Systematic Review of Prognosis Models in Predicting Tooth Loss in Periodontitis.

This study reviews and appraises the methodological and reporting quality of prediction models for tooth loss in periodontitis patients, including the use of regression and machine learning models. Studies involving prediction modeling for tooth loss in periodontitis patients were screened. A search was performed in MEDLINE via PubMed, Embase, and CENTRAL up to 12 February 2022, with citation chasing. Studies exploring model development or external validation studies for models assessing tooth loss in periodontitis patients for clinical use at any time point, with all prediction horizons in English, were considered. Studies were excluded if models were not developed for use in periodontitis patients, were not developed or validated on any data set, predicted outcomes other than tooth loss, or were prognostic factor studies. The CHARMS checklist was used for data extraction, TRIPOD to assess reporting quality, and PROBAST to assess the risk of bias. In total, 4,661 records were screened, and 45 studies were included. Only 26 studies reported any kind of performance measure. The median C-statistic reported was 0.671 (range, 0.57-0.97). All studies were at a high risk of bias due to inappropriate handling of missing data (96%), inappropriate evaluation of model performance (92%), and lack of accounting for model overfitting in evaluating model performance (68%). Many models predicting tooth loss in periodontitis are available, but studies evaluating these models are at a high risk of bias. Model performance measures are likely to be overly optimistic and might not be replicated in clinical use. While this review is unable to recommend any model for clinical practice, it has collated the existing models and their model performance at external validation and their associated sample sizes, which would be helpful to identify promising models for future external validation studies.

Hospital Careful Hand Feeding Program Reduced Feeding Tube Use in Patients with Advanced Dementia.

OBJECTIVES: Tube feeding is prevalent among patients with advanced dementia despite empirical data that suggest its lack of benefit. To provide an alternative to tube feeding for end-of-life patients, a careful hand feeding program was launched in a Hong Kong geriatric convalescent hospital in February 2017. We aim to compare the rates of feeding tube insertion before and after program implementation and determine risk factors for feeding tube insertion. For patients on careful hand feeding, we evaluated their sustainability on oral feeding and the rates of hospital readmissions compared with tube feeding patients over the next 12 months. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Advanced dementia patients ≥60 years with indication for tube feeding due to feeding problems admitted from January 2015-June 2019. METHODS: Data was collected on demographic and clinical variables, initial feeding mode (careful hand feeding vs. tube feeding), subsequent feeding mode changes, and hospital admissions over the next 12 months. Rates of feeding tube insertion, sustainability on oral feeding, and hospital readmissions were compared using Chi-square test. Risk factors for feeding tube insertion were assessed using logistic regression models. RESULTS: Among 616 advanced dementia patients admitted with feeding problems, feeding tube insertion rate declined significantly after careful hand feeding program implementation (72% vs 51% p<.001). Independent risk factors for feeding tube insertion were admission prior to program implementation, presence of dysphagia alone, dysphagia combined with poor intake, and lack of advance care planning. Among patients on careful hand feeding, 91% were sustained on oral feeding over the next twelve months and did not differ significantly before or after careful hand feeding program implementation (p=.67). There was no significant difference in hospital readmission rates between careful hand feeding patients and tube feeding patients before (83% vs 86%, p=.55) and after careful hand feeding program implementation (87% vs 85%, p=.63). CONCLUSIONS AND IMPLICATIONS: A hospital careful hand feeding program significantly reduced the feeding tube insertion rate among advanced dementia patients with feeding problems. The vast majority of patients on careful hand feeding were sustained on oral feeding over the next 12 months but their rate of hospital readmissions remained similarly high after program implementation.

Asynchrony in Peritumoral Resting-State Blood Oxygen Level-Dependent fMRI Predicts Meningioma Grade and Invasion.

BACKGROUND AND PURPOSE: Meningioma grade is determined by histologic analysis, with detectable brain invasion resulting in a diagnosis of grade II or III tumor. However, tissue undersampling is a common problem, and invasive parts of the tumor can be missed, resulting in the incorrect assignment of a lower grade. Radiographic biomarkers may be able to improve the diagnosis of grade and identify targets for biopsy. Prior work in patients with gliomas has shown that the resting-state blood oxygen level-dependent fMRI signal within these tumors is not synchronous with normal brain. We hypothesized that blood oxygen level-dependent asynchrony, a functional marker of vascular dysregulation, could predict meningioma grade. MATERIALS AND METHODS: We identified 25 patients with grade I and 11 patients with grade II or III meningiomas. Blood oxygen level-dependent time-series were extracted from the tumor and the radiographically normal control hemisphere and were included as predictors in a multiple linear regression to generate a blood oxygen level-dependent asynchrony map, in which negative values signify synchronous and positive values signify asynchronous activity relative to healthy brain. Masks of blood oxygen level-dependent asynchrony were created for each patient, and the fraction of the mask that extended beyond the contrast-enhancing tumor was computed. RESULTS: The spatial extent of blood oxygen level-dependent asynchrony was greater in high (grades II and III) than in low (I) grade tumors (P < 0.001) and could discriminate grade with high accuracy (area under the curve = 0.88). CONCLUSIONS: Blood oxygen level-dependent asynchrony radiographically discriminates meningioma grade and may provide targets for biopsy collection to aid in histologic diagnosis.

Artificial Intelligence and Acute Stroke Imaging.

Artificial intelligence technology is a rapidly expanding field with many applications in acute stroke imaging, including ischemic and hemorrhage subtypes. Early identification of acute stroke is critical for initiating prompt intervention to reduce morbidity and mortality. Artificial intelligence can help with various aspects of the stroke treatment paradigm, including infarct or hemorrhage detection, segmentation, classification, large vessel occlusion detection, Alberta Stroke Program Early CT Score grading, and prognostication. In particular, emerging artificial intelligence techniques such as convolutional neural networks show promise in performing these imaging-based tasks efficiently and accurately. The purpose of this review is twofold: first, to describe AI methods and available public and commercial platforms in stroke imaging, and second, to summarize the literature of current artificial intelligence-driven applications for acute stroke triage, surveillance, and prediction.

The development and realisation of a multi-faceted system for green building planning: A case in Ningbo using the fuzzy analytical hierarchy process.

After the Green Building Regulations in the Zhejiang Province was put into effect in May 2016, cities and prefectures in the province were given directives to set their own individual targets for the provision of green buildings. The city of Ningbo decided to use this opportunity to develop a systematic procedure, using Fuzzy Analytical Hierarchy Process (FAHP), to identify which allotments within the municipal area have the greatest potential of delivering green buildings, ensuring the set targets are fair and deliverable. This paper explains in detail the use of FAHP in the production of the Specific Plans for Green Buildings for the city of Ningbo in the Zhejiang Province of China. This innovative multi-faceted method incorporates the level of development in each of the 3213 land allotments in the municipal area, assessing each one for critical aspects such as environmental potential, local economic development land-use and land prices in order to determine an individual roadmap for the ratio of green buildings to be built in each region within the city. This method incorporates a scientific process, in which Pairwise Comparison Analysis was conducted for the selected criteria and aspects to determine the weighting factors and scores in each case. This allowed planners to rank all allotments in the municipal area in terms of their potential to provide green buildings, and thus make the setting of targets to provide these accordingly. This approach breaks away from the traditional method which relies on simple estimation, which is often unjustified. Over the two years since this method was introduced, the effects had been positive, within all the allotments abiding to the set targets. Other cities and regions in China, such as the provinces of Liaoning and Hebei, have also adopted this process. The Specific Plans for Green Buildings in Ningbo also include the adoption rate of prefabricated buildings and the mandatory date for when by which new residential buildings should be fully-furnished before they are sold (this is not currently the case in most residential buildings in China). These aspects are also discussed in this paper.

Predictive Value of Noncontrast Head CT with Negative Findings in the Emergency Department Setting.

BACKGROUND AND PURPOSE: Noncontrast head CTs are routinely acquired for patients with neurologic symptoms in the emergency department setting. Anecdotally, noncontrast head CTs performed in patients with prior negative findings with the same clinical indication are of low diagnostic yield. We hypothesized that the rate of acute findings in noncontrast head CTs performed in patients with a preceding study with negative findings would be lower compared with patients being imaged for the first time. MATERIALS AND METHODS: We retrospectively evaluated patients in the emergency department setting who underwent noncontrast head CTs at our institution during a 4-year period, recording whether the patient had undergone a prior noncontrast head CT, the clinical indication for the examination, and the examination outcome. Positive findings on examinations were defined as those that showed any intracranial abnormality that would necessitate a change in acute management, such as acute hemorrhage, hydrocephalus, herniation, or interval worsening of a prior finding. RESULTS: During the study period, 8160 patients in the emergency department setting underwent a total of 9593 noncontrast head CTs; 88.2% (7198/8160) had a single examination, and 11.8% (962/8160) had at least 1 repeat examination. The baseline positive rate of the "nonrepeat" group was 4.3% (308/7198). The 911 patients in the "repeat" group with negative findings on a baseline/first CT had a total of 1359 repeat noncontrast head CTs during the study period. The rate of positive findings for these repeat examinations was 1.8% (25/1359), significantly lower than the 4.3% baseline rate (P < .001). Of the repeat examinations that had positive findings, 80% (20/25) had a study indication that was discordant with that of the prior examination, compared with only 44% (593/1334) of the repeat examinations that had negative findings (P < .001). CONCLUSIONS: In a retrospective observational study based on approximately 10,000 examinations, we found that serial noncontrast head CT examinations in patients with prior negative findings with the same study indication are less likely to have positive findings compared with first-time examinations or examinations with a new indication. This finding suggests a negative predictive value of a prior noncontrast head CT examination with negative findings with the same clinical indication.

Small vessel disease and intracoronary plaque composition: a single centre cross-sectional observational study.

Cardiac events are commonly triggered by rupture of intracoronary plaque. Many studies have suggested that retinal small vessel abnormalities predict cardiac events. The present study examined retinal microvascular abnormalities associated with intracoronary plaque. This was a single centre cross-sectional observational study of consecutive subjects who underwent coronary angiography and intracoronary optical coherence tomography (OCT) of occlusive coronary artery disease. Subjects' retinal images were deidentified and graded for microvascular retinopathy (Wong and Mitchell classification), and vessel calibre using a semiautomated method based on Knudtson's modification of the Parr Hubbard formula. Control subjects had no significant plaque on angiography. Analysis used the Fisher's exact test or student t-test. Thirty-two subjects with intracoronary plaque including 22 males (79%) had a mean age of 62.6 ± 9.4 years. Twenty-four (86%) had hypertension, 10 (36%) had diabetes, and 21 (75%) were current or former smokers. Their average mean arterial pressure was 90.5 ± 5.8 mm Hg, and mean eGFR was 74 ± 15/min/1.73 m2. On angiography, 23 (82%) had a left anterior descending artery (LAD) stenosis, their mean diseased vessel score was 1.86 ± 1.21, and mean total stent number was 1.04 ± 1.00. Plaque type was mainly (>50%) fibrous (n = 7), lipid (n = 7), calcific (n = 10), or mixed (n = 4). Control subjects had a lower mean diastolic BP (p = 0.01), were less likely to have an LAD stenosis (p < 0.001), a lower mean diseased vessel score (p < 0.001) and fewer stents (p = 0.02). Subjects with plaque were more likely to have a moderate microvascular retinopathy than those with none (p = 0.004). Moderate retinopathy was more common with lipid (p = 0.05) or calcific (p = 0.003) plaque. Individuals with calcific plaque had a larger arteriole calibre (158.4 ± 15.2 µm) than those with no plaque (143.8 ± 10.6 µm, p = 0.02), but calibre was not related to diabetes or smoking. Calibre did not correlate with plaque length, thickness or arc angle. Thus, subjects with intracoronary artery plaque are more likely to have a moderate microvascular retinopathy. Those with calcific plaque have larger retinal arterioles which is consistent with our previous finding of larger vessel calibre in triple coronary artery disease. Retinal microvascular imaging warrants further evaluation in identifying severe coronary artery disease.

Cenicriviroc, a dual CCR2 and CCR5 antagonist leads to a reduction in plasma fibrotic biomarkers in persons living with HIV on antiretroviral therapy.

Background: Chronic HIV is associated with increased inflammation and tissue fibrosis despite suppressive antiretroviral therapy (ART). Monocytes and macrophages have been implicated in the pathogenesis of fibrosis, facilitated by chemokine receptor interactions.Methods: We assessed systemic fibrotic biomarkers (transforming growth factor beta-1 [TGF-ß1], thrombospondin-1 [TSP-1], C-terminal pro-peptide of collagen type I [CICP], and IL-11) in banked plasma from a previously published 24-week open-label trial of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, among persons living with HIV (PLWH) on stable ART with undetectable plasma HIV RNA (<50 copies/mL). Fibrotic markers were assessed by ELISA and Luminex. Untreated HIV-seronegative individuals (n = 6) of similar age and demographics served as a comparator group.Results: Median age of PLWH was 55 years. At baseline, PLWH had higher median TGF-ß1 (2.11 vs 1.62 ng/mL, p = 0.01), TSP-1 (236.74 vs 83.29 ng/mL, p < 0.0001), and CICP (200.46 vs 111.28 ng/mL, p = 0.01), but lower IL-11 (36.00 vs 53.74 pg/mL, p = 0.01) compared to HIV-uninfected individuals. Over 24 weeks, median TGF-ß1 (-0.74 ng/mL, p = 0.006), TSP-1 (-52.12 ng/mL, p < 0.0001), and CICP (-28.12 ng/mL, p < 0.0001) decreased and IL-11 (28.98 pg/mL, p < 0.0001) increased in PLWH. At week 24, TGF-ß1, CICP, and IL-11 were similar between the two groups (p > 0.05), while TSP-1 remained elevated in PLWH (p = 0.009) compared to controls.Conclusions: PLWH had higher levels of the plasma fibrotic markers TGF-ß1, TSP-1, and CICP. After 24 weeks of CVC, fibrotic markers generally returned to levels comparable to HIV-uninfected controls. Dual CCR2 and CCR5 blockade may ameliorate the detrimental fibrotic events that persist in treated HIV.

Prevalence and Screening of Mental Illness among Remand Prisoners in Hong Kong.

OBJECTIVES: This study aimed to validate the Correctional Mental Health Screen (CMHS) in the Hong Kong prison population and determine the prevalence of psychiatric disorders among remand prisoners in Hong Kong and the associated factors of mental illness. METHODS: This cohort study was conducted at the Lai Chi Kok Reception Centre and the Tai Lam Centre for Women in Hong Kong. Remand prisoners aged ≥21 years were recruited between May and August 2014. Sociodemographic and clinical data were collected. Each remand prisoner was assessed using the appropriate CMHS for males or for females, then interviewed by a specialist psychiatrist using the Structured Clinical Interview for DSM-IV for current affective disorder and psychotic disorder for cross-validation. RESULTS: A total of 245 remand prisoners were recruited (150 males and 95 females; mean age, 25.8 years). Of them, 51% (55% males and 44% females) had a lifetime history of psychiatric disorder, whereas 39.6% (46% males and 29.5% females) had a current psychiatric disorder. The most common psychiatric disorder was substance use disorder (>36%), followed by mood disorder (>20%), psychotic disorder (5.3%), and lifetime neurotic disorder (3.7%). Living in a public housing estate (odds ratio [OR] = 1.99), a history of childhood conduct problem (OR = 2.40), and a forensic history (OR = 1.97) were associated with an increased risk of having a psychiatric disorder. The CMHS had good diagnostic efficiency after cross-validation with the Structured Clinical Interview for DSM-IV. CONCLUSION: Psychiatric disorders are prevalent in remand prisoners in Hong Kong. The CMHS is an effective tool to screen remand prisoners for timely treatment of prisoners with mental health needs.

Effects of whole body vibration on spinal proprioception in healthy individuals.

BACKGROUND: Low back pain (LBP) is a common health problem with high reoccurrence rate. As patients with LBP are often found to be proprioception impaired, new proprioception exercises should be explored. Whole body vibration (WBV) has been proven to improve muscle function and proprioception. OBJECTIVE: The aim of this study was to determine the effects of WBV on spinal proprioception when WBV was administered in standing and seated postures. METHODS: Twenty healthy male individuals (mean age: 23.2±1.2 years) were recruited and randomly assigned to two WBV groups: WBV in standing or WBV in seated posture. Their body posture, lumbar repositioning ability, maximum reaching distance and lumbopelvic coordination during dynamic motion in flexion and extension were assessed before, immediately after, 30 minutes after and 1 hour after 5 minutes of WBV (18 Hz, 6 mm amplitude) exposure. A Mixed ANOVA was used to analyze the effects of group and time factors on these four outcome measures. RESULTS: There were no significant interaction (group and time) and group effects on all outcome measures. Participants were found to have significant different time effect on body posture, lumbar repositioning ability, maximum reaching distance and lumbopelvic coordination. CONCLUSIONS: WBV could significantly improve spinal proprioception including body posture, lumbar repositioning ability, maximum reaching distance and lumbopelvic coordination in healthy individuals. WBV protocol is recommended to confirm its clinical application for improving spinal proprioception and its effects on patients with LBP is warranted.

Hybrid 3D/2D Convolutional Neural Network for Hemorrhage Evaluation on Head CT.

BACKGROUND AND PURPOSE: Convolutional neural networks are a powerful technology for image recognition. This study evaluates a convolutional neural network optimized for the detection and quantification of intraparenchymal, epidural/subdural, and subarachnoid hemorrhages on noncontrast CT. MATERIALS AND METHODS: This study was performed in 2 phases. First, a training cohort of all NCCTs acquired at a single institution between January 1, 2017, and July 31, 2017, was used to develop and cross-validate a custom hybrid 3D/2D mask ROI-based convolutional neural network architecture for hemorrhage evaluation. Second, the trained network was applied prospectively to all NCCTs ordered from the emergency department between February 1, 2018, and February 28, 2018, in an automated inference pipeline. Hemorrhage-detection accuracy, area under the curve, sensitivity, specificity, positive predictive value, and negative predictive value were assessed for full and balanced datasets and were further stratified by hemorrhage type and size. Quantification was assessed by the Dice score coefficient and the Pearson correlation. RESULTS: A 10,159-examination training cohort (512,598 images; 901/8.1% hemorrhages) and an 862-examination test cohort (23,668 images; 82/12% hemorrhages) were used in this study. Accuracy, area under the curve, sensitivity, specificity, positive predictive value, and negative-predictive value for hemorrhage detection were 0.975, 0.983, 0.971, 0.975, 0.793, and 0.997 on training cohort cross-validation and 0.970, 0.981, 0.951, 0.973, 0.829, and 0.993 for the prospective test set. Dice scores for intraparenchymal hemorrhage, epidural/subdural hemorrhage, and SAH were 0.931, 0.863, and 0.772, respectively. CONCLUSIONS: A customized deep learning tool is accurate in the detection and quantification of hemorrhage on NCCT. Demonstrated high performance on prospective NCCTs ordered from the emergency department suggests the clinical viability of the proposed deep learning tool.

Deep-Learning Convolutional Neural Networks Accurately Classify Genetic Mutations in Gliomas.

BACKGROUND AND PURPOSE: The World Health Organization has recently placed new emphasis on the integration of genetic information for gliomas. While tissue sampling remains the criterion standard, noninvasive imaging techniques may provide complimentary insight into clinically relevant genetic mutations. Our aim was to train a convolutional neural network to independently predict underlying molecular genetic mutation status in gliomas with high accuracy and identify the most predictive imaging features for each mutation. MATERIALS AND METHODS: MR imaging data and molecular information were retrospectively obtained from The Cancer Imaging Archives for 259 patients with either low- or high-grade gliomas. A convolutional neural network was trained to classify isocitrate dehydrogenase 1 (IDH1) mutation status, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status. Principal component analysis of the final convolutional neural network layer was used to extract the key imaging features critical for successful classification. RESULTS: Classification had high accuracy: IDH1 mutation status, 94%; 1p/19q codeletion, 92%; and MGMT promotor methylation status, 83%. Each genetic category was also associated with distinctive imaging features such as definition of tumor margins, T1 and FLAIR suppression, extent of edema, extent of necrosis, and textural features. CONCLUSIONS: Our results indicate that for The Cancer Imaging Archives dataset, machine-learning approaches allow classification of individual genetic mutations of both low- and high-grade gliomas. We show that relevant MR imaging features acquired from an added dimensionality-reduction technique demonstrate that neural networks are capable of learning key imaging components without prior feature selection or human-directed training.

Enhanced brain delivery with lower hepatic exposure of lazaroid loaded nanostructured lipid carriers developed using a design of experiment approach.

The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimal LAZ-NLCs were spherical in shape with measured size of 172.3 ±â€¯3.54 nm, surface charge of -4.54 ±â€¯0.87 mV and encapsulation efficiency of 85.01 ±â€¯2.60%. The optimal LAZ-NLCs were also evaluated for hemolytic potential, storage stability and solid-state properties. The plasma pharmacokinetics along with brain and hepatic distributions of control lazaroid citrate solution and optimal LAZ-NLCs formulation were evaluated in Sprague-Dawley rats after the single bolus intravenous administration. The optimized LAZ-NLCs and the control lazaroid citrate solution had similar plasma pharmacokinetic profiles; however, differential organ bio-distributions were observed. The lazaroid exposure in brain was enhanced by two times with a decreased liver exposure by half for the NLCs group compared to the solution group.

A Multiparametric Model for Mapping Cellularity in Glioblastoma Using Radiographically Localized Biopsies.

BACKGROUND AND PURPOSE: The complex MR imaging appearance of glioblastoma is a function of underlying histopathologic heterogeneity. A better understanding of these correlations, particularly the influence of infiltrating glioma cells and vasogenic edema on T2 and diffusivity signal in nonenhancing areas, has important implications in the management of these patients. With localized biopsies, the objective of this study was to generate a model capable of predicting cellularity at each voxel within an entire tumor volume as a function of signal intensity, thus providing a means of quantifying tumor infiltration into surrounding brain tissue. MATERIALS AND METHODS: Ninety-one localized biopsies were obtained from 36 patients with glioblastoma. Signal intensities corresponding to these samples were derived from T1-postcontrast subtraction, T2-FLAIR, and ADC sequences by using an automated coregistration algorithm. Cell density was calculated for each specimen by using an automated cell-counting algorithm. Signal intensity was plotted against cell density for each MR image. RESULTS: T2-FLAIR (r = -0.61) and ADC (r = -0.63) sequences were inversely correlated with cell density. T1-postcontrast (r = 0.69) subtraction was directly correlated with cell density. Combining these relationships yielded a multiparametric model with improved correlation (r = 0.74), suggesting that each sequence offers different and complementary information. CONCLUSIONS: Using localized biopsies, we have generated a model that illustrates a quantitative and significant relationship between MR signal and cell density. Projecting this relationship over the entire tumor volume allows mapping of the intratumoral heterogeneity in both the contrast-enhancing tumor core and nonenhancing margins of glioblastoma and may be used to guide extended surgical resection, localized biopsies, and radiation field mapping.

Effect of an on-hip load-carrying belt on physiological and perceptual responses during bimanual anterior load carriage.

Manual load carriage continues to be a major contributor of musculoskeletal injury. This study investigates the physiological and subjective effects of an on-hip load-carrying belt (HLCB) during bimanual anterior load carriage. Fifteen healthy male participants walked on a level ground treadmill at 4.5 km/h for 5 min carrying 5, 10 and 15 kg loads with hands and arms in front of the body, with and without using the HLCB (WD and ND). Heart rate, normalized oxygen uptake, minute ventilation and, central and peripheral ratings of perceived exertion were the dependent variables. The mean heart rate, normalized oxygen uptake, minute ventilation and peripheral rating of perceived exertion increased significantly with load under both WD and ND conditions. At a load of 15 kg, the mean heart rate, normalized oxygen uptake, minute ventilation and peripheral rating of perceived exertion were significantly lower by 6.6%, 8.0%, 11.8% and 13.9% respectively in WD condition when compared to the ND condition. There was no significant difference between WD and ND conditions with 5 or 10 kg load. It can be concluded that the HLCB could reduce a person's physiological and peripheral perceptual responses when walking on a level ground treadmill at 4.5 km/h with a load of 15 kg. Using a HLCB or similar device is therefore recommended for bimanual anterior load carriage for loads of 15 kg or probably larger.

UPLC-MS/MS assay of 21-aminosteroid (lazaroid U74389G) for application in pharmacokinetic study.

Lazaroids are potent inhibitors of lipid peroxidation, both in vitro and in vivo. Additionally, a member of the lazaroid family, U-74389G (LAZ) has been shown to have specific radio-protective and anti-proliferative effects. However, there is no quantitative analytical method developed for measuring the therapeutic levels of LAZ for the aforementioned effects. This article highlights the development and validation of a sensitive UPLC-MS/MS method for the quantification of LAZ, and its subsequent application in pharmacokinetic studies in rats with the lower limit of quantification (LLOQ) of 1.95 ng/mL. LAZ and internal standard diadzein (IS) were separated using ACQUITY UPLC(®) BEH C18 column. Gradient elution was used at a flow rate of 0.45 mL/min with mobile phases consisting of 0.1% formic acid in water and 0.1% formic in acetonitrile. LAZ (m/z 612→260) and IS (m/z 255→199) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode on QTRAP(®) 5500 System. The UPLC-MS/MS method was validated as per the US FDA Guidelines for Bio-analytical Validation. LAZ was extracted from rat plasma (100 µL) using protein precipitation by acetonitrile with mean recovery and matrix factor in range of 47.7-56.1%, and 85.6-89.4%, respectively. The calibration curve for LAZ was linear in the range of 1.95-250 ng/mL. The inter-day and intra-day accuracy and precision values for LLOQ, low, medium, high and very high concentration QC samples were within ±15%. LAZ was tested under different storage conditions, for short-term bench-top stability (1h and 3h at 25°C), long-term stability (1 month at -80°C), freeze-thaw cycle stability (1 cycle and 3 cycles) and stability of processed samples in auto-sampler (24h at 10°C) with stability values within ±15% range of nominal concentrations. The validated UPLC-MS/MS method was further applied to a pharmacokinetic study in rats after a single intravenous dose of LAZ at 5 mg/kg.

Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial.

BACKGROUND: Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). OBJECTIVES: The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4-C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. SETTING: Acute trauma centers worldwideMethods:A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025. RESULTS: Currently enrolling in 11 centers. CONCLUSION: This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI.

Liver disease knowledge and acceptability of non-invasive liver fibrosis assessment among people who inject drugs in the drug and alcohol setting: The LiveRLife Study.

BACKGROUND: The aim of this study was to assess factors associated with baseline knowledge of HCV and liver disease, acceptability of transient elastography (TE) assessment (FibroScan(®)), and willingness and intent to receive HCV treatment among persons with a history of injection drug use participating in a liver health promotion campaign. METHODS: The LiveRLife campaign involved three phases: (1) campaign resource development; (2) campaign resource testing; and (3) campaign implementation. Participants were enrolled in an observational cohort study with recruitment at four clinics - one primary health care facility, two OST clinics, and one medically supervised injecting centre - in Australia between May and October 2014. Participants received educational material, nurse clinical assessment, TE assessment, dried blood spot testing, and completed a knowledge survey. RESULTS: Of 253 participants (mean age 43 years), 68% were male, 71% had injected in the past month, and 75% self-reported as HCV positive. Median knowledge score was 16/23. In adjusted analysis, less than daily injection (AOR 5.01; 95% CI, 2.64-9.51) and no daily injection in the past month (AOR 3.54; 95% CI, 1.80-6.94) were associated with high knowledge (≥16). TE was the most preferred method both pre- (66%) and post-TE (89%) compared to liver biopsy and blood sample. Eighty-eight percent were 'definitely willing' or 'somewhat willing' to receive HCV treatment, and 56% intended to start treatment in the next 12 months. Approximately 68% had no/mild fibrosis (F0/F1, ≥2.5 to ≤7.4kPa), 13% moderate fibrosis (F2, ≥7.5 to ≤9.4kPa), 10% severe fibrosis (F3, ≥9.5 to ≤12.4kPa), and 9% had cirrhosis (F4, ≥12.5kPa). CONCLUSION: Liver disease and HCV knowledge was moderate. High acceptability of TE by PWID provides strong evidence for the inclusion of TE in HCV-related care, and could help to prioritise HCV treatment for those at greatest risk of liver disease progression.

Effect of daily short-duration weight-bearing on disuse-induced deterioration of musculoskeletal system.

OBJECTIVES: To investigate deterioration of musculoskeletal system due to prolonged disuse and the potential of daily short-duration weight-bearing as countermeasures. METHODS: Twenty-four adult male Sprague-Dawley rats were divided into Control Group (CG, no intervention), Tail-suspension Group (TG, tail-suspension without treatment), and Weight-Bearing Group (WBG, tail-suspension with 20 min/day, 5 days/week body weight loading). After four weeks of treatment, femur and tibia, soleus and extensor digitorum longus were evaluated for bone and muscle quality respectively. Tensile properties of bone-tendon insertion (BTI) were evaluated using patella-patellar tendon complex. RESULTS: Disuse induced deterioration on bone, muscle, and BTI after four weeks. Compared with CG, TG and WBG showed significant decrease in bone mineral density (BMD) of trabecular bone in distal femur (4.3-15.2%), muscle mass (31.3-52.3%), muscle cross-sectional area (29.1-35%), and failure strength of BTI (23.9-29.4%). Tensile test showed that the failure mode was avulsion of bone at the BTI. No significant difference was detected between TG and WBG for all assessments on bone, muscle, and BTI. CONCLUSIONS: Disuse caused deterioration of bone, muscle, and BTI while daily short-duration of weight-bearing did not prevent this deterioration. Mechanical stimulation with higher intensity and longer duration may be necessary to prevent musculoskeletal deterioration resulted from prolonged disuse.