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The majority of patients with glioblastoma (GBM) experience disease progression. At recurrence, treatment options have limited efficacy. Many studies report a limited and short duration response rate. Although clinical trials represent the "gold standard" for providing evidence on efficacy of specific treatment strategies, real-world data can be considered more representative of the "real" GBM population.To describe the management of GBM recurrence in a large real-world sample.We analysed retrospectively the data stored in the database of the Neuro-oncology Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy. We considered only data of patients with histological diagnosis of GBM and disease recurrence during their follow-up. We excluded patients who did not receive treatment after the diagnosis.We analysed 422 patients (64% males, 36% females) with a mean age of 59.6 (range 16-87) years. At GBM recurrence, 135 (32.0%) patients underwent palliative care, and 287 (68.0%) underwent other treatments. Patients on palliative care were older, had a worse performance status, and a shorter time between GBM diagnosis and its recurrence. Patients who received chemotherapy in combination with other treatments (surgery and/or radiation therapy) at GBM recurrence had a longer survival than those in palliative care (p 0.001). Surgery or radiation therapy alone did not have any effect on survival as compared with palliative care (p 0.001).This study confirms the importance of a multidisciplinary approach even at GBM recurrence, suggesting that combination treatments play a key role in management of disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Introduction: Pain is the most common and distressing medical symptom in hospitalized patients in all wards. Pain prevalence among hospitalized patients is an indicator of the quality of health care. Objective: The aim of this study is to describe pain prevalence in two Italian hospitals. Material and method: This is an observational study. It involved hospitalized patients of both sexes, able and unable to self-report. Descriptive analysis and multivariate analysis were applied. Results: A sample of 754 inpatients were included. In Terni Ho-spital (n = 255), pain prevalence was 80.8%. The mean pain severity was 5.2 (sd ± 3.33). At Rome's San Camillo Hospital (n=499), pain prevalence was 46.9%. Acute pain is more prevalent in women (OR= 0.65; CI 95% 0.43-0.99) and increases with age (OR= 0.97; CI 95% 0.96-0.99). Chronic pain is more prevalent in men (OR= 2.34; CI 95% 1.41-3.97) and increases with age (OR= 1.04; CI 95% 1.03-1.06). Discussion and conclusion.: San Camillo Hospital presents data showing reduced pain prevalence, and describing pain even in patients unable to self-report. It is reasonable to believe that pain control by the staff at San Camillo is better, even though both hospitals are equally important regional institutions.

Summary Background The CLEFT-Q includes 12 independently functioning scales that measure appearance (face, nose, nostrils, teeth, lips, jaws), health-related quality of life (psychological, social, school, speech distress), and speech function, and an eating/drinking checklist. Previous qualitative research revealed that the CLEFT-Q has content validity in noncleft craniofacial conditions. This study aimed to examine the psychometric performance of the CLEFT-Q in an international sample of patients with a broad range of facial conditions. Methods Data were collected between October 2016 and December 2019 from 2132 patients aged 8 to 29 years with noncleft facial conditions. Rasch measurement theory (RMT) analysis was used to examine Differential Item Function (DIF) by comparing the original CLEFT-Q sample and the new FACE-Q craniofacial sample. Reliability and validity of the scales in a combined cleft and craniofacial sample (n=4743) were examined. Results DIF was found for 23 CLEFT-Q items when the datasets for the two samples were compared. When items with DIF were split by sample, correlations between the original and split person locations showed that DIF had negligible impact on scale scoring (correlations ≥0.995). In the combined sample, RMT analysis led to the retention of original content for ten CLEFT-Q scales, modification of the Teeth scale, and the addition of an Eating/Drinking scale. Data obtained fit with the Rasch model for 11 scales (exception School, p=0.04). Person Separation Index and Cronbach alpha values met the criteria. Conclusion The scales described in this study can be used to measure outcomes in children and young adults with cleft and noncleft craniofacial conditions.

Pilocytic astrocytoma (PA) rarely spreads along neuraxis, and association with superficial siderosis (SS) and chronic signs of intracranial hypertension is exceptional.A 48-year-old woman presented with slow onset hearing loss in the past year. Clinical examination revealed dysarthria, positive Romberg test, and severe optic neuropathy. Cerebrospinal fluid (CSF) analysis showed numerous red blood cells, increased proteins and LDH, and high opening pressure. Brain and spine MRI demonstrated extensive superficial siderosis, bone remodeling of the skull base and spine, and diffuse nodular leptomeningeal enhancement. Histological examination of a nodule in the dorsal spine evidenced PA.We report a case of PA associated with dural remodeling and SS. The mechanism of SS is unclear but might be related to meningeal tumor infiltration and altered CSF composition and resorption.

OBJECTIVE To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (JIA). METHODS Response to anakinra was defined as achievement of clinically inactive disease (CID) at 6 months without glucocorticoid treatment. Demographic, clinical, and laboratory characteristics of 56 patients were evaluated in univariate and multivariate analyses as predictors of response to treatment. Six single-nucleotide polymorphisms (SNPs) in the IL1RN gene, previously demonstrated to be associated with a poor response to anakinra, were genotyped by quantitative polymerase chain reaction (qPCR) or Sanger sequencing. Haplotype mapping was performed with Haploview software. IL1RN messenger RNA (mRNA) expression in whole blood from patients, prior to anakinra treatment initiation, was assessed by qPCR. RESULTS After 6 months of anakinra treatment, 73.2% of patients met the criteria for CID without receiving glucocorticoids. In the univariate analysis, the variable most strongly related to the response was disease duration from onset to initiation of anakinra treatment, with an optimal cutoff at 3 months (area under the curve 84.1%). Patients who started anakinra treatment ≥3 months after disease onset had an 8-fold higher risk of nonresponse at 6 months of treatment. We confirmed that the 6 IL1RN SNPs were inherited as a common haplotype. We found that homozygosity for ≥1 high-expression SNP correlated with higher IL1RN mRNA levels and was associated with a 6-fold higher risk of nonresponse, independent of disease duration. CONCLUSION Our findings on patients with systemic JIA confirm the important role of early interleukin-1 inhibition and suggest that genetic IL1RN variants predict nonresponse to therapy with anakinra.

Purpose To implement and optimize a pilot transitions of care model for scheduled chemotherapy admissions in patients with hematologic malignancies at our institution. Methodology: We utilized the plan-do-study-act (PDSA) quality improvement technique to prospectively measure success of interventions related to improving transitions of care processes that occurred in multiple stages including development of standardized operating procedures, electronic medical record documentation, and education to the malignant hematology multidisciplinary group. Chart review was performed retrospectively for at least nine patients per PDSA cycle. Areas of intervention addressed and measured regarding communication between the ambulatory care and acute care settings included: admission purpose, processes related to insurance benefits investigations for specialty medications required in the post-discharge setting, and plan for growth factors, prophylactic antimicrobials, and follow-up. Results and conclusions: We included 28 patients and performed a total of three PDSA cycles demonstrating specific improvements in: communication regarding status of benefits investigations performed for specialty medications prior to admission, resolution of these benefits investigations at various time points, improvement in efficient use of the electronic medical record for chemotherapy orders, and patient instructions for appropriate use of prophylactic antimicrobials. Although improvement was noted initially with prescribing of discharge antiemetics and antimicrobials, regression to baseline was noted with the third PDSA cycle.

Background and objectives ANCA-associated vasculitis is extremely rare in children. We report the clinicopathologic features, long-term outcomes, and prognostic factors of a large pediatric cohort of patients with ANCA-associated kidney vasculitis. Design, setting, participants, & measurements This retrospective study included 85 consecutive patients with kidney biopsy specimen–proven ANCA-associated vasculitis from tertiary referral centers in Italy and Canada. Kidney biopsy specimens were categorized as focal, crescentic, sclerotic, or mixed, according to the Berden classification. The prognostic significance of baseline clinical, laboratory, and histologic findings was analyzed with respect to kidney failure or CKD stage 3–5/kidney failure. Results A total of 53 patients had microscopic polyangiitis (62%), and 32 had granulomatosis with polyangiitis (38%). Rapidly progressive GN was the most frequent presentation (39%); a third of the patients also had nephrotic-range proteinuria. Kidney biopsy specimens were classified as focal in 21% of the patients, crescentic in 51%, sclerotic in 15%, and mixed in 13%. Remission-induction therapies included cyclophosphamide in 78% of patients. A total of 25 patients (29%) reached kidney failure. The median (interquartile range) time to kidney failure or last follow-up was 35 (6–89) months in the whole cohort, and 73 (24–109) months among the patients who did not reach this outcome. Patients whose biopsy specimens showed sclerotic histology had significantly shorter kidney survival (hazard ratio, 11.80; 95% confidence interval, 2.49 to 55.99) and survival free of CKD stage 3–5 (hazard ratio, 8.88; 95% confidence interval, 2.43 to 32.48), as compared with those with focal/mixed histology. Baseline eGFR, low serum albumin, hypertension, central nervous system complications, and sclerotic histology, which reflected severe kidney involvement, were associated with both kidney failure and CKD stage 3–5/kidney failure at unadjusted analysis; no independent prognostic factors emerged at multivariable analysis. Conclusions Children with ANCA-associated kidney vasculitis often have aggressive presentation; a third of such children progress to kidney failure and this usually occurs early during follow-up. A severe clinical presentation is associated with the development of CKD or kidney failure.

The 1p/19q codeletion is the result of a translocation between chromosome 1 (Chr1p) and chromosome 19 (Chr19q) with the loss of derivative (1;19)(p10;q10) chromosome. The 1p/19q codeletion has predictive and prognostic significance, and it is essential for the classification of gliomas. In routine practice, the fluorescence in situ hybridization (FISH) diagnosis of 1p/19q codeletion is sometimes unexpected. This study aimed to develop a next-generation sequencing panel for the concurrent definition of the 1p/19q codeletion and IDH1/IDH2 mutation status to resolve these equivocal cases. A total of 65 glioma samples were investigated using a 1p/19q-single-nucleotide polymorphism (SNP)-IDH panel. The panel consists of 192 amplicons, including SNPs mapping to Chr1 and Chr19 and amplicons for IDH1/IDH2 analysis. The 1p/19q SNP-IDH panel consistently identified IDH1/IDH2 mutations. In 49 of 60 cases (81.7%), it provided the same 1p/19q results obtained by FISH. In the remaining 11 cases, the 1p/19q SNP-IDH panel uncovered partial chromosome imbalances as a result of interstitial amplification or deletion of the regions where the FISH probes map, leading to a mistaken overdiagnosis of 1p/19q codeletion by FISH. The 1p/19q SNP-IDH next-generation sequencing panel allows reliable analysis of the 1p/19q codeletion and IDH1/IDH2 mutation at the same time. The panel not only allows resolution of difficult cases but also represents a cost-effective alternative to standard molecular diagnostics procedures.

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Context Genes causing familial forms of diabetes mellitus are only partially known. Objective We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. Methods Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. Results A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio—a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. Conclusion Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.

The relationship between subjective appraisal of cognitive deficits and symptom severity in schizophrenia is unclear. Insight reportedly affects both factors. Our aim is to further asses the relationship between subjective perception of cognitive deficits, symptom severity and lack of insight as a mediator variable. 109 subjects with schizophrenia were evaluated. Positive and Negative Syndrome Scale (PANSS) was modelled as independent variable, Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) as dependent and "Lack of Insight" (LoI) PANSS Item as mediator one. Mediation was assessed using bootstrap estimation approach. LoI acts as a suppressor variable (i.e., it enhances the relation between the independent and dependent variable) between Negative Symptoms and SSTICS, while showing a mediation effect between Depressive symptoms and SSTICS. LoI has a central role in mediating the relationship between negative and depressed symptoms on the one hand and self-appraisals of cognitive deficits (SACD) assessed with SSTICS on the other. Its suppressor role between negative symptoms and STICSS favour a direct effect of negative symptoms on SACD. On the other hand, its mediator role between depression and SSTICS is consistent with several reports of the 'insight paradox' of an enhanced severity of depression in patients with higher awareness of their disability.

Background Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). Methods This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. Results Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%–9.7%) in the plasma group and 6.2% (95% CI, 5.6%–7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, −2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64–1.62). Conclusions Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047., This study used electronic health record data to emulate a target trial of early COVID-19 convalescent plasma and 30-day mortality risk. No differences in mortality risk were found between patients with nonsevere COVID-19 who were treated and untreated with plasma.

The aim of this study was to evaluate the relationship between molecular markers and clinicopathological features in patients operated on for low-grade epilepsy-associated neuroepithelial tumors. Molecular-genetic signatures are becoming increasingly important in characterizing these lesions, which represent the second most common cause of focal epilepsy in patients undergoing epilepsy surgery. Data from 22 patients operated on for histopathologically confirmed low-grade epilepsy-associated neuroepithelial tumors were retrospectively collected. All specimens were examined for BRAF and IDH mutational status, 1p/19q codeletion and CD34 expression. The relationship between bio-molecular markers and several demographic, clinical and pathological features were analyzed. BRAF mutation was found in 11 (50.0%) patients and CD34 expression in 13 (59.1%). No patients presented IDH mutation or 1p/19q codeletion. Multiple seizure types were present in 5 (45.5%) patients with BRAF mutation and in none of those with BRAF wild type (p = 0.035). Moreover, BRAF mutation was predominant in right-sided lesions (p = 0.004) and CD34 expression was significantly associated with a longer duration of epilepsy (p = 0.027). Several other clinicopathological features, such as association with focal cortical dysplasia and postoperative seizure outcome, showed no significant correlation with molecular markers. Further studies are necessary both to confirm these data in larger cohort of patients and to investigate possible relationships between molecular markers and other clinicopathological features.

According to the 2016 World Health Organization (WHO) classification of tumors of the central nervous system, assessment of exon 4 mutations in isocitrate dehydrogenase 1 or 2 genes (IDH1 or IDH2) is an essential step in the characterization of gliomas. The p.R132H mutation is the most frequent alteration in IDH genes, however other non-canonical IDH mutations can be identified. The aim of this study is to investigate in depth the prevalence of non-R132H IDH ("non-canonical") mutations in brain tumors classified according to the 2016 WHO scheme and their clonal distribution in neoplastic cells. A total of 288 consecutive cases of brain gliomas (grade II-IV) were analyzed for exon 4 IDH1 and IDH2 mutations. IDH1 and IDH2 analysis was performed using next generation sequencing. Non-canonical IDH mutations were identified in 13/52 (25.0%) grade II gliomas (astrocytomas: 8/31, 25.8%; oligodendrogliomas: 5/21, 23.8%) and in 5/40 (12.5%) grade III gliomas (astrocytomas: 3/25, 12.0%; oligodendrogliomas: 2/15, 13.3%). They were not identified in 196 grade IV gliomas (192 glioblastomas, 4 gliosarcomas). In the large majority (>80%) of tumors IDH mutations, both IDH1-R132H and the non-canonical ones, were present in the large majority (>80%) of neoplastic cells. Our data highlight the importance of investigating not only the IDH1-R132H mutation but also the non-canonical ones. These mutations are clonally distributed, with proportions of mutated neoplastic cells overlapping with those of p.R132H, a finding consistent with their driver role in gliomagenesis.

Background: Diffuse grade II and grade III gliomas are actually classified in accordance with the presence of isocitrate dehydrogenase mutation (IDH-mut) and the deletion of both 1p and 19q chromosome arms (1p/19q codel). The role of tumour grading as independent prognostic factor in these group of tumours remains matter of debate. The aim of this study was to determine if grade is an independent prognostic factor and not somehow associated to IDH mutation and 1p/19q status of the tumour. Methods: We analysed 399 consecutive patients with newly diagnosed, histologically proven World Health Organisation (WHO) 2016 grade II or grade III IDH-mut gliomas, assessed by polymerase chain reaction, immunohistochemistry or next-generation sequencing (NGS). Results: The analysis included 399 patients with grade II (n = 250, 62.7%) or grade III (n = 149, 37.3%) diffuse gliomas. Median follow-up time was 105.3 months. Median survival was 148.1 months. In multivariate analysis, grade II (hazard ratio [HR] = 0.342, 95% confidence interval [CI]: 0.221–0.531; P < 0.001) and 1p/19q codeletion (HR = 0.440, 95% CI: 0.290–0.668; P < 0.001) were independently associated with a lower risk for death. The difference in survival remained significant (p = 0.006 in astrocytomas, p = 0.014 in oligodendrogliomas) when adjusted for histological subtype. Residual disease after surgery (or biopsy) negatively affected survival (HR: 2.151, 95% CI: 1.375–3.367, P = 0.001). Post-surgical treatment with radiotherapy + adjuvant chemotherapy improved survival compared with follow-up and other treatments (HR: 0.316, 95% CI: 0.156–0.641, P = 0.001). Conclusions: In our study, histopathological grade still affects survival in IDH-mutant WHO grade II and III diffuse gliomas. This effect appears to be independent from molecular features, extension of surgical resection and post-surgical treatments. Therefore, physicians should continue to take into account tumour grade, along their molecular characteristics, for a better clinical and therapeutic management of the patients.

Background: Some endocrinologists were involved in the management of patients with suspected or confirmed COVID-19 during the first wave of the pandemic. This study aims to analyze burnout levels among the Association of Medical Endocrinologists (AME) members before and during the pandemic. Methods: We recruited two AME members samples at two different times: before COVID-19 (n = 811) and during the first wave of the ongoing pandemic (n = 579). Both the samples filled the Maslach Burnout Inventory. We performed MANOVAs to evaluate demographic and COVID-19 related differences in burnout levels and Pearson’s Chi-square test to compare burnout severity before and during the pandemic. Results: Women reported higher Emotional Exhaustion and reduced Professional Accomplishment than men. The oldest physicians had lower levels of Emotional Exhaustion and Depersonalization and higher Professional Accomplishment than younger workers. Independent contractors displayed lower levels of burnout compared to established contractors. Finally, the pandemic, per se, did not lead to changes in burnout levels. Discussion: Women and young physicians are at higher risk of burnout. It is also possible that front- line professionals are at higher risk during a health care crisis. Moreover, it is likely that the length of exposure to the pandemic has not been sufficient to impact burnout levels. Conclusions: Short-term exposure to pandemic-related activities seemed to have a low impact on burnout severity, except for physicians directly involved in managing COVID-19 cases. It is strongly recommended the availability of psychological support in public hospitals.

Breast cancer (BC) is the most common cancer in women and, among different BC subtypes, triple negative (TN) and human epidermal growth factor receptor 2 (HER2)-positive BCs have the worst prognosis. In this study, we investigated the anticancer activity of the root ethanolic and hexane extracts from Lithospermum erythrorhizon, a traditional Chinese herbal medicine known also as tzu ts’ao or tzu-ken, against in vitro and in vivo models of TNBC and HER2-positive BC. Treatment with L. erythrorhizon root extracts resulted in a dose-dependent inhibition of BC cell viability and in a significant reduction of the growth of TNBC cells transplanted in syngeneic mice. Acetylshikonin, a naphthoquinone, was identified as the main bioactive component in extracts and was responsible for the observed antitumor activity, being able to decrease BC cell viability and to interfere with autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice. Acetylshikonin anticancer effect depends on its ability to act as a potent inhibitor of dihydrofolate reductase (DHFR), to down-regulate key mediators governing cancer growth and progression, such as HER2, Src and STAT3, and to induce apoptosis by caspase-3 activation. The accumulation of acetylshikonin in blood samples as well as in brain, kidney, liver and tumor tissues was also investigated by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) highlighting that L. erythrorhizon treatment is effective in delivering the active compound into the target tissues. These results provide evidence that L. erythrorhizon extract and in particular its main component acetylshikonin are effective against aggressive BC subtypes and reveal new acetylshikonin mechanisms of action.

Background The European region achieved interruption of malaria transmission during the 1970s. Since then, malaria control programs were replaced by surveillance systems in order to prevent possible re-emergence of this disease. Sporadic cases of non-imported malaria were recorded in several European countries in the past decade and locally transmitted outbreaks of Plasmodium vivax, most probably supported by Anopheles sacharovi, have been repeatedly reported from Greece since 2009. The possibility of locally-transmitted malaria has been extensively studied in Italy where the former malaria vector An. labranchiae survived the control campaign which led to malaria elimination. In this study, we present paradigmatic cases that occurred during a 2017 unusual cluster, which caused strong concern in public opinion and were carefully investigated after the implementation of the updated malaria surveillance system. Methods For suspected locally-transmitted malaria cases, alerts to Ministry of Health (MoH) and the National Institute of Health (ISS) were mandated by the Local Health Services (LHS). Epidemiological investigations on the transmission modes and the identification of possible infection’s source were carried out by LHS, MoH and ISS. Entomological investigations were implemented locally for all suspected locally-transmitted cases that occurred in periods suitable to anopheline activity. Molecular diagnosis by nested-PCR for the five human Plasmodium species was performed to support microscopic diagnosis. In addition, genotyping of P. falciparum isolate was carried out to investigate putative sources of infection and transmission modalities. Results In 2017, a cluster of seven non-imported cases was recorded from August through October. Among them, P. ovale curtisi was responsible of one case whereas six cases were caused by P. falciparum. Two cases were proved to be nosocomial while the other five were recorded as cryptic at the end of epidemiological investigations. Conclusions The epidemiological evidence shows that the locally acquired events are sporadic, often remain unresolved and classified as cryptic ones despite investigative efforts. The “cluster” of seven non-imported cases that occurred in 2017 in different regions of Italy therefore represents a conscious alert that should lead us to maintain a constant level of surveillance in a former malaria endemic country.

To analyze relationships between CD34 expression and several demographic, clinical, and pathologic features in patients with histopathologic evidence of low-grade epilepsy-associated tumors who underwent epilepsy surgery.A retrospective study enrolling 187 patients with low-grade epilepsy-associated tumors who underwent surgery between January 2009 and June 2015 at 8 Italian epilepsy surgery centers was conducted. All cases were histologically diagnosed according to the World Health Organization classification of central nervous system tumors. Univariate and multivariate analyses were performed to identify variables associated with CD34 expression.Of 187 patients, 95 (50.8%) were CD34 positive. Tumor type and duration of epilepsy were independently associated with CD34 expression on multivariate analysis. Ganglioglioma and pleomorphic xanthoastrocytoma were the histologic types with the strongest association with CD34 positivity with an odds ratio of 9.2 and 10.4, respectively, compared with dysembryoplastic neuroepithelial tumors. Patients with a duration of epilepsy10 years had a significantly greater likelihood to show CD34 expression, with an odds ratio of 2.8 compared with patients with a duration of epilepsy2 years. On univariate analysis, CD34 expression appeared to be significantly related to older age at surgery, higher antiepileptic drug intake, and female sex.CD34 expression holds promise as a useful biomolecular marker for patients with low-grade epilepsy-associated tumors with evidence of a link with clinicopathologic features. This study confirmed the association between CD34 expression and tumor type and demonstrated a significantly higher probability of CD34 expression in patients with longer duration of epilepsy, independent of histology.

Although cognitive deficit in persons with schizophrenia is well documented, the assessment of the patient's perception of its own cognitive functioning is a relevant issue not adequately studied. Several evaluation tools have been elaborated, however none has been validated in Italian. The aim of the study is the validation of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), a rating scale designed to measure subjective cognitive deficits complaints in persons with schizophrenia.span class="text116"Method. 146 persons meeting the DSM-5 diagnostic criteria for schizophrenia have been recruited. The SSTICS was translated in Italian in accordance with international standard methods. Subjects were also evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Subjective Well-being under Neuroleptic scale (SWN). Cronbach's alpha coefficient was used to assess internal consistency. Constructs were examined using exploratory factor analysis (principal component with varimax rotation). The factorial model was then tested via confirmatory factor analysis.The factorial analysis revealed a 4-factor structure, which is more parsimonious than those obtained in previous studies. Correlations between STICSS and the other rating scales were significant for several domains.The Italian version of the SSTICS showed good psychometric properties and is suitable to measure the patients' subjective perception of cognitive impairment. Subjective evaluation can integrate objective measures of cognitive performances, supporting a multidimensional model of functional impairment in schizophrenia.

Aging related alterations in body composition are associated with higher all-cause mortality risk. To examine the associations between 10-year mortality risk with both BMI and body composition, as well as to establish whether these relationships are modified by age and gender, using data from community-dwelling older Brazilian adults. We used data from two waves i.e., 2000 and 2010 of the SABE (Health, Well-being, and Aging) study conducted in Sao Paulo, Brazil, involving a probabilistic sample of community-dwelling older adults aged 60 years and older. The variables of the study were: mortality (in 10-year follow-up period), body mass index (BMI), body composition (waist circumference, waist hip ratio, triceps skinfold thickness, mid-upper arm circumference, calf circumference, and arm muscle area) and covariables (sociodemographic characteristics, life style, self-reported health conditions, number of chronic diseases, Mini mental state exam, and Geriatric depression scale). Poisson regression estimates with STATA statistical software were used for statistical analyses, considering all p-values < 0.05. Over the 10-year follow-up period, there were 769 deaths (40.2%). The mortality rate was 61.0 for men and 111.8 for the ≥80 age group. In the fully adjusted model, statistically significant hazard ratios were found for low muscle mass (IRR: 1.33), underweight (IRR: 1.29), and low fat mass (IRR: 1.31) with mortality. Men in extreme BMI categories (underweight - IRR: 1.47; obesity I - IRR: 1.66; and obesity II - IRR: 1.91) and women with low muscle and low fat mass were significantly associated with mortality risk. In the ≥80 age group it was observed that low muscle mass (IRR: 168.7), inadequate body reserves (IRR: 1.63), low fat mass (IRR: 140.7), and underweight (IRR: 142.9) were associated with mortality risk. Waist circumference demonstrated protection for mortality in the high-risk categorization for the ≥80 age group. Our results showed that underweight, low fat mass, and low muscle mass were associated with mortality risk, presenting different roles considering gender and age in older Brazilian adults over a 10-year follow-up period.

Background The age is a variable positively related to healthcare expenditures on diabetes (DM), however other factors could also be associated. Physical activity, normal weight and walking habit could be inversely associated to healthcare expenditures related to DM control. The aim of this study was to describe healthcare diabetic-related expenditures and analyze the associations with Body Mass Index (BMI), Physical Activity Level (PAL), and walking habit among the elderly Brazilians. Methods A cross-sectional analysis was carried out on a population-based study (SABE Study) in Brazil. Healthcare expenditures were estimated for the medicine prescriptions, outpatient service and hospitalization. The sample was classified according to BMI, the PAL, and according to weekly frequency of walking habit.The annual healthcare expenditures were estimated, and the multiple logistic regression was used to analyze the associations between variables. Results The sample included 295 elderly diabetics, with a mean age 70 years. The excess weight group presented significantly higher annual expenditures with medicine prescriptions, hospitalization, and outpatient services. Absence of walking habit was related to higher costs and inversely associated to higher expenditures to medicine prescriptions (OR 2.82, IC95% 1.48 - 5.40) and hospitalizations (OR 5.79, IC95% 1.10 - 10.93), independent of BMI, sex, age and the presence of hypertension. Conclusion BMI and insufficient PAL were associated to higher public expenditures related to DM control in elderly people. Walking habit was inversely associated to healthcare expenditures on behalf of the diabetes control among Brazilian elderly population.

Background and objective There is great interest, supported by clinical experience, in the relationship between Eating Disorders (EDs) and psychiatric symptoms and diseases. The psychopathology of EDs is also referred to many risk and protective factors, and there is some evidence in the literature, also about genetic and neurobiological factors involved. The aim of this review is to examine and synthesize the recent scientific literature on this topic, in particular the complex relationship between Anorexia Nervosa and Neuropsychiatric Disorders. Methods We analyzed the best of published literature on the topic, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on November 2017. Results Psychiatric comorbidities are very common in anorexia nervosa. Mood disorders, major depressive disorders, anxiety disorders, obsessive-compulsive disorders, developmental disorders among autistic spectrum and attention-deficit hyperactivity disorder and even some personality disorders, substance abuse and borderline traits have been reported, and some observations suggest a positive genetic correlation between anorexia nervosa and schizophrenia. Conclusion The great amount of scientific articles dealing with the relationship between EDs and psychopathology confirms the complexity of these problems and the difficulties in diagnosis and treatment. An accurate diagnosis and assessment of clinical risk about psychological, psychiatric, nutritional and somatic aspects are therefore essential for an appropriate therapeutic management of patients affected by anorexia nervosa.

Primary Angiitis of the Central Nervous System (PACNS) is a rare form of idiopathic CNS vasculitis. Neuroimaging is often abnormal and characterized by multifocal brain lesions, but brain biopsy definitely confirms the diagnosis. We report the rare case of a 45-year-old female presenting with symptoms of intracranial hypertension and leukodystrophy-like neuroimaging findings. A comprehensive diagnostic work-up led to the unexpected diagnosis of a definite PACNS which was successfully treated by immunosuppressive treatment. Although rarely, PACNS can present as diffuse leukoencephalopathy on neuroimaging, and mimic even an inherited leukodystrophy. Therefore, in adults with leukodystrophy-like neuroimaging findings, careful examination of clinical and non-clinical features is mandatory to avoid missing the diagnosis of a treatable acquired disease.

Background Hippocampal sclerosis (HS) is the most common cause of drug-resistant medial temporal lobe epilepsy (MTLE). Structural abnormalities such as HS, granule cell pathology (GCP), and focal cortical dysplasia (FCD) have been classified histopathologically, possibly allowing a more accurate assessment of prognostic seizure and neuropsychologic outcomes. We correlated seizure outcome with comprehensive temporal lobe pathologic findings, identified according to the most recent classification systems of HS, GCP, and FCD. Methods All the 83 patients who underwent anterior temporal lobectomy (ATL) for drug-resistant MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were collected. Patients were divided in 2 main groups: 1) isolated HS with/without GCP (HS +/- GCP); and 2) HS associated with FCD with/without GCP (HS+FCD +/- GCP). Patients were followed up at least 1 year, and seizure outcome was reported in accordance with Engel classification. Results Group I: HS +/- GCP: Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-no GCP (P < 0.05). Moreover, a better outcome for the patients affected by GCP type I was observed (P < 0.05). Group II: HS+FCD +/- GCP: Patients with HS variant type I presented a better seizure outcome than the patients with HS type II (Engel class IA HS type I vs. type II: 69% vs. 40%). Conclusions A pathology-based approach to epilepsy surgery might improve the interpretation of the results, could predict which cases will enjoy a better seizure outcome, and could help to the comprehension of the causes of failures.

We investigate the epidemiology and outcomes of squamous cell carcinoma (SCC) in recessive dystrophic epidermolysis bullosa (RDEB) from the Australasian EB registry cohort. Seventeen out of 49 (34.6%) RDEB patients developed at least one SCC. Data detailing SCC was obtainable from 16/17 RDEB-SCC patients. A total number of 161 primary SCCs occurred in 16 RDEB-SCC patients with a mean of 10 SCCs per person. The earliest age of first SCC development was 16 years. Eleven out of 16 RDEB-SCC patients eventually developed metastatic SCCs. The majority of the tumours were well and moderately differentiated. The cumulative risk of SCC development by age 35 was 76.1% for RDEB-Generalized Severe (RDEB-GS) and 10% for RDEB-Generalized Intermediate (RDEB-GI). Amongst those who developed SCCs, their median time to death after first SCC was 5 years for RDEB-GI and 4 years for RDEB-GS. This is the first retrospective study of RDEB-SCC in Australasia.

Research using questionnaires has shown that physical activity level (PAL) is associated with healthcare costs. The purpose of this study was to examine the association between objectively measured PAL and healthcare costs among hypertensive and diabetic noninstitutionalized Brazilian older people. The method consisted of a cross-sectional study forming part of the SABE Study, composed of 377 older people interviewed in 2010. Expenditures were estimated taking into account self-reported medicine prescription, outpatient service, and hospitalizations, with the highest quartile of expenditures considered as a risk category. PAL was estimated using an Actigraph accelerometer. Associations were expressed as odds ratios and 95% confidence intervals, adjusted for covariates. Overall expenditures were higher in the sedentary group. The insufficiently active group presented greater odds for higher total, outpatient, and hospitalization expenditure. It was concluded that healthcare expenditures were lower in more active hypertensive and diabetic older people. The promotion of physical activity could be relevant in the attenuation of the burden of chronic diseases in economic losses.

To investigate the predictive role of Intravoxel Incoherent Motion Diffusion-Weighted Imaging (IVIM-DWI) parameters on cervical nodal response to chemo-radiotherapy (CRT) of head and neck squamous cell carcinoma (HNSCC).Patients with pathologically confirmed HNSCC were included in the present prospective study, having at least one positive cervical lymph node (LN). They received concomitant CRT and underwent three serial IVIM-DWI investigations: before, at mid-treatment and after treatment completion. Tissue diffusion coefficient D, perfusion-related diffusion coefficient D* and perfusion fraction f were calculated by a bi-exponential fit. The two-sided Mann-Whitney rank test was used to compare the imaging parameters of patients with regional failure (RF) and regional control (RC). A p value lower than 0.05 was considered to be statistically significant.Thirty-four patients were accrued. Twenty-four out of 34 LN (70.6%) showed persistent RC after a median follow-up time of 27.6 months (range: 12.0-50.2 months), while ten cases of RF (29.4%) were confirmed with a median time of 6.8 months (range: 1.5-19.5 months). Patients with RC showed significantly lower pre-treatment D values compared to the RF patients (p=0.038). At mid-treatment, the patients with RF showed significantly higher D values (p=0.025), and exhibited larger percent reductions in f and the product D*×f from the baseline (p=0.008 and0.001, respectively). No additional information was provided by the examination at the end of treatment.Pre-treatment and mid-treatment IVIM-DWI showed potential for prediction of treatment response of cervical LN in HNSCC patients.

Background Anisakis simplex is the only fishery-product associated parasite causing clinical allergic responses in humans so far. However, other anisakids, due to the presence of shared or own allergens, could also lead to allergic reactions after sensitization. The aim of this study was to determine if Pseudoterranova decipiens belonging to the family Anisakidae has allergenic activity and is able to induce sensitization after oral administration in a murine (BALB/c mice) model. Results The ingestion of A. pegreffii proteins by BALB/c mice, which had been previously sensitized by intraperitoneal inoculation with the corresponding live L3 larvae, triggers signs of allergy within 60 min, whereas P. decipiens did to a lesser extent. Beside symptoms, allergic reactions were furtherly supported by the presence of histamine in sera of sensitized mice. Specific IgG1 and IgE responses were detected in sera of all sensitized mice from week four. Specific IgG2a response was detected in sera from mice sensitized to P. decipiens. After polyclonal or specific activation with anti-CD3/anti-CD28 or antigens, respectively, splenocytes from mice infected i.p. with A. pegreffii or P. decipiens larvae showed significantly higher production of IL-10 than naïve mice. After stimulation with specific antigens, significantly higher IL-5 and IL-13 amounts were produced by specific antigen stimulated splenocytes than by the naïve cells; only P. decipiens proteins induced IFN-ɣ. Conclusions The overall results suggest that infection with P. decipiens can sensitize mice to react to subsequent oral challenge with anisakid proteins, as described for A. simplex (sensu stricto) and A. pegreffii infections. The results show that anisakid proteins induce a dominant Th2 response, although P. decipiens could also induce a mixed type 1/type 2 pattern.

Summary Background Spring-assisted cranioplasty (SAC) has become an accepted treatment for patients with sagittal craniosynostosis; however, the early effects of springs on skull dimensions have never been assessed with objective measurements in the literature. The present study evaluated the changes in skull dimensions and intracranial volume (ICV) during the first 3 months after SAC for sagittal synostosis. Methods Sixteen patients with sagittal synostosis underwent SAC. The cephalic index (CI) and the distance between the spring foot plates were chronologically measured until spring removal at 3 months. Pre- and post-treatment CT scans available for 6 patients were used to assess changes in head shape. Thirteen patients underwent objective aesthetic assessment using pre- and post-operative photographs. Statistical analysis was performed using the linear mixed model for chronological data, t-test statistics for normative data comparisons and Wilcoxon's signed rank test for non-parametric data. Results For scaphocephalic patients, pre-operative and post-operative CIs were 0.70 and 0.74 ( p = 0.001), respectively. Cranial widening towards normative values was observed ( p = 0.0005). A continuous expansion in the distance between the spring foot plates was observed over the treatment period. Frontal and occipital angles were not affected by SAC despite apparent clinical improvements in frontal bossing and occipital prominence. CT analysis demonstrated relative reduction in the anterior cranial volume ( p = 0.01) and relative expansion of the superior occipital volume ( p = 0.03). Conclusions Spring expansion was most marked in the hours following spring insertion. The expansion rate reduced to the minimum by day 1 post-operatively. Clinical benefits of SAC resulted from an increase in the bi-temporal width that camouflaged the frontal bossing. Improvement in occipital prominence was due to superior occipital volume expansion, allowing the occiput to remodel to a more rounded shape.

Background Although regional socioeconomic (SE) factors have been associated with worse health outcomes, prior studies have not addressed important confounders or work disability. Methods A national sample of 59 360 workers’ compensation (WC) cases to evaluate impact of regional SE factors on medical costs and length of disability (LOD) in occupational low back pain (LBP). Results Lower neighborhood median household incomes (MHI) and higher state unemployment rates were associated with longer LOD. Medical costs were lower in states with more workers receiving Social Security Disability, and in areas with lower MHI, but this varied in magnitude and direction among neighborhoods. Medical costs were higher in more urban, more racially diverse, and lower education neighborhoods. Conclusions Regional SE disparities in medical costs and LOD occur even when health insurance, health care availability, and indemnity benefits are similar. Results suggest opportunities to improve care and disability outcomes through targeted health care and disability interventions.

Collegiate athletes are exposed to varying levels of academic and physical stressors, placing them at increased risk for stress-activated latent viral infections. However, the impact of allostatic stress load on the immune response to maximal exercise in athletes remains largely unknown. This study examined the effects of a 7-mo training period and cytomegalovirus (CMV) serostatus on immune cell response to high-intensity swim tests within a group of collegiate swimmers. Samples were collected from 15 National Collegiate Athletic Association Division I swimmers (9 men, 6 women: 19.87 ± 0.64 yr) before and after exhaustive in-pool swims at 2 time points (V1: immediately post-season 1 and V3: beginning of season 2). An additional off-season (V2) time point was collected in a subset of 9 swimmers. Natural killer (NK) cell, B cell, and T cells were quantified by flow cytometry. Linear mixed models were used to determine the effects of exercise, time point, and CMV serostatus (α = 0.05). Resting senescent CD8+ T cells were higher in CMV-seropositive participants at V3 ( P = 0.005). CMV-seronegative participants had a decrease in resting senescent CD8+ T cells from V1 to V3 ( P = 0.021). After acute exercise, CMV-seropositive participants had lower naïve CD8+ T cells ( P < 0.001) and higher senescent CD8+ T cells ( P < 0.001). Increased cumulative stress levels did not appear to affect B-cell and NK-cell compartments. Immune response to exercise was impacted by CMV serostatus and allostatic stress load. Young CMV-seropositive athletes exposed to elevated stressors should be monitored to determine long-term effects of training and academic stressors. NEW & NOTEWORTHY Allostatic stress load is associated with impaired immune response to maximal exercise in cytomegalovirus (CMV)-seropositive subjects but not in CMV-seronegative young healthy adults.

Early magnetic resonance imaging (eMRI) for nonspecific low back pain (LBP) not adherent to clinical guidelines is linked with prolonged work disability. Although the prevalence of eMRI for occupational LBP varies substantially among states, it is unknown whether the risk of prolonged disability associated with eMRI varies according to individual and area-level characteristics. The aim was to explore whether the known risk of increased length of disability (LOD) associated with eMRI scanning not adherent to guidelines for occupational LBP varies according to patient and area-level characteristics, and the potential reasons for any observed variations. A retrospective cohort of 59,360 LBP cases from 49 states, filed between 2002 and 2008, and examined LOD as the outcome. LBP cases with at least 1 day of work disability were identified by reviewing indemnity service records and medical bills using a comprehensive list of codes from the International Classification of Diseases, Ninth Edition (ICD-9) indicating LBP or nonspecific back pain, excluding medically complicated cases. We found significant between-state variations in the negative impact of eMRI on LOD ranging from 3.4 days in Tennessee to 14.8 days in New Hampshire. Higher negative impact of eMRI on LOD was mainly associated with female gender, state workers' compensation (WC) policy not limiting initial treating provider choice, higher state orthopedic surgeon density, and lower state MRI facility density. State WC policies regulating selection of healthcare provider and structural factors affecting quality of medical care modify the impact of eMRI not adherent to guidelines. Targeted healthcare and work disability prevention interventions may improve work disability outcomes in patients with occupational LBP. This study was funded by the Liberty Mutual Research Institute for Safety. The parent company, Liberty Mutual Insurance, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The publication of this article was funded by the Qatar National Library. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Purpose This study was conducted to investigate the interchangeability of infrared forehead, digital axillary, and infrared tympanic thermometers while identifying the most reliable non-invasive body temperature measurement method in paediatric settings. Design and methods A multicentre observational study was conducted enrolling all children less than or equal to 14 years of age requiring a temperature measurement and after obtaining their parent's informed consent. Socio-demographic characteristics and temperature values in Celsius (°C) were simultaneously collected using forehead, axillary, and tympanic thermometers. Results A total of 433 children were enrolled, 57.5% were male and the mean age was 5.3 ± 3.9 years. The average value of tympanic temperature (37.05 °C) was higher than forehead (36.87 °C) and axillary (36.8 °C). The mean difference between axillary and forehead temperatures (−0.06 °C) was not statistically significant (p = 0.158). Comparing the measurements of each type of thermometer with the overall average of the three measurements recorded as the virtual gold standard, Bland Altman analysis highlighted tympanic with narrower 95% limits of agreement (+0.96 °C to −0.68 °C). The tympanic thermometer also had the highest percentage (81.6%) of differences falling within the maximum clinically acceptable difference (±0.5 °C). Conclusions Differences between paired measurements of the three investigated devices demonstrated the devices are not interchangeable. Measurements using the tympanic thermometer more closely resembled the reference temperature indicating its preferential use in paediatric clinical practice. Practice implications To safely and consistently measure body temperature, nurses should not assume peripheral thermometers are interchangeable. It is essential to clinically validate all temperature values with clinical observations.

External ear abnormalities are common. These may affect ear shape, size, prominence and degree of development. They may also be associated with hearing loss. The early identification and management of hearing loss is essential. There are several options for reconstruction of the external ear using both autologous and non-autologous techniques. The aim of this article is to outline the different reconstructive options.

The aim of this study was to verify the presence of BRAF mutations in a series of six patients affected by drug-resistant focal epilepsy associated with neocortical posterior temporal gangliogliomas (GG) who were subjected to lesionectomy between June 2008 and November 2013. GG are an increasingly recognized cause of epilepsy and represent the most common tumor in young patients undergoing surgery for intractable focal epilepsy. BRAF mutations have been identified in up to 50% of GG. Interestingly, these six patients shared a specific anatomical posterior temporal site. In all patients, histological examination confirmed the diagnosis of GG, and two were also associated with a focal cortical dysplasia (FCD) type IIa. BRAF mutations were found in four out of six GG (66.6%). Furthermore, dysplastic tissue of Patient 2 showed a concomitant BRAF V600E mutation. All patients but one (83.3%) achieved Engel Class Ia seizure control. The patient carrying a concomitant BRAF mutation in GG and FCD fell into Engel Class II. Further analyses will be required in order to better understand the meaning of BRAF mutations in epilepsy-associated tumors and FCD and their possible role as a prognostic seizure outcome and tumor behavior marker.

OBJECTIVEIn the past decade, the role of the endoscopic endonasal approach (EEA) has relevantly evolved for skull base tumors. In this study, the authors review their surgical experience with using an EEA in the treatment of clival chordomas, which are deep and infiltrative skull base lesions, and they highlight the advantages and limitations of this ventral approach.METHODSAll consecutive cases of chordoma treated with an EEA between 1998 and 2015 at a single institution are included in this study. Preoperative assessment consisted of neuroimaging (MRI and CT with angiography sequences) and endocrinological, neurological, and ophthalmological evaluations, which were repeated 3 months after surgery and annually thereafter. Postoperative adjuvant therapies were considered.RESULTSSixty-five patients (male/female ratio 1:0.9) were included in this study. The median age was 48 years (range 9–80 years). Gross-total resection (GTR) was achieved in 47 cases (58.7%). On univariate analysis, primary procedures (p = 0.001), location in the superior or middle third of the clivus (p = 0.043), extradural location (p = 0.035), and histology of conventional chordomas (p = 0.013) were associated with a higher rate of GTR. The complication rate was 15.1%, and there were no perioperative deaths. Most complications did not result in permanent sequelae and included 2 CSF leaks (2.5%), 5 transient cranial nerve VI palsies (6.2%), and 2 internal carotid artery injuries (2.5%), which were treated with coil occlusion of the internal carotid artery without neurological deficits. Three patients (3.8%) presented with complications resulting in permanent neurological deficits due to a postoperative hematoma (1.2%) causing a hemiparesis, and 2 permanent ophthalmoplegias (2.5%). Seventeen patients (26.2%) have died of tumor progression over the course of follow-up (median 52 months, range 7–159 months). Based on Kaplan-Meier analysis, the survival rate was 77% at 5 years and 57% at 10 years. On multivariate analysis, the extent of tumor removal (p = 0.001) and the absence of previous treatments (p = 0.001) proved to be correlated with a longer survival rate.CONCLUSIONSThe EEA was associated with a high rate of tumor removal and symptom control, with low morbidity and preservation of a good quality of life. These results allow for a satisfactory overall survival rate, particularly after GTR and for primary surgery. Considering these results, the authors believe that an EEA can be a helpful tool in chordoma surgery, achieving a good balance between as much tumor removal as possible and the preservation of an acceptable patient quality of life.

The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists’ contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations. Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient’s condition, and disease severity or complications.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.

To compare long-term late local toxicity after either concomitant or sequential chemoradiation therapy after breast-conserving surgery.From 1997 to 2002, women aged 18 to 75 years who underwent breast-conserving surgery and axillary dissection for early breast cancer and in whom CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy was planned were randomized between concomitant and sequential radiation therapy. Radiation therapy was delivered to the whole breast through tangential fields to 50 Gy in 20 fractions over a period of 4 weeks, followed by an electron boost. Surviving patients were tentatively contacted and examined between March and September 2014. Patients in whom progressive disease had developed or who had undergone further breast surgery were excluded. Local toxicity (fibrosis, telangiectasia, and breast atrophy or retraction) was scored blindly to the treatment received. A logistic regression was run to investigate the effect of treatment sequence after correction for several patient-, treatment-, and tumor-related covariates on selected endpoints. The median time to cross-sectional analysis was 15.7 years (range, 12.0-17.8 years).Of 206 patients randomized, 154 (74.8%) were potentially eligible. Of these, 43 (27.9%) refused participation and 4 (2.6%) had been lost to follow-up, and for 5 (3.2%), we could not restore planning data; thus, the final number of analyzed patients was 102. No grade 4 toxicity had been observed, whereas the number of grade 3 toxicity events was low (8%) for each item, allowing pooling of grade 2 and 3 events for further analysis. Treatment sequence (concomitant vs sequential) was an independent predictor of grade 2 or 3 fibrosis according to both the National Cancer Institute Common Terminology Criteria for Adverse Events (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.34-12.2; P=.013) and the SOMA (Subjective, Objective, Management and Analytic) scale (OR, 3.75; 95% CI, 1.19-11.79; P=.018), as well as grade 2 or 3 breast atrophy or retraction (OR, 3.87; 95% CI, 1.42-10.56; P=.008). No effect on telangiectasia was detected.At long-term follow-up, concomitant chemoradiation therapy has a detrimental effect on both fibrosis and retraction with an approximately 4-fold increase in the odds of grade 2 or 3 toxicity.

Approximately 10% of the employed population in the United States works in multiple jobs. They are more likely to work long hours and in nonstandard work schedules, factors known to impact sleep duration and quality, and increase the risk of injury. In this study we used multivariate regression models to compare the duration of sleep in a 24-hour period between workers working in multiple jobs (MJHs) with single job holders (SJHs) controlling for other work schedule and demographic factors. We used data from the Bureau of Labor Statistics US American Time Use Survey (ATUS) pooled over a 9-year period (2003–2011). We found that MJHs had significantly reduced sleep duration compared with SJHs due to a number of independent factors, such as working longer hours and more often late at night. Male MJHs, working in their primary job or more than one job on the diary day, also had significantly shorter sleep durations (up to 40 minutes less on a weekend day) than male SJHs, even after controlling for all other factors. Therefore, duration of work hours, time of day working and duration of travel for work may not be the only factors to consider when understanding if male MJHs are able to fit in enough recuperative rest from their busy schedule. Work at night had the greatest impact on sleep duration for females, reducing sleep time by almost an hour compared with females who did not work at night. We also hypothesize that the high frequency or fragmentation of non-leisure activities (e.g. work and travel for work) throughout the day and between jobs may have an additional impact on the duration and quality of sleep for MJHs.

Background A common issue in descriptive injury epidemiology is that in order to calculate injury rates that account for the time spent in an activity, both injury cases and exposure time of specific activities need to be collected. In reality, few national surveys have this capacity. To address this issue, we combined statistics from two different national complex surveys as inputs for the numerator and denominator to estimate injury rate, accounting for the time spent in specific activities and included a procedure to estimate variance using the combined surveys. Methods The 2010 National Health Interview Survey (NHIS) was used to quantify injuries, and the 2010 American Time Use Survey (ATUS) was used to quantify time of exposure to specific activities. The injury rate was estimated by dividing the average number of injuries (from NHIS) by average exposure hours (from ATUS), both measured for specific activities. The variance was calculated using the ‘delta method’, a general method for variance estimation with complex surveys. Results Among the five types of injuries examined, ‘sport and exercise’ had the highest rate (12.64 injuries per 100 000 h), followed by ‘working around house/yard’ (6.14), driving/riding a motor vehicle (2.98), working (1.45) and sleeping/resting/eating/drinking (0.23). The results show a ranking of injury rate by activity quite different from estimates using population as the denominator. Conclusions Our approach produces an estimate of injury risk which includes activity exposure time and may more reliably reflect the underlying injury risks, offering an alternative method for injury surveillance and research.

The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide ± cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).

Research investigating hydration strategies specialized for women&rsquo, s soccer players is limited, despite the growth in the sport. The purpose of this study was to determine the effects of fluid balance and electrolyte losses in collegiate women&rsquo, s soccer players. Eighteen NCAA Division I women&rsquo, s soccer players were recruited (age: 19.2 &plusmn, 1.0 yr, weight: 68.5 &plusmn, 9.0 kg, and height: 168.4 &plusmn, 6.7 cm, mean &plusmn, SD), including: 3 forwards (FW), 7 mid-fielders (MD), 5 defenders (DF), and 3 goalkeepers (GK). Players practiced outdoor during spring off-season training camp for a total 14 practices (WBGT: 18.3 &plusmn, 3.1 &deg, C). The main outcome measures included body mass change (BMC), sweat rate, urine and sweat electrolyte concentrations, and fluid intake. Results were analyzed for comparison between low (LOW, 16.2 &plusmn, 2.6&deg, C, n = 7) and moderate risk environments for hyperthermia (MOD, 20.5 &plusmn, 1.5 &deg, C, n = 7) as well as by field position. The majority (54%) of players were in a hypohydrated state prior to practice. Overall, 26.7% of players had a %BMC greater than 0%, 71.4% of players had a %BMC less than &minus, 2%, and 1.9% of players had a %BMC greater than &minus, 2% (all MD position). Mean %BMC and sweat rate in all environmental conditions were &minus, 0.4 &plusmn, 0.4 kg (&minus, 0.5 &plusmn, 0.6% body mass) and 1.03 &plusmn, 0.21 mg&middot, cm&minus, 2&middot, min&minus, 1, respectively. In the MOD environment, players exhibited a greater sweat rate (1.07 &plusmn, 0.22 mg&middot, 1) compared to LOW (0.99 &plusmn, 1, p = 0.02). By position, DF had a greater total fluid intake and a lower %BMC compared to FW, MD, and GK (all p &lt, 0.001). FW had a greater sweat sodium (Na+) (51.4 &plusmn, 9.8 mmol&middot, L&minus, 1), whereas GK had the lowest sweat sodium (Na+) (30.9 &plusmn, 3.9 mmol&middot, 1). Hydration strategies should target pre-practice to ensure players are adequately hydrated. Environments deemed to be of moderate risk of hyperthermia significantly elevated the sweat rate but did not influence fluid intake and hydration status compared to low-risk environments. Given the differences in fluid balance and sweat responses, recommendations should be issued relative to soccer position.

Background Few studies have specifically investigated the inverse relationship between reduced quality of life in different domains and elevated C-reactive protein (CRP) serum levels in older adults. Therefore, this study investigates the cross-sectional association between quality of life and inflammation in older Brazilian adults. Methods Data were collected from 1255 participants from the third wave (2010) of the Brazilian Health, Well-being and Aging study (SABE), a community-based cohort study of aging. Inflammation was assessed using CRP serum levels and quality of life (QoL) was measured using the 12-item Short-Form Health Survey (SF-12) questionnaire. The covariates included age, sex, education level, financial sufficiency, number of non-communicable diseases, self-reported doctor diagnosed diseases, Activity of Daily Living (ADL) difficulties, Body Mass Index (BMI), and waist circumference. Results The fully adjusted models showed that older adults with low scores in the physical domain of the SF12 (OR 1.34, 95%CI 1.02;1.77) and high BMI values (> 30) (OR 2.05, 95%CI 1.50;2.81) were more likely to present high CRP serum levels. Conclusion Our findings suggest a significant association of lower scores in the physical domain of quality of life and the presence of obesity with high CRP serum levels.

Made available in DSpace on 2018-12-11T17:22:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-12-05 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de Mato Grosso Ethnopharmacological relevance: Terminalia argentea Mart. (Combretaceae), known mainly as “capitão” is a native tree, not endemic, that occurs in the Amazon, Caatinga, Cerrado and Atlantic Forest in Brazil. Leaf infusion is popularly mentioned by riverine communities that inhabit the microregion of Northern Araguaia (Mato Grosso, Brazil) for the treatment of gastric ulcer, bronchitis and haemorrhage. Considering the wide medicinal use, lack of studies that evaluate the safety of use and the scarcity of phytochemical studies of T. argentea leaves, this work was carried out with the objective of evaluating the toxicity of the hydroethanolic extract of the leaves of T. argentea Mart. (HETa) in experimental models in vivo and in vitro, as well as to advance the phytochemical analysis of HETa. Materials and methods: HETa was prepared by macerating the leaf powder in hydroethanolic solution. Phytochemical characterisation was carried out by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and mass spectrometry through direct flow infusion coupled with electrospray ionization and ion-trap analyzer (DFI-ESI-IT-MS analyses) The contents of phenols, flavonoids and phytosterols were analysed by colorimetric methods. Cytotoxicity was assessed by the Alamar blue assay on Chinese hamster ovary epithelial cells (CHO-K1) and human gastric adenocarcinoma cells (AGS). In vitro genotoxicity of HETa (10, 30 or 100 μg/mL) was assessed by micronucleus (MN) and comet tests using CHO-K1 cells. The acute toxicity assessment was performed by oral administration of HETa in single dose Swiss mice (males and females) up to 2000 mg/kg and sub-chronic toxicity by daily oral administration of HETa (50, 200 and 800 mg/kg) in Wistar rats for 30 days. The parameters related to the clinical and toxicological observations were determined every 6 days and at the end of the treatment the blood was collected for biochemical and haematological analysis, and some organs were removed for macroscopic and histopathological analysis. Results: Preliminary phytochemistry and TLC analysis of HETa revealed the presence of phenolic compounds (18.8%), flavonoids (10.8%), saponins, tannins and phytosterols (19%). The HPLC data revealed the presence of gallic acid, rutin, ellagic acid, catechin, quercetin and kaempferol. In the analysis by DFI-ESI-IT-MS, the presence of gallic acid, rutin, ellagic acid and quercetin was confirmed and identified caffeic acid, quinic acid, galloylmucic acid, quercetin xyloside, quercetin rhamnoside, quercetin glucoside, caffeoyl ellagic acid, quercetin galloyl xyloside, terminalin, quercetin galloyl glucose, corilagin, quercetin digalloyl xyloside, quercetin digalloyl glucoside, punicalin and punicalagin. HETa showed no cytotoxic effect on CHO-K1 and AGS cells. In the MN assay, HETa increased the number of MNs and nuclear buds (NBUDs) in binucleate cells at the three concentrations tested and the nucleoplasmic bridges (NPBs) number at 30 μg/mL. In the comet test, HETa (10 and 100 μg/mL) alone showed a genotoxic effect on CHO-K1 cells. In pre-treatment, HETa at all concentrations tested prevented DNA damage induced by H2O2. In co-treatment with H2O2, HETa showed genotoxic effects at the three concentrations, and post-treatment DNA damage in exposed CHO-K1 cells to H2O2 was repaired in 22.5% with 10 μg/mL HETa. In the acute toxicity test, the HETa did not cause death in the mice, being verified only by piloerection and reversible in 2 h in males and in 4 days in females. No macroscopic changes were observed in the analysed organs. In the sub-chronic toxicity test, the HETa did not cause death in the rats after 30 days and the few changes were: absolute (103/mm3) and relative (%) values of basophils increased by 477.8% and 423% (p < 0.001), respectively, with 50 mg/kg; reduction in feed intake (23.6%, p < 0.01) only on day 18; total cholesterol concentration (13.1%, p < 0.05) and relative heart weight (13.2% %, p < 0.05) at a dose of 800 mg/kg. These effects were not dose-dependent nor followed by clinical signs and symptoms of intoxication, nor of macroscopic and histopathological changes in the organs of animals treated with HETa. Conclusions: The results demonstrated that HETa had no cytotoxic in vitro effects for CHO-K1 and AGS cells. In in vitro genotoxicity assays, the HETa induced different responses, according to concentration and experimental condition. In the MN test the HETa presented genotoxic potential by increasing the number of MNs, NBUDs and NPBs. In the comet assay, HETa was genotoxic by itself and in the co-treatment protocol with H2O2. In pre-treatment or post-treatment protocols with H2O2, HETa presented an antigenotoxic effect by preventing or repairing, respectively, the genotoxicity induced by H2O2. In the in vivo models, HETa was shown to be relatively safe after acute administration in mice [no-observed-adverse effect level (NOAEL) of 2000 mg/kg] and sub-chronic in rats (NOAEL of 800 mg/kg), confirming the riverine information that it is non-toxic in the dosage used. Phytochemical analysis of HETa revealed the presence of phenolic compounds, flavonoids, saponins, tannins and phytosterols. Among the flavonoids and tannins, we highlight gallic acid, rutin, ellagic acid, quercetin, caffeic acid, quinic acid, corilagin, punicalin and punicalagin. Thus, it can be stated that HETa has a good safety margin for therapeutic use. Área de Farmacologia Departamento de Ciências Básicas em Saúde Faculdade de Medicina Universidade Federal de Mato Grosso (UFMT) UNESP - Universidade Estadual Paulista Instituto de Biociências Laboratório de Bioprospecção de Produtos Naturais câmpus do Litoral Paulista Laboratório de Pesquisa em Produtos Naturais Faculdade de Medicina Universidade Federal de Tocantins (UFT) Laboratório de Histologia Departamento de Ciências Básicas em Saúde Faculdade de Medicina Universidade Federal de Mato Grosso (UFMT) Instituto Federal de Educação Ciência e Tecnologia de Mato Grosso (IFMT) Campus Avançado de Lucas do Rio Verde UNESP - Universidade Estadual Paulista Instituto de Biociências Laboratório de Bioprospecção de Produtos Naturais câmpus do Litoral Paulista CAPES: 100234/2013 Fundação de Amparo à Pesquisa do Estado de Mato Grosso: 157529/2014

Background Functional magnetic resonance imaging may provide several quantitative indices strictly related to distinctive tissue signatures with radiobiological relevance, such as tissue cellular density and vascular perfusion. The role of Intravoxel Incoherent Motion Diffusion Weighted Imaging (IVIM-DWI) and Dynamic Contrast-Enhanced (DCE) MRI in detecting/predicting radiation-induced volumetric changes of parotids both during and shortly after (chemo)radiotherapy of oropharyngeal squamous cell carcinoma (SCC) was explored. Methods Patients with locally advanced oropharyngeal SCC were accrued within a prospective study offering both IVIM-DWI and DCE-MRI at baseline; IVIM-DWI was repeated at the 10th fraction of treatment. Apparent diffusion coefficient (ADC), tissue diffusion coefficient Dt, perfusion fraction f and perfusion-related diffusion coefficient D* were estimated both at baseline and during RT. Semi-quantitative and quantitative parameters, including the transfer constant Ktrans, were calculated from DCE-MRI. Parotids were contoured on T2-weighted images at baseline, 10th fraction and 8th weeks after treatment end and the percent change of parotid volume between baseline/10th fr (∆Vol10fr) and baseline/8th wk. (∆Volpost) computed. Correlations among volumetric changes and patient-, treatment- and imaging-related features were investigated at univariate analysis (Spearman’s Rho). Results Eighty parotids (40 patients) were analyzed. Percent changes were 18.2 ± 10.7% and 31.3 ± 15.8% for ∆Vol10fr and ∆Volpost, respectively. Among baseline characteristics, ∆Vol10fr was correlated to body mass index, patient weight as well as the initial parotid volume. A weak correlation was present between parotid shrinkage after the first 2 weeks of treatment and dosimetric variables, while no association was found after radiotherapy. Percent changes of both ADC and Dt at the 10th fraction were also correlated to ∆Vol10fr. Significant relationships were found between ∆Volpost and baseline DCE-MRI parameters. Conclusions Both IVIM-DWI and DCE-MRI can help to detect/predict early (during treatment) and shortly after treatment completion the parotid shrinkage. They may contribute to clarify the correlations between volumetric changes of parotid glands and patient−/treatment-related variables by assessing individual microcapillary perfusion and tissue diffusivity. Electronic supplementary material The online version of this article (10.1186/s13014-018-1137-4) contains supplementary material, which is available to authorized users.

Spinal Tuberculosis in children is uncommon, even more so in cases of involvement of posterior vertebral elements, and its diagnosis is often delayed. Here we report the case of a young female presenting neuroradiological features and clinical symptoms suspicious for malignant tumor. Histological examination of biopsy specimen evidenced a Pott's disease. We highlight the importance of suspecting this disorder in children with both aspecific systemic and neurological symptoms, in order to reach a timely diagnosis for appropriate and targeted intervention, avoiding the risk of overtreatment and malpractice claims.

The present study provides norms for Deese/Roediger–McDermott (DRM) lists that were used to create false memories in native speakers of Italian. The word lists reported in this article are based on the DRM lists that have been used extensively to examine illusory memories in English speakers (Deese in Journal of Experimental Psychology, 58, 17–22, 1959; Roediger & McDermott in Journal of Experimental Psychology: Learning, Memory, & Cognition, 21, 803–814, 1995). We translated the 24 critical lures from 24 English DRM lists and created semantically associated Italian word lists that were then normed with native Italian speakers. Overall, the participants recalled 63 % of the list items and 22 % of the critical lures with the word lists developed. In addition, 56 % of the list items and 82 % of the critical lures were recognized by the participants. The present study provides a set of Italian lists that can be used by researchers interested in evaluating false memories in Italian-speaking participants.