imaging using Hadamard-encoded multiple postlabeling delays may be applicable as a screening tool because it can detect reduced CBF on brain perfusion SPECT with 100% sensitivity and a 100% negative predictive value in adult patients with ischemic Moyamoya disease.

Acetazolamide-Loaded Dynamic 7T MR Quantitative Susceptibility Mapping in Major Cerebral Artery Steno-Occlusive Disease: Comparison with PET.

BACKGROUND AND PURPOSE: Dynamic changes in cerebrovascular reactivity after acetazolamide administration vary markedly among patients with major cerebral arterial steno-occlusive disease. MR quantitative susceptibility mapping can dynamically quantify the cerebral magnetic susceptibility. The purpose of this study was to determine whether dynamic changes in susceptibility after administration of acetazolamide on 7T quantitative susceptibility mapping are associated with pre-existing states of CBV and the cerebral metabolic rate of oxygen in the cerebral hemispheres with major cerebral arterial steno-occlusive disease. MATERIALS AND METHODS: Sixty-five patients underwent 7T MR imaging at baseline and at 5, 10, 15, and 20 minutes after acetazolamide administration. Differences between the susceptibility of venous structures and surrounding brain tissue were calculated in the quantitative susceptibility mapping images. Susceptibility differences at 5, 10, 15, and 20 minutes after acetazolamide administration relative to baseline were calculated in 97 cerebral hemispheres with major cerebral arterial steno-occlusive disease. CBV and the cerebral metabolic rate of oxygen were also calculated using 15O-gas PET in the resting state. RESULTS: Dynamic changes of susceptibility after acetazolamide administration were classified into 3 patterns: abnormally increasing 5 or 10 minutes after acetazolamide administration; abnormally decreasing within 20 minutes after acetazolamide administration; and remaining unchanged after acetazolamide administration. CBV was significantly greater in the first pattern than in the latter 2. The cerebral metabolic rate of oxygen differed significantly in descending order from the first to middle to last pattern. CONCLUSIONS: Dynamic changes of susceptibility after acetazolamide administration on 7T MR quantitative susceptibility mapping are associated with pre-existing states of CBV and the cerebral metabolic rate of oxygen in major cerebral arterial steno-occlusive disease.

Relationships between dysphagia and tongue pressure during swallowing in Parkinson's disease patients.

Although dysphagia is a life-threatening problem in patients with Parkinson's disease (PD), the pathophysiology of oropharyngeal dysphagia is yet to be understood. This study investigated the tongue motor function during swallowing in relation to dysphagia and the severity of PD. Thirty patients with PD (14 males and 16 females; average age, 69.4 years), Hoehn and Yahr stage II-IV, in Osaka University Hospital are participated in this study. During swallowing 5 ml of water, tongue pressure on the hard palate was measured using a sensor sheet with 5 measuring points. The maximal tongue pressure at each measuring point during swallowing was compared between patients with PD and healthy controls. Subjective assessment of oropharyngeal dysphagia was performed using Swallowing Disturbance Questionnaire-Japanese. The maximal tongue pressure at each measuring point was significantly lower in patients with PD than in healthy controls (8 males and 12 females; average age, 71.6 years). Furthermore, the maximal tongue pressure was significantly lower in dysphagic PD patients than non-dysphagic PD patients. Loss of tongue pressure production at the anterior part of the hard palate was strongly related to dysphagia in the oral phase as well as in the pharyngeal phase. An abnormal pattern of tongue pressure production was more frequently observed in dysphagic PD patients than in non-dysphagic PD patients. The results suggest that tongue pressure measurement might be useful for early and quantitative detection of tongue motor disability during swallowing in patients with PD.

Preoperative Cerebral Oxygen Extraction Fraction Imaging Generated from 7T MR Quantitative Susceptibility Mapping Predicts Development of Cerebral Hyperperfusion following Carotid Endarterectomy.

BACKGROUND AND PURPOSE: Preoperative hemodynamic impairment in the affected cerebral hemisphere is associated with the development of cerebral hyperperfusion following carotid endarterectomy. Cerebral oxygen extraction fraction images generated from 7T MR quantitative susceptibility mapping correlate with oxygen extraction fraction images on positron-emission tomography. The present study aimed to determine whether preoperative oxygen extraction fraction imaging generated from 7T MR quantitative susceptibility mapping could identify patients at risk for cerebral hyperperfusion following carotid endarterectomy. MATERIALS AND METHODS: Seventy-seven patients with unilateral internal carotid artery stenosis (≥70%) underwent preoperative 3D T2*-weighted imaging using a multiple dipole-inversion algorithm with a 7T MR imager. Quantitative susceptibility mapping images were then obtained, and oxygen extraction fraction maps were generated. Quantitative brain perfusion single-photon emission CT was also performed before and immediately after carotid endarterectomy. ROIs were automatically placed in the bilateral middle cerebral artery territories in all images using a 3D stereotactic ROI template, and affected-to-contralateral ratios in the ROIs were calculated on quantitative susceptibility mapping-oxygen extraction fraction images. RESULTS: Ten patients (13%) showed post-carotid endarterectomy hyperperfusion (cerebral blood flow increases of ≥100% compared with preoperative values in the ROIs on brain perfusion SPECT). Multivariate analysis showed that a high quantitative susceptibility mapping-oxygen extraction fraction ratio was significantly associated with the development of post-carotid endarterectomy hyperperfusion (95% confidence interval, 33.5-249.7; P = .002). Sensitivity, specificity, and positive- and negative-predictive values of the quantitative susceptibility mapping-oxygen extraction fraction ratio for the prediction of the development of post-carotid endarterectomy hyperperfusion were 90%, 84%, 45%, and 98%, respectively. CONCLUSIONS: Preoperative oxygen extraction fraction imaging generated from 7T MR quantitative susceptibility mapping identifies patients at risk for cerebral hyperperfusion following carotid endarterectomy.

Para-psychobiotic Lactobacillus gasseri CP2305 ameliorates stress-related symptoms and sleep quality.

AIMS: To confirm the stress-relieving effects of heat-inactivated, enteric-colonizing Lactobacillus gasseri CP2305 (paraprobiotic CP2305) in medical students taking a cadaver dissection course. METHODS AND RESULTS: Healthy students (21 males and 11 females) took paraprobiotic CP2305 daily for 5 weeks during a cadaver dissection course. The General Health Questionnaire and the Pittsburgh Sleep Quality Index were employed to assess stress-related somatic symptoms and sleep quality respectively. The aggravation of stress-associated somatic symptoms was observed in female students (P = 0·029). Sleep quality was improved in the paraprobiotic CP2305 group (P = 0·038), particularly in men (P = 0·004). Among men, paraprobiotic CP2305 shortened sleep latency (P = 0·035) and increased sleep duration (P = 0·048). Diarrhoea-like symptoms were also effectively controlled with CP2305 (P = 0·005) in men. Thus, we observed sex-related differences in the effects of paraprobiotic CP2305. In addition, CP2305 affected the growth of faecal Bacteroides vulgatus and Dorea longicatena, which are involved in intestinal inflammation. CONCLUSIONS: CP2305 is a potential paraprobiotic that regulates stress responses, and its beneficial effects may depend on specific cell component(s). SIGNIFICANCE AND IMPACT OF THE STUDY: This study characterizes the effects of a stress-relieving para-psychobiotic in humans.

Controlling joint instability delays the degeneration of articular cartilage in a rat model.

OBJECTIVE: Joint instability induced by anterior cruciate ligament (ACL) transection is commonly considered as a predisposing factor for osteoarthritis (OA) of the knee; however, the influence of re-stabilization on the protection of articular cartilage is unclear. The aim of this study was to evaluate the effect of joint re-stabilization on articular cartilage using an instability and re-stabilization ACL transection model. DESIGN: To induce different models of joint instability, our laboratory created a controlled abnormal joint movement (CAJM) group and an anterior cruciate ligament transection group (ACL-T). Seventy-five Wistar male rats were randomly assigned to the CAJM (n = 30), ACL-T (n = 30), or no treatment (INTACT) group (n = 15). Cartilage changes were assessed with soft X-ray analysis, histological and immunohistochemistry analysis, and real-time polymerase chain reaction (PCR) analysis at 2, 4, and 12 weeks. RESULTS: Joint instability, as indicated by the difference in anterior displacement between the CAJM and ACL-T groups (P < 0.001), and cartilage degeneration, as evaluated according to the Osteoarthritis Research Society International (OARSI) score, were significantly higher in the ACL-T group than the CAJM group at 12 weeks (P < 0.001). Moreover, joint re-stabilization maintained cartilage structure (thickness [P < 0.001], surface roughness [P < 0.001], and glycosaminoglycan stainability [P < 0.001]) and suppressed tumor necrosis factor-alpha (TNF-α) and caspase-3 at 4 weeks after surgery. CONCLUSION: Re-stabilization of joint instability may suppress inflammatory cytokines, thereby delaying the progression of OA. Joint instability is a substantial contributor to cartilage degeneration.

The effects of administration of the Lactobacillus gasseri strain CP2305 on quality of life, clinical symptoms and changes in gene expression in patients with irritable bowel syndrome.

AIMS: To clarify the effects of Lactobacillus gasseri CP2305 (CP2305) on quality of life and clinical symptoms and its functional mechanisms in patients with irritable bowel syndrome (IBS). METHODS AND RESULTS: After the patients were administered CP2305 daily for 4 weeks, the IBS-severity index score was significantly improved compared with that of the placebo group, and this improvement was accompanied by a reduction in health-related worry and changes in intestinal microbiota. The gene expression profiling of the peripheral blood leucocytes showed that CP2305 treatment significantly up-regulated genes related to eukaryotic initiation factor 2 (EIF2) signalling. Eighty-two genes were down-regulated in IBS patients compared with healthy controls. The expression of 23 of these genes exhibited a CP2305-dependent increase associated with an improvement in IBS severity. The majority of the restored genes were related to EIF2 signalling. CONCLUSIONS: CP2305 administration is a potential candidate therapeutic option for patients with IBS. SIGNIFICANCE AND IMPACT OF THE STUDY: Although probiotics have been proposed to benefit IBS patients, objective clinical evidence and elucidation of the functional mechanism remain insufficient. Our study demonstrated that CP2305 administration beneficially influences IBS patients in both subjective and objective evaluations, and gene expression profiling provided insights into the functional mechanism.

Effectiveness of Bortezomib in a Patient With Acute Rejection Associated With an Elevation of Donor-Specific HLA Antibodies After Small-Bowel Transplantation: Case Report.

BACKGROUND: A significant association between donor-specific antibody (DSA) and graft rejection has recently been documented. However, confirmed strategy has not been established for DSA-associated rejection after intestinal transplantation (ITx). CASE REPORT: A 20-year-old male patient with chronic intestinal obstruction caused by hypoganglionosis of the entire intestine underwent cadaveric donor ITx with grafting performed on 232 cm of the small intestine, cecum, and a part of the ascending colon. On post-operative day (POD) 14, a histological evaluation showed an acute rejection of indeterminate grade. The patient had severe acute rejection on POD 16, which prompted us to administer bolus steroids and polyclonal anti-thymocyte antibody, along with baseline maintenance immunosuppression. The histopathological findings of the graft indicated typical acute cellular rejection, although C4d was positive. We then detected donor-specific HLA antibody. The patient initially responded well to the therapy and showed decreased histological rejection signs. However, the refractory low-grade rejection persisted in the graft. During this period, the patient showed increased levels of DSA, and we speculated that the persistent rejection was associated with DSA; thus, bortezomib was administered at this stage as a salvage therapy. This rejection was thereafter successfully controlled without severe adverse effect. Twenty-three months after ITx, the patient is currently alive with complete enteral autonomy. CONCLUSIONS: A case of acute graft rejection followed by a marked elevation of DSA is presented. In this particular case, a modified treatment protocol using bortezomib in addition to the typical immunosuppressive agents was effective.

Pressure production in oral vestibule during gum chewing.

The aim of this study was to record oral vestibule pressure (OVP) by the lip and cheek contraction during gum chewing, to examine the characteristics of these pressures and coordination between the OVP and jaw movement. The subjects were eight healthy adult men (mean age of 29·3 ± 3·3 years). An experimental plate that incorporated four pressure sensors on the midline of the upper jaw (Ch. 1), upper right canine (Ch. 2), upper right first molar (Ch. 3) and upper left first molar (Ch. 4) was used for measuring OVP. The right masseter electromyogram (EMG) was recorded simultaneously. Subjects chewed gum on the right side 20 times, and eight consecutive strokes were used for the analysis of the sequential order, maximal magnitude and duration of each OVP. Onset of OVP was observed at the molar on the non-chewing side (Ch. 4) before chewing side (Ch. 3), and offset was largely simultaneous at each site. On the chewing side (Chs. 1-3), OVP onset during the interval of EMG activity reached to the peak around the end of interval and offset in the duration of EMG activity. The maximal pressure was significantly larger at Chs. 1-3 than at Ch. 4, but no significant differences were observed in duration of pressure among each site. These results suggest that OVP is coordinated with jaw movement during gum chewing, and larger pressure is produced on the chewing side than on the non-chewing side. Our findings are quantitative indices for the evaluation of lip and cheek function during mastication.