Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Summary

Objective

Add‐on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double‐blind, placebo‐controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo‐controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long‐term open‐label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient‐reported outcomes from GWPCARE5.

Methods

Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.

Results

By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open‐label extension. Median treatment duration was 274 days (range 1‐512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty‐two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale.

Significance

This trial shows that long‐term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment‐resistant DS.

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Expert insights: Are liquid biopsies ready for primetime?

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A Review of “Complicated Grief, Attachment, & Art Therapy: Theory, Treatment, and 14 Ready-to-Use Protocols”

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A Diagnostic Algorithm That Combines Quantitative 18F-FDG PET Parameters and Contrast-Enhanced CT Improves Posttherapeutic Locoregional Restaging and Prognostication of Survival in Patients With Esophageal Cancer

Purpose The aim of this study was to determine whether the combination of contrast-enhanced CT (CE-CT) and quantitative 18F-FDG PET parameters improves locoregional restaging in esophageal cancer (EC) after neoadjuvant therapy. Methods Eighty-eight consecutive patients with locally advanced esophageal cancer, who underwent restaging after neoadjuvant chemotherapy or chemoradiotherapy before esophagectomy, were included in this retrospective study. The diagnostic accuracy of CE-CT, visual 18F-FDG PET/CT (vPET/CT), and quantitative PET parameters was assessed for T and N staging. Histopathology was used as the reference standard. The prognostic value for recurrence-free survival, cancer-specific survival, and overall survival was assessed using Cox regression analysis. Results Sensitivity, positive predictive value, and accuracy were 78.8%, 70.2%, and 59.0% (CE-CT), and 81.1%, 81.1%, and 68.2% (vPET/CT) for T staging as well as 59.5%, 75.9%, and 50.0% (CE-CT), and 70.2%, 93.7%, and 67.0% (vPET/CT) for N staging, respectively. Tumor length and metabolic tumor volume (MTV) exhibited an incremental increase with advancing T stages (P = 0.002 and 0.038). Contrast-enhanced CT had the highest sensitivity to differentiate advanced T stages (T3/4 vs 0–2; area under the receiver operating curve [AUC], 0.86; P

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Similar Uptake of 99mTc-MDP and 67Ga-Citrate at the Sites of Metastatic Calcification

A 59-year-old woman presented with fever for 2 weeks. The patient had end-stage renal disease and was undergoing dialysis therapy for 10 years. Plain radiographs revealed extensive calcification in the subcutaneous tissues of the shoulders, thighs, and hips. In this case, 99mTC-MDP bone scan detected all sites of subcutaneous metastatic calcification in one sweep. 67Ga-citrate scintigraphy was also performed and showed similar uptake at the same locations as those revealed by the bone scan, suggesting the existence of an inflammatory process at the sites of metastatic calcification.

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FDG PET for Evaluation of Bone Marrow Status in T-Cell Lymphoma

Purpose In T-cell lymphoma, the role of FDG PET for bone marrow (BM) evaluation is not established yet. We investigated diagnostic performance and prognostic implication of FDG PET for BM evaluation in peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTCL). Patients and Methods Patients with PTCL or NKTCL, who underwent initial staging with FDG PET and BM biopsy, were retrospectively enrolled and analyzed. PET BM finding was evaluated using visual analysis and a quantitative index (marrow-to-liver ratio [MLR]). Diagnostic performance of PET for BM involvement was assessed with biopsy as the gold standard. Prognostic value of PET findings was also assessed regarding progression-free survival (PFS) and overall survival (OS). Results A total of 109 (63 PTCL and 46 NKTCL) patients were analyzed. Biopsy revealed BM involvement in 35.8% of cases. Sensitivity and specificity of PET for diagnosing positive BM biopsy were 61.5% and 75.7% by visual analysis and 64.1% and 72.9% by MLR. Diagnostic performance of PET was not different across lymphoma types. Survival analysis revealed that MLR and BM biopsy result is significant for both PFS and OS. In multivariate analysis, MLR was an independent prognostic factor for both PFS and OS. Marrow-to-liver ratio was also a significant prognostic factor in BM biopsy-negative patients. Conclusions Despite fair correlation with BM biopsy result, PET may not replace BM biopsy in PTCL and NKTCL. However, the BM finding on PET is an independent prognostic factor, suggesting additional biological implication of PET findings.

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Poorly Differentiated Primary Carcinoma of the Middle Ear on 18F-FDG PET/CT

Primary carcinoma of the middle ear is extremely rare. A 41-year-old woman with a history of skull base osteomyelitis and chronic suppurative right otitis media presented with 1 month of right-sided facial droop, tearing, and headaches. Initial head CT revealed bony destruction and soft tissue opacification involving the right middle ear. Surgical biopsy yielded poorly differentiated carcinoma. Subsequent 18F-FDG PET/CT and MRI scans demonstrated FDG-avid soft tissue in the right middle ear with associated heterogeneously enhancing soft tissue on MRI.

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Differentiated Thyroid Cancer Outcomes After Surgery and Activity-Adjusted 131I Theragnostics

Purpose The aim of this study was to determine clinical outcomes in patients with differentiated thyroid cancer after surgery and activity-adjusted 131I therapy informed by diagnostic 131I scans with SPECT/CT (Dx scan). Methods Single-institution retrospective cohort study analysis of clinical outcomes after 1 to 5 years (mean, 39.6 ± 23.4 months) of follow-up in 350 patients with differentiated thyroid cancer associated with histopathologic risk factors, nodal metastases, and/or distant metastases. Postoperatively, all patients underwent Dx scans for completion of staging and risk stratification, and 131I therapy was based on integration of information from histopathology, stimulated thyroglobulin and scintigraphy. Results Twenty-three patients (6.6%) underwent reoperative neck dissection for removal of unsuspected residual nodal metastases identified on Dx scans. Clinical outcomes were as follows: 84.3% complete response, 1.4% biochemical incomplete response, 2.3% indeterminate response, and 12% structural incomplete response. Of the entire cohort, only 8 patients (2.3%) had persistent iodine-avid metastatic disease, which required repeated 131I therapy. Of 31 patients with iodine-avid distant metastases identified on Dx scans, 13 patients (42%) achieved complete response with a single 131I treatment. Conclusions Detection of regional and distant metastases on postoperative Dx scans permits adjustment of prescribed 131I activity for targeted treatment, as compared with fixed-activity ablation. This approach resulted in complete response after a single 131I treatment in 88% patients with histopathologic risk factors and regional metastases and 42% patients with distant metastases. Most patients with structural incomplete response (81%) had elevated thyroglobulin levels with negative follow-up 131I scans and positive PET/CT and/or CT scans consistent with altered tumor biology (non–iodine-avid disease).

http://bit.ly/2EJHY19

Pericardial Solitary Fibrous Tumor on FDG PET/CT

Solitary fibrous tumor, which can occur in all parts of the body and is more frequently found in the visceral pleura, is a rare mesenchymal tissue-originating spindle cell tumor derived from CD34-positive dendriticmesenchymal cells, but it rarely occurs in the pericardium. We reported the FDG PET/CT findings of a pathologically confirmed benign pericardial solitary fibrous tumor in a 51-year-old woman.

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Predicting Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer: Combined Statistical Modeling Using Clinicopathological Factors and FDG PET/CT Texture Parameters

Purpose The aim of this study was to develop a combined statistical model using both clinicopathological factors and texture parameters from 18F-FDG PET/CT to predict responses to neoadjuvant chemotherapy in patients with breast cancer. Materials and Methods A total of 435 patients with breast cancer were retrospectively enrolled. Clinical and pathological data were obtained from electronic medical records. Texture parameters were extracted from pretreatment FDG PET/CT images. The end point was pathological complete response, defined as the absence of residual disease or the presence of residual ductal carcinoma in situ without residual lymph node metastasis. Multivariable logistic regression modeling was performed using clinicopathological factors and texture parameters as covariates. Results In the multivariable logistic regression model, various factors and parameters, including HER2, histological grade or Ki-67, gradient skewness, gradient kurtosis, contrast, difference variance, angular second moment, and inverse difference moment, were selected as significant prognostic variables. The predictive power of the multivariable logistic regression model incorporating both clinicopathological factors and texture parameters was significantly higher than that of a model with only clinicopathological factors (P = 0.0067). In subgroup analysis, texture parameters, including gradient skewness and gradient kurtosis, were selected as independent prognostic factors in the HER2-negative group. Conclusions A combined statistical model was successfully generated using both clinicopathological factors and texture parameters to predict the response to neoadjuvant chemotherapy. Results suggest that addition of texture parameters from FDG PET/CT can provide more information regarding treatment response prediction compared with clinicopathological factors alone.

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Intertumoral Heterogeneity of 18F-FDG and 68Ga-PSMA Uptake in Prostate Cancer Pulmonary Metastases

We present a case of a 61-year-old man with history of prostate cancer and rising PSA levels referred for restaging. 68Ga-PSMA-11 PET/CT identified 2 lung nodules with low and moderate PSMA uptake. Subsequent 18F-FDG PET/CT showed high hypermetabolism in the nodule with low PSMA uptake, and low hypermetabolism in the nodule with moderate PSMA uptake. The isolated pulmonary findings and metabolic appearance is an atypical presentation of prostate cancer metastases and raised concern for a second primary malignancy. Fine-needle aspiration of the 18F-FDG active lung nodule confirmed metastatic prostatic adenocarcinoma that subsequently responded to androgen deprivation therapy and abiraterone acetate.

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Quality and Safety in Health Care, Part XLIII: Selected Outcome Studies From the Implantable Cardioverter Defibrillator Registry

To compare outcome results from different institutions in a registry, it is necessary to have a way to take into account differences in the risk characteristics of the patients. This model has been constructed for the Implantable Cardioverter Defibrillator (ICD) Registry, and the most important variables have been identified. In another study, it has also been found that many of these patients have comorbidities, and the mortality rate 60 months after a replacement ICD was 41.2%. In a third study, it was determined that for individuals at least 65 years of age, 60 months after ICD placement, 50.9% of the recipients used hospice services or were dead.

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68Ga-PSMA Uptake in Anal Fistula on PET/CT Scan

68Ga–prostate-specific membrane antigen (PSMA) PET/CT scan for primary staging discovered increased 68Ga-PSMA uptake in a known anal fistula in a recently diagnosed high-risk prostate cancer patient. The patient had an ongoing history of surgical revisions of complex fistulas in the perianal region, contributing to active inflammation and infection. Recently, reports have demonstrated increased 68Ga-PSMA uptake in different benign inflammatory conditions. This case demonstrates another case of a benign condition associated with increased 68Ga-PSMA uptake.

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Practical Method for Calculation of Graft Index in Renal Transplant Scintigraphy: A Technical Note

Some quantitative indices have been described for renal transplant scintigraphy in evaluating graft dysfunction, some medical complications, and in predicting early and delayed graft function and long-term graft prognosis. Graft index is very useful and more accurate than many other indices in the prediction of delayed graft function and long-term prognosis. In this technical note, the method of calculation of graft index is shown in detail for the authors who want to use this index in further studies or in clinical practice.

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Simultaneous 18F-FDG PET/MRI Assists Diagnosis of a Rare Disease, MELAS

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a rare congenital mitochondrial DNA mutation disease. Here, we report a 4-year-old girl, who presented with short stature, mental retardation, and recurrent seizures, underwent simultaneous 18F-FDG PET/MRI examination. An interesting contradiction images were found on bilateral frontal, left temporal, occipital, and parietal lobes, which were with high blood flow shown on 3D-ASL perfusion images, but low uptake of 18F-FDG on PET images. The contradiction of high blood flow and low glucose metabolism gave us a clue to make the diagnosis of MELAS. The final diagnosis was MELAS confirmed by genetic testing.

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Intense Choline Activity in Renal Cell Carcinoma Without Obvious 18F-FDG Uptake

A 64-year-old man presented pain over the right kidney region for 1 year. Contrast-enhanced MRI showed a sharply demarcated soft-tissue mass in the lower part of the right kidney. This lesion had no obvious uptake of 18F-FDG on PET/CT imaging, and an unexpected hypermetabolic irregularly shaped nodule was noted in the upper lobe of the right lung. 11C-choline PET was further performed to reveal the pathological property of the kidney lesion, and high uptake was noticed. The patient received surgery for the 2 lesions, and the final pathological diagnoses were chromophobe renal cell carcinoma and synchronous lung adenocarcinoma.

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Selection of Reference Regions to Model Neurodegeneration in Huntington Disease by 18F-FDG PET/CT Using Imaging and Clinical Parameters

Objective Normalization to an appropriate reference region in 18F-FDG PET imaging may enhance diagnostic performance in Huntington disease (HD). We aimed to identify stable brain areas that could be used to model neurometabolic degeneration in HD correlating imaging (SUVrvalues at the basal ganglia [BBGG]) and clinical parameters (disease burden score [DBS]). Materials and Methods We performed brain 18F-FDG PET/CT in 38 manifest HD patients (meanage ± SD, 54 ± 14.3 years; CAGrepeats ± SD, 44.2 ± 3.1), 20 premanifest HD patients (meanage ± SD, 42.7 ± 11.7 years; CAGrepeats ± SD, 40 ± 3.8), and 18 healthy controls (NC; meanage ± SD, 45 ± 13.2 years). For quantitative analysis, we selected (a) defined reference regions from the Montreal Neurological Institute space atlas (pons, whole cerebellum, cerebral white matter, thalamus, and a pons–cerebellar vermis region of interest), and (b) reference clusters obtained by voxelwise statistical comparison across groups (P

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68Ga-PSMA PET/CT Urachus Metastases in Recurrent Prostate Cancer With Very Low PSA Level

Peritoneal carcinomatosis in prostate cancer is extremely rare and has been described in only few cases with high PSA level, androgen deprivation, or in symptomatic patients. To date, 2 cases of 68Ga-PSMA PET positive peritoneal metastases have been reported. We report a case of urachus metastases showed on 68Ga-PSMA PET/CT performed for biochemical recurrence with a very low PSA level at 0.50 ng/mL.

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18F-FDG PET/CT of Squamous Cell Carcinoma in a Thyroglossal Duct Cyst

Thyroglossal duct cyst is a common congenital cyst in the neck. The incidence of primary carcinoma of the thyroglossal duct is less than 1% in all age groups. We present the case of a 63-year-old man with rapid expansion of a known thyroglossal duct cyst with mixed solid/cystic components. 18F-FDG PET/CT showed a large anterior neck mass with a non–FDG-avid cystic component and a hypermetabolic heterogeneous mass on the right side confirmed by histopathology to be squamous cell carcinoma. Although rare, 18F-FDG PET/CT can assist with evaluating the extent of malignant involvement in thyroglossal duct cyst squamous cell carcinoma.

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Complete Remission After Single Radioiodine Therapy in Malignant Struma Ovarii With Bone and Lymph Node Metastases

A 67-year-old woman presented with malignant struma ovarii after radical bilateral salpingo-oophorectomy. The surgery revealed a 4.4 cm papillary thyroid carcinoma (follicular variant) within a right-sided ovarian teratoma. 124I sodium iodide positron emission tomography / computed tomography and cervical ultrasound showed 2 slightly hyperfunctional thyroid nodules and several metastases, including bone metastases with intense iodine uptake. Thyroidectomy was necessary in preparation for radioiodine therapy and proofed the thyroid nodules to be benign. Complete remission was achieved by single radioiodine therapy (30 months of follow-up).

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Management of Primary Lymph Nodal Gastrinoma With Liver Metastases Resulting in Zollinger-Ellison Syndrome

Primary lymph node gastrinoma has been defined as gastrin-producing tumor present in lymph nodes and predominantly found in well-defined anatomical region known as gastrinoma triangle. They are usually localized preoperatively with imaging, and their surgical resection results in long-term relief. The authors report a case of unresectable primary lymph nodal gastrinoma with liver metastases in a 14-year-old adolescent boy with proven histopathology detected on 68Ga-DOTANOC whole-body PET/CT scan followed by preoperative multiple 177Lu-DOTATATE cycles for cytoreduction. Subsequent surgical resection of residual mass resulted in complete response with a follow-up of around 4 years in this unusual case of Zollinger-Ellison syndrome.

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18F-FDG PET/CT Imaging in an Adolescent Patient With Primary Prostatic Stromal Sarcoma

Primary prostatic stromal sarcoma is an extremely rare disease that predominantly occurs in adults, accounting for only 0.1% of all prostate cancers. Prostatic stromal sarcoma is quite aggressive and can spread to lung, liver, bone, and other organs. Metastasis is one of the most important predictors for prognosis. Here, we reported a case of a 17-year-old adolescent boy diagnosed with primary prostatic stromal sarcoma through prostate biopsy, and stage was confirmed by 18F-FDG PET/CT.

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Dual-Phase 18F-FP-CIT PET in Corticobasal Syndrome

Corticobasal syndrome is the most common phenotype of corticobasal degeneration (CBD). 18F-FP-CIT PET and MRI are not helpful in distinguishing CBD from idiopathic Parkinson disease. Dual-phase 18F-FP-CIT PET is a recently developed imaging that shows regional cerebral perfusion in the early phase and dopamine transporter density in the late phase. We investigated the usefulness of dual-phase 18F-FP-CIT PET imaging in 3 patients with corticobasal syndrome. This image highlights that the early phases of 18F-FP-CIT PET may reflect regional cerebral perfusion with a pattern very similar to that of regional glucose metabolism in CBD.

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Bovine Mammary Gland Biopsy Techniques

This article presents a bovine mammary gland biopsy using core and needle biopsy tools. Harvested tissue can be used for cell culture or to assess mammary physiology and metabolism including gene expression, protein expression, protein modifications, immunohistochemistry, and metabolite concentrations.

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Effect of the type of electrical stimulation on spinal fusion in a rat posterolateral spinal fusion model

Publication date: Available online 22 December 2018

Source: The Spine Journal

Author(s): Pyung Goo Cho, Gyu Yeol Ji, Yoon Ha, Hye Yeong Lee, Dong Ah Shin

ABSTRACT

BACKGROUND CONTEXT

Posterolateral fusion (PLF) with autogenous iliac bone graft is one of the most common surgical procedures for lumbar spinal disease. However, its limited success demands new biologically competent graft enhancers or substitutes. Although the use of direct current (DC) electrical stimulation has been shown to increase rate of successful spinal fusions, little is known about the effect of the type of current in DC stimulation.

PURPOSE

To evaluate the effects of various DC stimulators on the strength and success rate of posterolateral fusion facilitated by using a nitinol mesh container, in rats.

STUDY DESIGN

This was an experimental animal study.

METHODS

A conductive, tubular nitinol mesh container was used to carry small pieces of bone grafts. The nitinol mesh container received electrical stimulation via a lead that connected the container to different types of DC stimulators. Sixty male Sprague-Dawley rats were divided into three groups (N = 20 in each): a control group that underwent PLF with a nitinol container filled with autograft, a constant DC group that received a nitinol container and constant DC (100 μA), and a pulsed DC group that received a nitinol container and pulsed DC (100 μA, 100 Hz, 200 μs). The rats underwent PLF between L4 and L5, and transverse processes were grafted with bilateral iliac grafts. A stimulator was implanted subcutaneously. The rats were sacrificed 8 weeks post-surgery, and lumbar spines were removed. Spinal fusion was evaluated by microcomputed tomography, manual testing, biomechanical testing, histological examination, and molecular analysis.

RESULTS

All animals in the DC stimulation groups displayed solid fusion, whereas only 70% of control animals showed solid fusion. Radiographic images, biomechanical testing, histological examination, and molecular analysis revealed improved fusion in the order control group < constant DC group < pulsed DC group. The volume of new bone mass was significantly higher in the pulsed DC group (p < 0.05). Fusion was more solid in the pulsed DC group than in control group (p < 0.05). The pulsed DC group displayed the lowest inflammatory responses.

CONCLUSIONS

Pulsed DC electrical stimulation is efficacious in improving both strength and fusion rate in a rat spinal fusion model. In addition, tubular nitinol mesh, made of conductive suture, appears useful for holding small pieces of bone grafts and maintaining a good environment for bone fusion.

CLINICAL RELEVANCE

Pulsed DC electrical stimulation may be potentially useful to increase the fusion rate after spinal fusion in humans. Future research is required to evaluate the safety and efficacy of tubular nitinol mesh and pulsed DC electrical stimulation in humans.

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A Novel Oxidovanadium (IV)-Orotate Complex as an Alternative Antidiabetic Agent: Synthesis, Characterization, and Biological Assessments

Diabetes is an increasingly common metabolic disorder with high comorbidity and societal and personal costs. Insulin replacement therapy is limited by a lack of oral bioavailability. Recent studies suggest vanadium has therapeutic potential. A newly synthesized complex between oxidovanadium (IV) and orotic acid (OAH3), [(OAH1)(VO)(NH3)2].3H2O, was characterized using spectroscopic and thermogravimetric techniques. In vivo potential was assessed in a streptozocin-induced rat model of diabetes. OAH3 acts as a bidentate ligand in the formation of the dark green, crystalline oxidovanadium (IV) complex in a square pyramidal configuration. Treatment with oxidovanadium (IV)-orotate in vivo significantly improved many biochemical parameters with minimal toxicity and restored pancreatic and hepatic histology. The results of the present work describe a safe, new compound for the treatment of diabetes.

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Selection of Neural Oscillatory Features for Human Stress Classification with Single Channel EEG Headset

A study on classification of psychological stress in humans using electroencephalography (EEG) is presented. The stress is classified using a correlation-based feature subset selection method that efficiently reduces the feature vector length. In this study, twenty-eight participants are involved by filling in the perceived stress scale-10 (PSS-10) questionnaire and their EEG is also recorded in closed eye condition to measure the baseline stress. The recorded data is labelled on the basis of the stress level that is indicated by the participant's PSS score. The feature selection method has shown that, among the EEG oscillations, low beta, high beta, and low gamma are the most significant neural oscillations for classifying human stress. The proposed method not only reduces the time to build a classification model but also improves the classification accuracy up to 78.57% using a single channel wearable EEG device.

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Kirschner Wire Temporary Intramedullary Fixation Combined with a Locking Anatomical Plate versus a Reconstruction Plate in the Treatment of Comminuted Clavicular Fractures: A Retrospective Study

We investigate the clinical efficacy of Kirschner wire temporary intramedullary fixation combined with a locking anatomical plate for the treatment of comminuted clavicular fractures. We retrospectively studied 112 patients [80 (71%) men] treated between February 2007 and February 2014. The patients were allocated to treatment with Kirschner wire temporary intramedullary fixation combined with a locking anatomical plate [minimally invasive group ()] or a reconstruction plate [traditional group ()]. The 112 patients were followed up for 12–48 months (mean, 14 months). The operation time was significantly shorter in than in . Intraoperative blood loss was significantly less in than in . The total incision length was significantly shorter and the visual analog scale pain score 24 h after surgery was significantly lower in than in . Fracture healing time was significantly shorter and the complication rate was significantly lower in than in . No significant difference in shoulder function score was observed between groups. We recommend Kirschner wire temporary intramedullary fixation combined with a locking anatomical plate as the treatment of choice for comminuted clavicular fractures because of the shorter operation time, lesser intraoperative blood loss, easier reduction of the operation, quicker fracture healing, and lower postoperative complication rate.

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miR-548b-3p Regulates Proliferation, Apoptosis, and Mitochondrial Function by Targeting CIP2A in Hepatocellular Carcinoma

The roles of miR-548b-3p in the progression of hepatocellular carcinoma (HCC) remain undiscovered. This study aims to explore the roles and mechanisms of miR-548b-3p in HCC. Using TCGA database, we found that miR-548b-3p expression was lower in HCC compared to the normal tissues, which was further confirmed by RT-qPCR of 20 cases of surgically resected HCC and corresponding normal tissues. miR-548b-3p mimic and inhibitor were transfected into Huh7 and SK-Hep-1 cells, respectively. MTT, colony formation, and cell cycle assays showed that miR-548b-3p mimic suppressed cell growth and G1/S cell cycle transition. In contrast, miR-548b-3p inhibitor facilitated cell growth and cell cycle transition. miR-548b-3p mimic also increased cisplatin sensitivity by upregulating apoptosis rate. JC-1 staining showed that miR-548b-3p mimic downregulated mitochondrial membrane potential, while miR-548b-3p inhibitor showed the opposite effects in SK-Hep-1 cells. Using prediction software, we found that CIP2A was on the target list of miR-548b-3p. miR-548b-3p mimic downregulated CIP2A and its downstream target protein c-Myc. Luciferase reporter assay demonstrated that CIP2A was as a direct target of miR-548b-3p. CIP2A depletion partly reduced the effect of miR-548b-3p mimic/inhibitor on c-Myc. CIP2A depletion also reduced the effect of miR-548b-3p mimic/inhibitor on proliferation. In conclusion, our data demonstrated that miR-548b-3p was downregulated in HCC. miR-548b-3p regulates proliferation, apoptosis and mitochondrial function by targeting CIP2A in HCC.

http://bit.ly/2EKnPrs

The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients

Physical exercise is considered an effective means to stimulate bone osteogenesis in osteoporotic patients. The authors reviewed the current literature to define the most appropriate features of exercise for increasing bone density in osteoporotic patients. Two types emerged: (1) weight-bearing aerobic exercises, i.e., walking, stair climbing, jogging, and Tai Chi. Walking alone did not appear to improve bone mass; however it is able to limit its progressive loss. In fact, in order for the weight-bearing exercises to be effective, they must reach the mechanical intensity useful to determine an important ground reaction force. (2) Strength and resistance exercises: these are carried out with loading (lifting weights) or without (swimming, cycling). For this type of exercise to be effective a joint reaction force superior to common daily activity with sensitive muscle strengthening must be determined. These exercises appear extremely site-specific, able to increase muscle mass and BMD only in the stimulated body regions. Other suggested protocols are multicomponent exercises and whole body vibration. Multicomponent exercises consist of a combination of different methods (aerobics, strengthening, progressive resistance, balancing, and dancing) aimed at increasing or preserving bone mass. These exercises seem particularly indicated in deteriorating elderly patients, often not able to perform exercises of pure reinforcement. However, for these protocols to be effective they must always contain a proportion of strengthening and resistance exercises. Given the variability of the protocols and outcome measures, the results of these methods are difficult to quantify. Training with whole body vibration (WBV): these exercises are performed with dedicated devices, and while it seems they have effect on enhancing muscle strength, controversial findings on improvement of BMD were reported. WBV seems to provide good results, especially in improving balance and reducing the risk of falling; in this, WBV appears more efficient than simply walking. Nevertheless, contraindications typical of senility should be taken into account.

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Time-Course Comparative Metabolite Profiling under Osmotic Stress in Tolerant and Sensitive Tibetan Hulless Barley

Tibetan hulless barley is widely grown in the extreme environmental conditions of the Qinghai-Tibet Plateau which is characterized by cold, high salinity, and drought. Osmotic stress always occurs simultaneously with drought and its tolerance is a vital part of drought tolerance. The diversity of metabolites leading to osmotic stress tolerance was characterized using widely-targeted metabolomics in tolerant (XL) and sensitive (D) accessions submitted to polyethylene glycol. XL regulated a more diverse set of metabolites than D, which may promote the establishment of a robust system to cope with the stress in XL. Compounds belonging to the group of flavonoids, amino acids, and glycerophospholipids constitute the core metabolome responsive to the stress, despite the tolerance levels. Moreover, 8 h appeared to be a critical time point for stress endurance involving a high accumulation of key metabolites from the class of nucleotide and its derivative which provide the ultimate energy source for the synthesis of functional carbohydrates, lipids, peptides, and secondary metabolites in XL. This intrinsic metabolic adjustment helped XL to efficiently alleviate the stress at the later stages. A total of 22 diverse compounds were constantly and exclusively regulated in XL, representing novel stress tolerance biomarkers which may help improving stress tolerance, especially drought, in hulless barley.

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Magnitude of Turnover Intention and Associated Factors among Health Professionals Working in Public Health Institutions of North Shoa Zone, Amhara Region, Ethiopia

Background. Health workers are one of the most important building blocks of the health system. High turnover rate contribute to the shortfalls and unbalanced distribution of health personnel in the health workforce. Turnover intention is the strongest predictor of actual turnover. Objective. To assess the magnitude of turnover intention and associated factors among health professionals working in public health institutions of North Shoa Zone, Amhara region, Ethiopia. Methods. A health facility based cross-sectional study was conducted from March to April 2016, on 612 health professionals working in public health institutions of North Shoa Zone, Amhara region, Ethiopia, using a multistage stratified sampling technique. Data were collected using a pretested self-administered structured questionnaire. The data were entered using Epidata version 3.1 and analyzed using SPSS version 22 software. Descriptive statistics were conducted to summarize the sample characteristics. Backward stepwise logistic regression model was fitted and AOR with 95% CI was calculated to identify the associated factors. P-value

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In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways

Two pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa were isolated from 2 patients after exposure to β-lactams. The genetic basis of ceftolozane/tazobactam resistance was evaluated, and β-lactam-resistant mechanisms were assessed by phenotypic assays. Whole genome sequencing identified mutations in AmpC including the mutation (V213A) and a deletion of 7 amino acids (P210–G216) in the Ω-loop. Phenotypic assays showed that ceftolozane/tazobactam resistance in the strain with AmpCV213A variant was associated with increased β-lactamase hydrolysis activity. On the other hand, the deletion of 7 amino acids in the Ω-loop of AmpC did not display enhanced β-lactamase activity. Resistance to ceftolozane/tazobactam in P. aeruginosa is associated with changes in AmpC; however, the apparent loss of β-lactamase activity in AmpC∆7 suggests that non-AmpC mechanisms could play an important role in resistance to β-lactam/β-lactamase inhibitor combinations.

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Endoscopic ultrasound‐guided tissue acquisition: Can fork and crown cut the tissue?

Abstract

Tissue acquisition under endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) is important in obtaining a pathological diagnosis in certain malignant and benign diseases. These include well‐differentiated adenocarcinomas, autoimmune pancreatitis, and sarcoidosis. Tissue specimens also allow for additional immunohistological evaluation, which is essential in the diagnosis of diseases such as lymphoma, neuroendocrine neoplasms, and gastrointestinal stromal tumors. More recently, tissue specimens have been of great importance in decision‐making pertaining to the administration of specific medicines, such as molecular target agents, as well as the use of molecular biological diagnostic approaches.

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Sarcoidosis Presenting as Acute Respiratory Distress Syndrome

Sarcoidosis is a multisystem granulomatous disease of unknown origin. It typically involves the lungs and mediastinal lymph nodes in a chronic fashion. However, acute syndrome has been reported possibly in response to systemic release of proinflammatory cytokines. Acute pulmonary manifestations, especially acute respiratory failure or acute respiratory distress syndrome, remain extremely uncommon in individuals without a prior diagnosis. We present the case of a 41-year-old African American female, who presented with ARDS. An extensive workup into the cause of her illness remained negative, and she subsequently succumbed to her illness. A diagnosis of sarcoidosis was made upon autopsy, after exclusion of other granulomatous illness. The case highlights the need to consider this uncommon diagnosis in patients with unexplained ARDS to guide therapy.

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Peptide Extract from Olivancillaria hiatula Exhibits Broad-Spectrum Antibacterial Activity

Increasing reports of infectious diseases worldwide have become a global concern in recent times. Depleted antibiotic pipelines, rapid and complex cases of antimicrobial resistance, and emergence and re-emergence of infectious disease have necessitated an urgent need for the development of new antimicrobial therapeutics, preferably with novel modes of action. Due to their distinct mode of action, antimicrobial peptides offer an interesting alternative to conventional antibiotics to deal with the problems enumerated. In this study, the antimicrobial potential of the peptide extract from the marine mollusc, Olivancillaria hiatula, was evaluated in vitro. Agar diffusion and broth dilution techniques were used to evaluate microbial susceptibility to the peptide extract. Microplate-based assays were also used to investigate time-dependent growth inhibition profiles of microbes in the presence of peptide and evaluate the peptide's ability to modulate the activities of standard antibiotics. Both Gram-positive and Gram-negative bacteria were inhibited by the peptide extract in the agar diffusion assay. The minimum inhibitory concentration (MIC) of peptide against test microorganisms was between 0.039 and 2.5 mg/mL. At the MIC, the peptide extract was bacteriostatic towards all tested microorganisms but bactericidal to Staphylococcus aureus. In the presence of the peptide extract, a prolonged lag phase was observed for all microbes, similar to standard ciprofloxacin. When administered together, peptide extracts enhanced the activities of ciprofloxacin and cefotaxime and were antagonistic towards erythromycin but indifferent towards metronidazole. Taken together, these results show the broad-spectrum antibacterial activity of peptide extract from Olivancillaria hiatula and demonstrate that antimicrobial peptides can be employed in combination with some conventional antibiotics for improved effects.

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Mechanisms of Intravascular Linear Ablation Induced Restenosis in Rabbit Abdominal Aorta

Objectives. Percutaneous coronary intervention (PCI) is the mainstay treatment for coronary artery disease but complications such as in-stent restenosis and thrombosis remain problematic. Radiofrequency balloon angioplasty (RBA) can improve lumen dimension, fusing intimal tears, and artery dissection but is associated with higher restenosis rate. Methods. After establishing an atherosclerosis model based on endothelial abrasion and high cholesterol diet, forty-five rabbits were randomly divided into three groups: RBA (n=20), percutaneous transluminal angioplasty (PTA) (n=20), and control groups (n=5). The RBA and PTA groups were subdivided according to harvested time posttreatment, respectively (1 hour, 7 days, 14 days, and 28 days). Aorta segments were then isolated for hematoxylin and eosin staining, Masson trichrome staining, immunohistochemistry, and Western blot for TLR-4, NF-κB, MCP-1, and VCAM-1expression. Results. At 28 days, intimal area was significantly lower in the RBA group compared to the PTA and control groups, whilst luminal and medial area were comparable in the RBA and PTA group but higher and lower than the control group, respectively. Expression of TLR-4, NF-κB, MCP-1, and VCAM-1 showed no significant difference between RBA and PTA groups. Conclusions. RBA can depress the intimal hyperplasia and promote dilatation of the artery to greater extents than PTA at 28 days. However, this did not involve TLR-4 signaling pathway, which likely plays a negligible role in mediating restenosis. Reduction of intimal hyperplasia may be due to injury of ablation to the tunica media and inhibition of VSMC proliferation and migration.

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The Removal of HBV in Plasma by Extracorporeal Immunoadsorption from Plasma: A Potential Therapy of Hepatitis B Patients

Objective. To establish a novel HBV specific immunoadsorbent for the removing of HBV particles. Methods. The anti-HBsAg monoclonal antibody was immobilized on sepharose beads to produce a sepharose anti-HBs column. Then the immunoadsorbent was evaluated and characterized by scanning electron microscopy. In addition, time-dependent effects of the eradication capacity of anti-HBsAg functionalized sepharose beads against HBV were investigated. Results. Proposed immunoadsorbents exhibited a favorable biocompatibility as well as specificity. With the optimized recycle time, the decontamination performance of HBV particles and quantity of HBsAg were assessed either by real-time quantitative PCR or ELISA, which showed that the immunoadsorbent could remove approximately 90% of the HBV and 90% of the HBsAg from human plasma samples. Conclusions. All these results indicated that the novel immunoadsorbent could effectively remove HBV particles and likely serve as a novel therapy option or at least supplementary for the treatment regimen of HBV.

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Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway

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Gegen Qinlian Decoction Attenuates High-Fat Diet-Induced Steatohepatitis in Rats via Gut Microbiota

Gut microbiota play an important role in modulating energy contribution, metabolism, and inflammation, and disruption of the microbiome population is closely associated with chronic metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Gegen Qinlian decoction (GGQLD), a well-known traditional Chinese herbal medicine (CHM), was previously found to regulate lipid metabolism and attenuate inflammation during NAFLD pathogenesis. However, the underlying mechanism of this process, as well as how the gut microbiome is involved, remains largely unknown. In this study, we investigated the effect of varying doses of GGQLD on the total amount and distribution of gut bacteria in rats fed a high-fat diet (HFD) for 8 weeks. Our analysis indicates that Oscillibacter and Ruminococcaceae_g_unclassified are the dominant families in the HFD group. Further, HFD-dependent differences at the phylum, class, and genus levels appear to lead to dysbiosis, characterized by an increase in the Firmicutes/Bacteroidetes ratio and a dramatic increase in the Oscillibacter genus compared to the control group. Treatment with GGQLD, especially the GGQLL dose, improved these HFD-induced changes in intestinal flora, leading to increased levels of Firmicutes, Clostridia, Lactobacillus, bacilli, and Erysipelotrichales that were similar to the controls. Taken together, our data highlight the efficacy of GGQLD in treating NAFLD and support its clinical use as a treatment for NAFLD/NASH patients.

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Safety and efficacy of high‐dose methotrexate for osteosarcoma in adolescents compared with young adults

Young adults take longer to clear methotrexate and receive fewer cycles of HDMTX compared to adolescents, but do not experience increased toxicity. Patients who receive more cycles of HDMTX may have better outcomes, regardless of age.

Abstract

Background

Doxorubicin, cisplatin, and high‐dose methotrexate (HDMTX) are the backbone of pediatric osteosarcoma treatment. However, due to toxicity concerns and the lack of data regarding efficacy in adults, high‐dose methotrexate is rarely used in the adult population.

Methods

This single‐center retrospective study examined 33 patients who received HDMTX (12 g/m², maximum 20 g) for the treatment of osteosarcoma at Oregon Health and Science University (OHSU) from 2011 to 2017. Time to serum methotrexate level ≤0.1 µmol/L was the primary outcome. Secondary outcomes included number of HDMTX doses received, methotrexate‐related toxicities, and disease outcomes including histologic response at resection and metastasis‐free survival.

Results

Median age was 20 years [range 7‐38]; 14 patients ≤18 years old and 19 patients >18 years old. Median time to clearance for patients ≤18 years was 79 hours (range 63‐116) compared to 120 hours (range 77‐315) for patients >18 years (P < 0.001). No correlation between age and histologic response at resection was observed (P = 0.50), but there was a significant positive correlation between the number of HDMTX doses received before resection and histologic response (r = 0.49, P = 0.006). There was no significant difference in metastasis‐free survival between age groups, although a trend toward improved survival was noted for patients who received at least seven doses of HDMTX.

Conclusion

Age over 18 years correlates with delayed methotrexate clearance and fewer administered doses of methotrexate, without increased toxicity. The potential benefit of HDMTX in young adults with osteosarcoma may outweigh toxicity risks.

http://bit.ly/2EFQKx1

A randomized controlled trial on the efficiency of free‐handed, pilot‐drill guided and fully‐guided implant surgery in partially edentulous patients

Abstract

Objectives

To compare the effectiveness of free‐handed (FH), pilot‐drill guided (PG) and fully‐guided (FG) implant surgery by means of the Apical Global Deviation (AGD) in relation to the additional financial cost and time spent.

Materials and methods

Thirty‐three partially edentulous patients in need of ≥2 implants in the posterior maxilla were randomly allocated to one of the following treatment groups: FH, PG, FG. Eleven patients (mean age 57; 8 females; altogether 26 implants) were treated by FH surgery, 11 (mean age 53; 7 females; altogether 24 implants) by PG surgery and 10 (mean age 60; 6 females; altogether 21 implants) by FG surgery. The accuracy in implant positioning was assessed by comparing the actual implant position to its planned position with the AGD as the main measure of effectiveness. Cost analysis included data on time investment (pre‐ and per‐operative) and operational cost. The efficiency of PG and FG surgery was assessed by means of the incremental cost‐effectiveness ratio (ICER), defined as the extra investment that is needed per unit reduction in AGD when compared to FH surgery.

Results

FG surgery was most effective (mean AGD: 0.97mm) and FH surgery was least effective (mean AGD: 2.11mm) in terms of surgical accuracy. As a result, 5/26 implants had to be restored with a cement‐retained restoration following FH surgery, although screw‐retention was planned for all implants in every group. The total time investment did not differ significantly between the 3 groups (p=0.811). A significant additional cost per implant was found for PG and FG as compared to FH surgery pointing to 8.29% (€176.54) and 10.45% (€222.52), respectively (p<0.001). The ICER revealed an additional cost of €5.48 and €4.12 per percent reduction in AGD for PG and FG surgery, respectively.

Conclusion

The extra operational cost for guided implant surgery is acceptable and clinically justified since cementation can be avoided. FG surgery is the most efficient surgical approach, even though the absolute operational cost is higher when compared to PG and FH surgery.

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Characterization of a Microalgal UV Mutant for CO2 Biofixation and Biomass Production

The mutagenesis is an emerging strategy for screening microalgal candidates for CO2 biofixation and biomass production. In this study, by 96-well microplates-UV mutagenesis, a mutant stemmed from Scenedesmus obliquus was screened and named as SDEC-1M. To characterize SDEC-1M, it was cultivated under air and high level CO2 (15% v/v), and its parental strain (PS) was considered as control. Growth characterizations showed that SDEC-1M grew best in high level CO2. It indicated that the mutant had high CO2 tolerance (HCT) and growth potential under high level CO2. Richer total carbohydrate content (37.26%) and lipid content (24.80%) demonstrated that, compared to its parental strain, SDEC-1M was apt to synthesize energy storage materials, especially under high CO2 level. Meanwhile, the highest light conversion efficiency (approximately 18 %) was also obtained. Thus, the highest overall biomass productivities were achieved in SDEC-1M under high level CO2, largely attributed to that the highest productivities of total lipid, total carbohydrate, and crude protein were also achieved in the meantime. By modified UV, therefore, mutagenized SDEC-1M was the better candidate for CO2 biofixation and biofuel production than its parental strain.

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Superb Microvascular Imaging Compared with Contrast-Enhanced Ultrasound for Assessing Laser Ablation Treatment of Benign Thyroid Nodules

Purpose. To compare superb microvascular imaging (SMI) with contrast-enhanced ultrasonography (CEUS) for evaluating the ablation of benign thyroid nodules. Methods. 225 Patients with 256 benign thyroid nodules underwent conventional ultrasound, color Doppler flow imaging (CDFI), CEUS, and SMI before and after laser ablation. They were routinely followed up at 1, 3, 6, and 12 months. The volume and volume reduction rate of the ablated nodules was calculated. Results. On SMI, the complete ablated nodules had no microvascular perfusion, while the incompletely ablated nodules had microvascular perfusion at the edge of the nodule. The percentages of the detected incompletely ablated nodules of SMI (37/256, 14.45%) and CEUS (41/256, 16.02%) were comparable, and both were significantly higher than CDFI (P

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Working Cannula-Based Endoscopic Foraminoplasty: A Technical Note

Purpose. Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive disc surgery that can be performed under local anesthesia and requires only an eight-mm skin incision. For the patients with lumbar foraminal stenosis, the migrated disc is difficult to remove with a simple transforaminal approach. In such cases, the foraminoplasty techniques can be used. However, obtaining efficient foramen enlargement while minimizing radiation exposure and protecting the nerves can be challenging. Methods. In this study, we propose a new technique called the Kiss-Hug maneuver. Under endoscopic viewing, we used the bevel tip of a working cannula as a bone reamer to enlarge the foramen. This allowed us to efficiently enlarge the lumbar foramen endoscopically without the redundancy and complications associated with reamers or trephines. Results. Details of the four steps of the Kiss-Hug maneuver are reported along with adverse events. The advantages of this new technique include minimizing radiation exposure to both the surgeon and the patient and decreasing the overall operation time. Conclusion. The endoscopic Kiss-Hug maneuver is a useful and reliable foraminoplasty technique that can enhance the efficiency of foraminoplasty while ensuring patient safety and reducing radiation exposure.

http://bit.ly/2Tc7UGL

The Effect of Desensitizing Toothpastes and Coffee Staining on the Optical Properties of Natural Teeth and Microhybrid Resin Composites: An In-Vitro Study

Objective. To evaluate the effect of different desensitizing toothpastes and coffee staining on the discoloration rate of natural human tooth and composite materials. Materials and Methods. A total of 56 human teeth and 56 composite specimens were used. After initial color measurements were taken, specimens and teeth were exposed to simulated toothbrushing with six desensitizing toothpastes containing different active ingredients: stannous fluoride, strontium acetate, potassium citrate and hydroxyapatite, cetylpyridinium chloride, arginine, and novamin. Specimens were then exposed to coffee staining. Throughout the staining procedure, the storing solution was refreshed every day and the specimens were brushed with the tested toothpastes. Color measurements and changes were recorded at each stage and analyzed with one-way ANOVA, Dunnett tests, and paired sample t-test (p

http://bit.ly/2CtOCH1