Optimization of an Injectable, Resorbable, Bioactive Cement Able to Release the Anti-Osteoclastogenic Biomolecule ICOS-Fc for the Treatment of Osteoporotic Vertebral Compression Fractures.

Vertebral compression fractures are typical of osteoporosis and their treatment can require the injection of a cement through a minimally invasive procedure to restore vertebral body height. This study reports the development of an injectable calcium sulphate-based composite cement able to stimulate bone regeneration while inhibiting osteoclast bone resorption. To this aim, different types of strontium-containing mesoporous glass particles (Sr-MBG) were added to calcium sulphate powder to impart a pro-osteogenic effect, and the influence of their size and textural features on the cement properties was investigated. Anti-osteoclastogenic properties were conferred by incorporating into poly(lactic-co-glycolic)acid (PLGA) nanoparticles, a recombinant protein able to inhibit osteoclast activity (i.e., ICOS-Fc). Radiopaque zirconia nanoparticles (ZrO2) were also added to the formulation to visualize the cement injection under fluoroscopy. The measured cement setting times were suitable for the clinical practice, and static mechanical testing determined a compressive strength of ca. 8 MPa, comparable to that of human vertebral bodies. In vitro release experiments indicated a sustained release of ICOS-Fc and Sr2+ ions up to 28 days. Overall, the developed cement is promising for the treatment of vertebral compression fractures and has the potential to stimulate bone regeneration while releasing a biomolecule able to limit bone resorption.

Thoracic Spine CT Hidden Treasures: Lung Assessment and Extraspinal Findings in Patients with Vertebral Fractures Studied with Full FOV during Breath Hold: Technical Note.

Thoracic spine CTs are usually performed during free breathing and with a narrow field of view; this common practice systematically excludes the assessment of lungs and other extraspinal structures, even if these have been irradiated during the examination. At our institution we perform thoracic spine CT during breath hold with additional full FOV reconstructions; this allows us to also evaluate lungs and extraspinal pathologies in the same examination with no added costs or further radiation exposure. If this simple and costless technical change is routinely applied to thoracic spine CT many concomitant extraspinal pathologies can be ruled out, from neoplasms to pneumonia; the suggested modification also allows an early diagnosis and avoids recalling and re-irradiating the patient in case these findings are partially included in the study. This practice can be further useful during the current pandemic in order to screen any lung opacities suspicious for COVID-19.

Severe acute respiratory syndrome coronavirus-2 medical solid waste treatment: A need for efficient and effective strategies in low-resourced settings.

Understanding infections related to handling healthcare waste products is of critical importance and the application of simple and low-cost strategies remain a priority in low-income and middle-income countries to protect healthcare workers. We examined the potential effect of relative humidity (RH), air temperature and ultraviolet irradiation (UI) to establish an efficient and effective way to facilitate disposal of medical waste. Literature is emerging on the effect of high RH and high temperature, which would increase airborne mass deposition and decrease the viability of viruses in both airborne particles and on surfaces. On the other hand, severe acute respiratory syndrome coronavirus-2 has been proven to be susceptible to UI when suspended in air like other coronaviruses. An innovative approach utilizing environmental conditions might represent an effective and efficient way to ensure better and sustainable protection of the healthcare workers in low-resourced settings.

Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi®) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells.

The treatment of cystic fibrosis (CF) patients homozygous for the F508del mutation with Orkambi®, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability in the clinical response was also observed. The aim of this study was to evaluate the response to Orkambi® in a small cohort of F508del/F508del patients (n = 14) in terms of clinical and laboratory parameters, including ex vivo CFTR activity in mononuclear cells (MNCs), during a 12-month treatment. Patients responded with an increase in percent predicted forced expiratory volume in 1 s (FEV1%) and body mass index (BMI) as well as with a decrease in white blood cell (WBC) total counts and serum C-reactive protein (CRP) levels, although not significantly. Sweat chloride and CFTR-dependent chloride efflux were found to decrease and increase, respectively, as compared with pre-therapy values. CFTR and BMI showed a statistically significant correlation during Orkambi® treatment. Clustering analysis showed that CFTR, BMI, sweat chloride, FEV1%, and WBC were strongly associated. These data support the notion that CFTR-dependent chloride efflux in MNCs should be investigated as a sensitive outcome measure of Orkambi® treatment in CF patients.

Can Carotid Endarterectomy be Performed Safely within 14 days after Intravenous Thrombolysis for Acute Stroke?

BACKGROUND: Carotid endarterectomy (CEA) represents a standard procedure in case of symptomatic carotid stenosis of 50-99% within 2 weeks from onset of stroke or transient ischemic attack (TIA) symptoms. The optimal time to perform CEA after intravenous thrombolysis (IVT) is still unclear. The aim of this study was to analyze the safety of CEA performed within 2 weeks from IVT. MATERIALS AND METHODS: A consecutive series of 70 patients affected by symptomatic carotid stenosis have been treated as per the international guidelines during 3 years. Eleven (15.7%) patients have been treated with IVT before CEA for ischemic stroke; remaining 59 (84.3%) patients received only CEA. CEA was performed in median 8 days (range: 2-13) after IVT. We examined the grade of disability before and after surgery as well as at 3 months follow-up, using the modified Ranking Scale (mRS). RESULTS: Among the patients who underwent CEA + IVT, CEA was performed in median 8 days (range: 2-13) after IVT. One patient received CEA within 48 hours from IVT, 3 patients within 72 hours, and 7 patients within 2 weeks. The complications within 90 days from surgery, in CEA + IVT group, were 3 cases of intracerebral hemorrhage (ICH) without symptoms. In patients who received only CEA, the complications were 1 case of stroke and 2 cases of ICH. The mortality registered was 0% in both groups. Among CEA + IVT group at 90 days after surgery, 9 patients had a mRS grade of 0-2, 2 patients had mRS of 3-5. CONCLUSIONS: In our series, IVT before CEA did not seem to increase the rate of complications. However, the study has several limitations, and further studies must be performed before solid evidence is available for recommendations regarding the timing of CEA after IVT.

Effectivenesss of ivacaftor in severe cystic fibrosis patients and non-G551D gating mutations.

BACKGROUND: Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined. METHODS: Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV1 ] < 40%, or on lung transplant waiting list, or with a fast worsening trend of lung function). Data were collected for 1 year before and 1 year after ivacaftor commencement. RESULTS: Thirteen patients received ivacaftor for a median of 320 days. Mean (SD) ppFEV1 increased from 35.1% (14.3%) before treatment to 46.6% (18.8%) after 12 months of treatment (absolute increase 11.5%, relative increase 32.8%). Mean distance of the 6-minute walking test improved significantly, from 535.1 m before to 611.6 m after 12 months of treatment (P = .002). The number of pulmonary exacerbations decreased significantly, from 57 during the year before ivacaftor to 28 in the year following ivacaftor (P = .0048). Five of the 13 patients (38.5%) had no exacerbations during the 12 months after starting ivacaftor. Median weight increased significantly, from 52.7 kg to 55.6 kg (P = .0031). Mean (SD) sweat chloride concentration decreased significantly, from 99.5 (22.8) mmol/L to 39.3 (15.8) mmol/L (P < .0001). No safety concerns were registered. CONCLUSIONS: Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations.

A cloud-based computer-aided detection system improves identification of lung nodules on computed tomography scans of patients with extra-thoracic malignancies.

OBJECTIVES: To compare unassisted and CAD-assisted detection and time efficiency of radiologists in reporting lung nodules on CT scans taken from patients with extra-thoracic malignancies using a Cloud-based system. MATERIALS AND METHODS: Three radiologists searched for pulmonary nodules in patients with extra-thoracic malignancy who underwent CT (slice thickness/spacing 2 mm/1.7 mm) between September 2015 and March 2016. All nodules detected by unassisted reading were measured and coordinates were uploaded on a cloud-based system. CAD marks were then reviewed by the same readers using the cloud-based interface. To establish the reference standard all nodules ≥ 3 mm detected by at least one radiologist were validated by two additional experienced radiologists in consensus. Reader detection rate and reporting time with and without CAD were compared. The study was approved by the local ethics committee. All patients signed written informed consent. RESULTS: The series included 225 patients (age range 21-90 years, mean 62 years), including 75 patients having at least one nodule, for a total of 215 nodules. Stand-alone CAD sensitivity for lesions ≥ 3 mm was 85% (183/215, 95% CI: 82-91); mean false-positive rate per scan was 3.8. Sensitivity across readers in detecting lesions ≥ 3 mm was statistically higher using CAD: 65% (95% CI: 61-69) versus 88% (95% CI: 86-91, p<0.01). Reading time increased by 11% using CAD (296 s vs. 329 s; p<0.05). CONCLUSION: In patients with extra-thoracic malignancies, CAD-assisted reading improves detection of ≥ 3-mm lung nodules on CT, slightly increasing reading time. KEY POINTS: • CAD-assisted reading improves the detection of lung nodules compared with unassisted reading on CT scans of patients with primary extra-thoracic tumour, slightly increasing reading time. • Cloud-based CAD systems may represent a cost-effective solution since CAD results can be reviewed while a separated cloud back-end is taking care of computations. • Early identification of lung nodules by CAD-assisted interpretation of CT scans in patients with extra-thoracic primary tumours is of paramount importance as it could anticipate surgery and extend patient life expectancy.

The factor structure of the short form of the Wisconsin schizotypy scales.

The Chapman psychosis-proneness scales-also known as Wisconsin schizotypy scales (WSS)-are among the most used tools to measure schizotypy. The factor structure of the short-form WSS was investigated in a mixed sample of patients with chronic mental disorders and of healthy subjects from the general population. One hundred patients with a chronic mental disorder were enrolled over a 6-month period. For each patient, two controls of same sex and similar age (±5 years) were enrolled; 131 accepted to take part in the study. The unidimensional, the correlated four-factor, the second-order two-factor models, and the bifactor model with two or four orthogonally independent factors of the short-form WSS were tested with confirmatory factor analysis. Good reliability of the short-form WSS was confirmed, as its capacity of differentiating people with and without schizotypy. The bifactor models were superior to other models. However, in both bifactor models the explained common variance (ECV) attributable to the general factor and the percentage of uncontaminated correlations (PUC) were too low to use a general summary score as a measure of a single latent schizotypy variable. Symptoms scores derived from the short-form WSS can be better appreciated within a multidimensional model of schizotypy.

Thrombolysis in Acute Ischemic Stroke after Idarucizumab for Dabigatran Etexilate Reversal in Elderly: A Case Report.

INTRODUCTION: Dabigatran is one of the nonvitamin K antagonist oral anticoagulants. Thrombolytic treatment with intravenous recombinant tissue plasminogen activator is contraindicated in patients taking a DOAC. Idarucizumab was recently approved for dabigatran-activity reversing in severe bleeding, emergency surgery, or urgent procedures, but many attempts have been made to use idarucizumab in patients presenting with acute ischemic stroke in order to be eligible for thrombolysis. CASE: Our patient was an 89-year-old woman with severe aphasia who was treated with dabigatran for nonvalvular atrial fibrillation. She received an infusion of idarucizumab followed by thrombolytic therapy, with complete remission of symptoms after 24 hours. DISCUSSION: Idarucizumab is a safe option for patients with acute ischemic stroke treated with dabigatran; otherwise eligibles for thrombolysis, even in very old people like our patient.

Gastric paraganglioma: case report and review of the literature.

Very few cases of gastric paragangliomas have been reported in the literature to date. We report a rare case of parietal gastric paraganglioma fortuitously detected during intraoperative exploration. A 82-years-old woman presented to our emergency room for abdominal pain. On physical examination abdomen was painful on palpation and Blumberg's sign was present. The laboratory exams showed a neutrophilia in absence of leukocytosis. Acute appendicitis was suspected and a laparoscopy was performed. At exploration, the vermiform appendix was normal while a lumpy, hard-fibrous and white-pinkish extraluminal lesion of the anterior wall of the gastric body near the greater curvature of about 2 cm in diameter was present. Laparoscopic resection of the gastric lesion was performed. The patient was discharged in good condition in the fourth postoperative day. Pathologic examination revealed a gangliocitic paraganglioma. The patient is alive and well without evidence of relapse 6 months after surgery. Gastric paraganglioma is a very rare tumor and its diagnosis is very difficult. Surgical excision is the treatment of choice which can be performed successfully with laparoscopy.

CFTR-dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy.

AIM: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well. METHODS: Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR. RESULTS: Ivacaftor determined a significant decrease in sweat chloride concentrations at all time points during treatment. Body mass index (BMI), FEV1 , and FVC showed an increasing trend. While C-reactive protein decreased significantly at 2 months, the opposite behavior was noticed for circulating monocytes. CFTR activity in MNC was found to increase significantly at 3 and 6 months. Neutrophil oxidative burst peaked at 2 months and then decreased to baseline. HVCN1 mRNA expression was significantly higher than baseline at 1-3 months and decreased after 6 months of treatment. The chloride efflux in MNC correlated positively with both FEV1 and FVC. On the other hand, sweat chloride correlated positively with CRP and WBC, and negatively with both respiratory function tests. A cluster analysis confirmed that sweat chloride, FEV1 , FVC, BMI, and MNC chloride efflux behaved as a single entity over time. DISCUSSION: In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR.

Impact of a risk-based follow-up in patients affected by gastrointestinal stromal tumour.

BACKGROUND: Follow-up aims to precociously identify recurrences, metastases or treatment-related adverse events so as to undertake the appropriate therapy. Guidelines admit lack of knowledge on optimal surveillance schedule, but suggest follow-up based on experts' opinion and risk stratification. To identify the impact, if any, of regular follow-up, we interrogated our prospectively collected database whether early detection of recurrences affected both clinical management and, likely, the outcome. PATIENTS AND METHODS: We required information to be available on primary surgery and ≥3°years of follow-up for non-recurring patients. We analysed recurrence characteristics (asymptomatic versus symptomatic, low- versus high tumour burden) and computed tomography (CT) scan counts to detect one recurrence. Kaplan-Meier method estimated recurrence-free survival (RFS), post-recurrence progression-free survival (PR-PFS), and disease-specific overall survival (OS). Comparisons used Hazard ratios (HR) with 95% confidence intervals (CIs). Multivariate analyses employed the Cox proportional hazards model. All tests were two-sided. RESULTS: Between 01/2001 and 12/2012 we found 233 study-eligible patients. Estimated 5- and 10-year RFS were 61.8% and 50.4%, respectively. After a 68-month median follow-up, we observed 94 (40.3%) recurrences [73/94 (77.7%) asymptomatic versus 21/94 (22.3%) symptomatic and 45/94 (47.9%) low- versus 49/94 (52.1%) high tumour burden]. Multivariate analysis revealed that symptomatic and high tumour burden recurrences were highly predictive of both worse PR-PFS (HR:3.19, P < 0.001; HR:2.80, P = 0.003, respectively) and OS (HR:3.65, P < 0.001; HR:2.38, P = 0.026, respectively). Finally, 29 second (primary) cancers were detected during follow-up. CONCLUSIONS: Regular follow-up detects recurrences at an earlier stage and may be associated with a better PR-PFS and OS for these patients. In the absence of randomised trials, these evidences support follow-up effort and cost.

Preparation and characterisation of an innovative injectable calcium sulphate based bone cement for vertebroplasty application.

In this study, an innovative injectable and bioresorbable composite cement (Spine-Ghost) has been developed by combining a radiopaque glass-ceramic powder (SCNZgc) and spray-dried mesoporous bioactive particles (W-SC) into type III alpha calcium sulphate hemihydrate (α-CSH) (composition α-CSH/SCNZgc/W-SC, 70/20/10 wt%). The Spine-Ghost cement and pure α-CSH (as a reference) were characterised in terms of physical and mechanical properties and compared to a commercial reference (Cerament®- Bonesupport AB, Sweden). The Spine-Ghost cement had a setting time comparable with Cerament® showing a good injectability in the range of 8-20 minutes after the end of mixing. In addition, the Spine-Ghost cement showed a good radiopacity when compared with standard PMMA (BonOs Inject, aap Biomaterials GmbH Germany) and higher compressive strength when compared to healthy cancellous bone. The bioactivity of both Spine-Ghost and Cerament® was evaluated through in vitro soaking in simulated body fluid (SBF). Spine-Ghost samples were highly bioactive, inducing the precipitation of hydroxyapatite crystals in the first week of soaking in vitro. It was also found that the degradation kinetics of the Spine-Ghost cement were faster than those of pure α-CSH and comparable to those of Cerament® after approximately 1 month of soaking in SBF. Moreover, the Spine-Ghost cement was cytocompatible in indirect-contact culture in vitro. Overall results indicate that the Spine-Ghost cement might be a very good candidate for vertebroplasty application and could enhance new bone formation in vivo.

The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.

Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.

Parkinsonism in a pair of monozygotic CADASIL twins sharing the R1006C mutation: a transcranial sonography study.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common hereditary cerebral small vessel disease, is caused by mutations in the NOTCH3 gene on chromosome 19. Clinical manifestations of CADASIL include recurrent transient ischemic attacks, strokes, cognitive defects, epilepsy, migraine and psychiatric symptoms. Parkinsonian features have variably been reported in CADASIL patients, but only a few patients showed a clear parkinsonian syndrome. We studied two patients, a pair of monozygotic twins, carrying the R1006C mutation of the NOTCH3 gene and affected by a parkinsonian syndrome. For the first time in CADASIL patients, we used transcranial sonography (TCS) to assess basal ganglia abnormalities. TCS showed a bilateral hyperechogenic pattern of substantia nigra in one twin, and a right hyperechogenic pattern in the other. In both patients, lenticular nuclei showed a bilateral hyperechogenic pattern, and the width of the third ventricle was slightly increased. The TCS pattern found in our CADASIL patients is characteristic neither for Parkinson's disease, nor for vascular parkinsonism and seems to be specific and related to the disease-specific pathological features.