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Objective: Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti‐Sp4 autoantibodies co‐occurred in patients with anti–transcription intermediary factor 1 (anti‐TIF1) autoantibody‐positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti‐Sp4 autoantibodies in juvenile‐onset IIM were investigated. Methods: Serum samples from 336 patients with juvenile myositis in a cross‐sectional cohort and 91 healthy controls were screened for anti‐Sp4 autoantibodies using enzyme‐linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti‐Sp4 autoantibodies were compared. Results: Anti‐Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti‐Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti‐Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti‐TIF1 autoantibody–positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti‐Sp4 autoantibodies. None of the patients with anti‐Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti‐Sp4 autoantibodies. Conclusion: Anti‐Sp4 autoantibodies were found in patients with juvenile‐onset IIM, predominantly those with coexisting anti‐TIF1 autoantibodies. Patients with anti‐Sp4 autoantibodies represent a phenotypic subset of anti‐TIF1 autoantibody–positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti‐Sp4 autoantibodies. [ABSTRACT FROM AUTHOR]

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome‐immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12‐year‐old girl with CANDLE syndrome with tofacitinib. [ABSTRACT FROM AUTHOR]

Background Although orthotopic liver transplantation ( OLT) is nowadays considered standard practice at experienced centres, it can still be affected by a significant risk of massive bleeding and its related complications. Solvent/detergent plasma ( S/ D Plasma) has been proposed as an alternative to fresh frozen plasma ( FFP) to curtail such complications. This study aimed at evaluating the efficacy of S/ D Plasma in OLT patients by comparing it to FFP. Materials and Methods Sixty-three OLT patients were randomized into two groups depending on whether they were transfused with FFP or S/ D plasma. A thromboelastography-based protocol aimed at achieving and maintaining predetermined coagulation goals was used to guide plasma transfusions. At the beginning and the end of surgery, standard laboratory coagulation tests were performed together with the assessment of the VII, VIII, V, XII factors and S protein blood levels. Results The two study groups equally achieved the thromboelastography goals but with a reduced amount of transfusions in the S/ D plasma group ( P < 0·0001). At the end of surgery, factors V and XII and S protein blood levels were lower in the S/ D plasma patients who also showed lower INR, a PTT and antithrombin III levels. Conclusion In cirrhotic patients undergoing OLT, the use of S\ D plasma associated with thromboelastography allows the same clinical results but with a significant reduction in the amount of plasma transfusions. [ABSTRACT FROM AUTHOR]

Ragweed pollen extract ( RWE) possesses intrinsic NADPH oxidase activity that induces oxidative stress by initiating the production of intracellular reactive oxygen species ( ROS). The ROS are important contributors to the manifestation of allergic inflammation; furthermore, concomitant exposure to an allergen and an endotoxin trigger a stronger inflammatory response. One of the main pro-inflammatory cytokines produced in inflammatory responses is interleukin-1β ( IL-1β), and its production is associated with caspase-1-containing inflammasome complexes. Intracellular ROS have been implicated in NLRP3 inflammasome-mediated IL-1β production, therefore, we aimed to study whether RWE influences the function of NLRP3 inflammasome. Here we describe that, in the presence of NADPH, RWE significantly elevates lipopolysaccharide-induced IL-1β production of THP-1 cells as well as human primary macrophages and dendritic cells. We also demonstrate that increased IL-1β production is mediated through NLRP3 inflammasome in THP-1 macrophages. We provide evidence that RWE elevates cytosolic ROS level in these cells, and ROS inhibitors abolish IL-1β production. Furthermore, we show that RWE enhances lipopolysaccharide-induced gene transcription/expression of pro- IL-1β and key components of the inflammasome via a ROS-dependent mechanism. [ABSTRACT FROM AUTHOR]

We present the case of an 8-year-old girl who presented with distal extremity necrosis of the hands, feet, nose, and ears as an acute manifestation of cutaneous polyarteritis nodosa (CPAN). She was emergently managed with intravenous steroids, nifedipine, sildenafil, pentoxifylline, nitroglycerin paste, aspirin, low-molecular-weight heparin, and intravenous gamma globulin. The necrosis was controlled, and reperfusion was attained to salvage the extremities. It is important for clinicians to be aware that acute distal extremity necrosis can be a manifestation of CPAN in children. Etiology is often not clear on presentation, but once infection is excluded, acute management with systemic steroids and systemic vasodilators is indicated regardless of the cause. Iloprost and bosentan may represent options for adjunctive vasodilators. More studies are needed to create guidelines for the acute and long-term management of these children. Close follow-up of children with CPAN, especially with a history of vaso-occlusive symptoms, is important to allow prompt intervention in the event of distal extremity infarction. [ABSTRACT FROM AUTHOR]

Antithrombin plasma levels (AT) have been found decreased in women with preeclampsia (PE), but little is known about the trend of AT during the course of this disease. We prospectively investigated AT in consecutive women admitted to our hospital with a diagnosis of PE, to assess if AT fluctuations could be associated with the evolution of the disease. AT, platelet count andd-dimer levels were determined every other day. In the 73 patients studied, AT, platelet count and fibrinogen progressively reduced during the observational period, reaching a nadir on the day of delivery, whereasd-dimer progressively increased over time. Statistical analysis was restricted to the 39 women that had an AT measurement performed on each of days −1, 0 and +1, with respect to the day of delivery. These subjects showed a significant decrease in AT on the day of delivery compared to the day just before (77.8 ± 15.1% vs. 85.4 ± 14.2%, P = 0.027), followed by a recovery on the first day after delivery (87.6 ± 21.3% from 77.8 ± 15.1%, P = 0.005). Our study demonstrates that a significant drop in AT levels is associated with the clinical worsening of PE, regardless of its severity. [ABSTRACT FROM AUTHOR]

A Registry of inherited bleeding disorders was set up in the Region of Emilia-Romagna (RER) to collect information about these diseases and to improve the quality of care. From January 2003, the eight Haemophilia Centres (HC) in the RER began to use computerized clinical records; every 6 months, they send data to Parma Hospital to be processed and published in a website ( ). Great efforts are made to ensure high quality of data. Results of general interest are included in a free ‘public area’ and more sensitive data in a ‘reserved area’ (open only to HC and to health authorities). A total of 610 individuals are included: 249 haemophilia A (HA), 63 haemophilia B (HB), 173 von Willebrand’s disease, 69 rare bleeding disorders, seven platelet disorders and 49 haemophilia carriers; 131 were genotyped, 188 were tested for inhibitors (16 affected). The most frequent bleeding was haemarthrosis. The joint score (evaluated in 104 haemophiliacs) was higher in severe HA. There were 22 HIV-positive and 182 hepatitis C virus-positive patients (21% have chronic hepatitis, two hepatocellular carcinoma). In 2005, two patients received primary prophylaxis, 47 secondary prophylaxis, four children were on immune-tolerance induction. From 2003 to 2005 the use of recombinant products was greatly increased and the majority of patients received them. The mean clotting factor consumption for prophylaxis was higher than on-demand treatment. The main features of registry are to collect high quality and comprehensive data of all patients followed by HC, to improve quality of care and it’s availability on the web. [ABSTRACT FROM AUTHOR]

Summary In 80 consecutive, anticoagulated patients scheduled for minor surgery, we reduced warfarin daily dosage by 50% on days 4, 3 and 2 before the surgery, restoring the original dose the day immediately before surgery. The evening after surgery, patients took a double warfarin dose, and then the usual maintenance dose was reintroduced. The mean International Normalized Ratio (INR) value assessed 1 week before surgery was 2.63 (range 1.88–3.87); it decreased at the moment of performing surgery to 1.68 (range 1.42–2.20; P < 0.05 with respect to the preoperative value), and returned to 2.43 7 days after (range 1.96–3.51, P = ns with respect to the preoperative value). No significant difference was found comparing prothrombin fragment 1.2 (F1.2) levels 1 week before surgery and on the morning of surgery (0.49 ng/ml vs 0.67 ng/ml, P = ns), suggesting that no activation of blood coagulation had taken place following the reduction of anticoagulant therapy. Patients developed neither major nor minor bleeding, nor thromboembolism during the procedures or up to 1 month after surgery. In our experience, this method for the management of anticoagulation before minor surgery has been shown to be safe and useful, avoiding the cumbersome shift to either intravenous or subcutaneous heparin. [ABSTRACT FROM AUTHOR]

Aims: Intracerebral hemorrhage (ICH) is a condition that arises due to the rupture of cerebral blood vessels, leading to the flow of blood into the brain tissue. One of the pathological alterations that occurs during an acute ICH is an impairment of the blood-brain barrier (BBB), which leads to severe perihematomal edema and an immune response., Discussion: A complex interplay between the cells of the BBB, for example, pericytes, astrocytes, and brain endothelial cells, with resident and infiltrating immune cells, such as microglia, monocytes, neutrophils, T lymphocytes, and others accounts for both damaging and protective mechanisms at the BBB following ICH. However, the precise immunological influence of BBB disruption has yet to be richly ascertained, especially at various stages of ICH., Conclusion: This review summarizes the changes in different cell types and molecular components of the BBB associated with immune-inflammatory responses during ICH. Furthermore, it highlights promising immunoregulatory therapies to protect the integrity of the BBB after ICH. By offering a comprehensive understanding of the mechanisms behind BBB damage linked to cellular and molecular immunoinflammatory responses after ICH, this article aimed to accelerate the identification of potential therapeutic targets and expedite further translational research., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

As people age, they tend to spend more time indoors, and the colours in their surroundings may significantly impact their mood and overall well-being. However, there is a lack of empirical evidence to provide informed guidance on colour choices, irrespective of age group. To work towards informed choices, we investigated whether the associations between colours and emotions observed in younger individuals also apply to older adults. We recruited 7393 participants, aged between 16 and 88 years and coming from 31 countries. Each participant associated 12 colour terms with 20 emotion concepts and rated the intensity of each associated emotion. Different age groups exhibited highly similar patterns of colour-emotion associations (average similarity coefficient of .97), with subtle yet meaningful age-related differences. Adolescents associated the greatest number but the least positively biased emotions with colours. Older participants associated a smaller number but more intense and more positive emotions with all colour terms, displaying a positivity effect. Age also predicted arousal and power biases, varying by colour. Findings suggest parallels in colour-emotion associations between younger and older adults, with subtle but significant age-related variations. Future studies should next assess whether colour-emotion associations reflect what people actually feel when exposed to colour., (© 2023 The British Psychological Society.)

Introduction: A yield of ≥18 nodes from neck dissection has been shown to be associated with improved locoregional recurrence rates and survival. We sought to determine factors associated with lymph node yields below this threshold., Materials and Methods: A retrospective review of patients who underwent neck dissection as part of definitive surgical treatment for mucosal head and neck squamous cell carcinoma (SCC) between January 2015 and December 2018 at an academic tertiary referral center was performed. Patients with a history of prior radiation or neck dissection were excluded., Results: There were 412 neck dissections performed in 323 patients. Specimens containing <18 nodes decreased from 16.2% in 2015-2016 to 7.4% of neck dissections in 2017-2018. The proportion of neck dissections removing <3 levels decreased from 9.1% of neck dissections in 2015-2016 to 4.0% in 2017-2018. Multivariable regression analysis demonstrated that dissection of ≥3 levels (OR = 0.2 [0.1-0.4]) and neck dissection in 2017-2018 compared to 2015-2016 (OR = 0.4 [0.2-0.8]) were significantly associated with a lower odds of <18 nodes. Stage, site, race, sex, human papillomavirus status, positive nodes, surgeon volume, and pathologist volume were not associated with neck dissection specimens with <18 nodes, after controlling for all other variables., Conclusions: Increased recognition of the importance of node count as a quality indicator, and the extent of neck dissection is associated with increased nodal yield from neck dissection. These data suggest that node count can be used as a quality measure of neck dissection for mucosal SCC., Level of Evidence: 4 Laryngoscope, 133:2160-2165, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc - . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To examine the relationship between surgeon volume and operative morbidity and mortality for laryngectomy., Data Sources: The Nationwide Inpatient Sample was used to identify 45,156 patients who underwent laryngectomy procedures for laryngeal or hypopharyngeal cancer between 2001 and 2011. Hospital and surgeon laryngectomy volume were modeled as categorical variables., Methods: Relationships between hospital and surgeon volume and mortality, surgical complications, and acute medical complications were examined using multivariable regression., Results: Higher-volume surgeons were more likely to operate at large, teaching, nonprofit hospitals and were more likely to treat patients who were white, had private insurance, hypopharyngeal cancer, low comorbidity, admitted electively, and to perform partial laryngectomy, concurrent neck dissection, and flap reconstruction. Surgeons treating more than 5 cases per year were associated with lower odds of medical and surgical complications, with a greater reduction in the odds of complications with increasing surgical volume. Surgeons in the top volume quintile (>9 cases/year) were associated with a decreased odds of in-hospital mortality (OR = 0.09 [0.01-0.74]), postoperative surgical complications (OR = 0.58 [0.45-0.74]), and acute medical complications (OR = 0.49 [0.37-0.64]). Surgeon volume accounted for 95% of the effect of hospital volume on mortality and 16%-47% of the effect of hospital volume on postoperative morbidity., Conclusion: There is a strong volume-outcome relationship for laryngectomy, with reduced mortality and morbidity associated with higher surgeon and higher hospital volumes. Observed associations between hospital volume and operative morbidity and mortality are mediated by surgeon volume, suggesting that surgeon volume is an important component of the favorable outcomes of high-volume hospital care. Laryngoscope, 133:834-840, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

The cerebral lateralization of written language has received very limited research attention in comparison to the wealth of studies on the cerebral lateralization of oral language. The purpose of the present study was to further our understanding of written language lateralization, by elucidating the relative contribution of language and motor functions. We compared written word generation with a task that has equivalent visuomotor demands but does not include language: the repeated drawing of symbols. We assessed cerebral laterality using functional transcranial Doppler ultrasound (fTCD), a non-invasive, perfusion-sensitive neuroimaging technique in 23 left- and 31 right-handed participants. Findings suggest that the linguistic aspect of written word generation recruited more left-hemispheric areas during writing, in right-handers compared to left-handers. This difference could be explained by greater variability in cerebral laterality patterns within left-handers or the possibility that the areas subserving language in left-handers are broader than in right-handers. Another explanation is that the attentional demands of the more novel symbol copying task (compared to writing) contributed more right-hemispheric activation in right-handers, but this could not be captured in left-handers due to ceiling effects. Future work could investigate such attentional demands using both simple and complex stimuli in the copying condition., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background Low-grade inflammation in the young may contribute to the early development of cardiovascular disease. We assessed whether circulating levels of glycoprotein acetyls (GlycA) were better able to predict the development of adverse cardiovascular disease risk profiles compared with the more commonly used biomarker high-sensitivity CRP (C-reactive protein). Methods and Results A total of 3306 adolescents and young adults from the Avon Longitudinal Study of Parents and Children (mean age, 15.4±0.3; n=1750) and Cardiovascular Risk in Young Finns Study (mean age, 32.1±5.0; n=1556) were included. Baseline associations between inflammatory biomarkers, body composition, cardiovascular risk factors, and subclinical measures of vascular dysfunction were assessed cross-sectionally in both cohorts. Prospective risk of developing hypertension and metabolic syndrome during 9-to-10-year follow-up were also assessed as surrogate markers for future cardiovascular risk. GlycA showed greater within-subject correlation over 9-to-10-year follow-up in both cohorts compared with CRP, particularly in the younger adolescent group (r=0.36 versus 0.07). In multivariable analyses, GlycA was found to associate with multiple lifestyle-related cardiovascular disease risk factors, cardiometabolic risk factor burden, and vascular dysfunction (eg, mean difference in flow-mediated dilation=-1.2 [-1.8, -0.7]% per z-score increase). In contrast, CRP levels appeared predominantly driven by body mass index and showed little relationship to any measured cardiovascular risk factors or phenotypes. In both cohorts, only GlycA predicted future risk of both hypertension (risk ratio [RR], ≈1.1 per z-score increase for both cohorts) and metabolic syndrome (RR, ≈1.2-1.3 per z-score increase for both cohorts) in 9-to-10-year follow-up. Conclusions Low-grade inflammation captured by the novel biomarker GlycA is associated with adverse cardiovascular risk profiles from as early as adolescence and predicts future risk of hypertension and metabolic syndrome in up to 10-year follow-up. GlycA is a stable inflammatory biomarker which may capture distinct sources of inflammation in the young and may provide a more sensitive measure than CRP for detecting early cardiovascular risk.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use., (© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Aims: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol., Methods: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders., Results/conclusion: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: To systematically review the effects of pharmacological and lifestyle interventions on body weight as a secondary outcome in people with type 1 diabetes., Methods: The Ovid Medline, Embase and Cochrane Library databases were searched for relevant pharmacological (glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose co-transporter-2 [SGLT-2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor and metformin) and lifestyle intervention studies (diet and exercise) for adults with type 1 diabetes reporting body weight change and HbA1c published from January 2000 to May 2020. Meta-analyses were performed for 16 randomized controlled trials (RCTs)., Results: Thirty-three RCTs (n = 9344 participants), 26 pharmacological (on average 43.9 years, 83.1 kg, HbA1c 8.1%; 55.8% male) and seven lifestyle-based interventions (on average 37.0 years, 85.0 kg, HbA1c 8.1%; 84.6% male), were analysed. The GLP-1 receptor agonist liraglutide 0.6 mg (mean difference [MD]: -2.22 kg [95% CI: -2.55 to -1.90]), 1.2 mg (MD: -3.74 kg [95% CI: -4.16 to -3.33]) and 1.8 mg (MD: -4.85 kg [95% CI: -5.29 to -4.41]), and the SGLT-2 inhibitors empagliflozin 2.5 mg (MD: -1.47 kg [95% CI: -2.23 to -0.71]), 10 mg (MD: -2.77 kg [95% CI: -3.24 to -2.31]) and 25 mg (MD: -3.06 kg [95% CI: -3.57 to -2.55]) and sotagliflozin 200 mg (MD: -2.40 kg [95% CI: -2.87 to -1.94]) and 400 mg (MD: -3.23 [95% CI: -3.73 to -2.72]) were associated with significant reductions in body weight. No significant effect on body weight was found for DPP-4 inhibitors, other GLP-1-receptor agonists, metformin, or for lifestyle interventions (i.e. exercise and diet)., Conclusions: In people with type 1 diabetes, several adjuvant pharmacological interventions showed weight reduction as a secondary outcome. Future studies in overweight people with type 1 diabetes are needed to establish whether the lifestyle and pharmacological interventions reviewed here have potential as components of complex interventions aimed at body weight reduction as a primary outcome., (© 2020 John Wiley & Sons Ltd.)

Objectives/hypothesis: To investigate differences in the immunogenomic landscape among young patients presenting with oral cavity squamous cell carcinoma (OCSCC)., Study Design: Retrospective database review., Methods: Normalized messenger mRNA expression data were downloaded from The Cancer Genome Atlas (TCGA) database. OCSCC patients were categorized into young and older age groups with a cutoff of 45 years. Human papillomavirus-positive tumors were excluded. Cell fractions, marker expression, and mutational load were compared between age groups using the Wilcoxon rank sum test. Adjustment for multiple comparisons was performed using the Benjamini-Hochberg method, with a false discovery rate of 0.05., Results: Two hundred forty-five OCSCC tumors were included; 21 (8.6%) were young (37.1 ± 7.5 years) and 224 (91.4%) were older (64.5 ± 10.3 years). There was no significant difference between groups in the fraction of B and T lymphocytes, macrophages, monocytes, natural killers, and dendritic cells. Cytolytic activity score was decreased in young patients (8.33 vs. 18.9, P = .023). Additionally, young patients had significantly lower expression of immunomodulatory markers of immune activation, including PD-1 (PDCD1, P = .003), CTLA4 (P = .025), TIGIT (P = .002), GITR (TNFRSF18, P = .005), OX40 (TNFRSF4, P = .009), LAG-3 (P < .001), and TIM-3 (HAVCR2, P = .002). Young patients had a significantly lower number of single nucleotide variant-derived neoantigens (26.2 vs. 60.6, P < .001)., Conclusions: OCSCC patients aged 45 years and younger appear to have an attenuated immune response that may be related to a lower frequency of immunogenic mutations. This may contribute to the pathogenesis of these tumors, and ultimately help inform personalized immune-based therapeutic strategies for young patients with OCSCC., Level of Evidence: NA Laryngoscope, 131:304-311, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Aim: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men., Methods: Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL)., Results: BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 10 3 vs. 29.9 [23.3, 38.4] × 10 3 pmol L -1  × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m -2 body surface area min -1 , P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = -0.674, P = .001). These associations were not found in BA men., Conclusions: While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin., (© 2020 John Wiley & Sons Ltd.)

Objectives: To evaluate the performance characteristics of seven predetermined imaging features on pretreatment computed tomography (CT) in identifying extranodal extension (ENE) in cervical lymph node metastases from human papillomavirus-positive oropharyngeal carcinoma (HPV-OPC)., Study Design: Retrospective study., Methods: Seventy-three patients with HPV-OPC who underwent primary surgery and cervical lymph node dissection were included. Preoperative contrast-enhanced CT (cCT) imaging was evaluated by two radiologists blinded to pathological results. Each cCT was scored for seven imaging features of interest: 1) indistinct capsular contours, 2) irregular nodal margins, 3) perinodal fat stranding, 4) perinodal fat planes, 5) nodal necrosis, 6) intranodal cysts, and 7) nodal matting. Logistic regression was employed to determine radiologist-specific odds ratios (OR) of predicting ENE for each imaging feature and radiologist-specific receiver operating characteristics (sensitivity [Sn], specificity [Sp], area under the curve [AUC], positive predictive value [PPV], negative predictive value [NPV]) for each imaging feature., Results: Thirty-two (44%) patients had ENE-positive lymph nodes. The presence of irregular margins (OR A = 12.3, 95% confidence interval [CI] A = 2.3-65.9; OR B = 7.0, 95% CI B = 1.4-36.3) and absence of perinodal fat plane (OR A = 6.8, 95% CI A = 2.0-23.3; OR B = 14.2, 95% CI B = 1.7-120.5) were significantly associated with ENE for each radiologist. Irregular nodal margin status was most specific for ENE (Sn A = 45%, Sp A = 94%, AUC A = 69%, PPV A = 82%, NPV A = 73%; Sn B = 28%, Sp B = 95%, AUC B = 61%, PPV B = 80%, NPV B = 64%). Absence of perinodal fat plane was most sensitive for ENE (Sn A = 87%, Sp A = 50%, AUC A = 69%, PPV A = 59%, NPV A = 62%; Sn B = 96%, Sp B = 34%, AUC B = 65%, PPV B = 53%, NPV B = 63%)., Conclusions: Of the seven imaging features hypothesized to be associated with ENE-status, the presence of irregular nodal margins and absence of perinodal fat plane were the most specific and sensitive features, respectively., Level of Evidence: 4 Laryngoscope, 130:1479-1486, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Aim: To investigate the associations of blood pressure variability (BPV), expressed as long-term (visit-to-visit) and short-term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all-cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension-mediated organ damage (HMOD) in adult patients with type 2 diabetes., Materials and Methods: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit-to-visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all-cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta-analysis and meta-regression., Results: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all-cause mortality (HR 1.12, 95% CI 1.04-1.21), MACEs (HR 1.01, 95% CI 1.04-1.17), extended MACEs (HR 1.07, 95% CI 1.03-1.11) and MiCs (HR 1. 12, 95% CI 1.01-1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long-term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima-media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels., Conclusions: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes., (© 2019 John Wiley & Sons Ltd.)

Aims: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries., Methods: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed., Results: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany)., Conclusion: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH)., (© 2019 European Medicines Agency. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives/hypothesis: To examine the cumulative effect of diagnostic steps for primary tumor identification in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP), including lingual tonsillectomy, and the impact of primary tumor identification on subsequent treatment., Study Design: Retrospective analysis., Methods: We reviewed the records of 110 patients diagnosed with HNSCCUP between 2003 and 2015. Results of diagnostic imaging (fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]), tumor detection with direct laryngoscopy with biopsies, palatine tonsillectomy, and transoral robotic surgery (TORS) lingual tonsillectomy were recorded. Associations between demographic and treatment variables with overall survival (OS) and progression-free survival (PFS) were modeled with Cox proportional hazards models., Results: FDG-PET/CT was suspicious for a primary site in 23/77 (30%) patients. Direct laryngoscopy identified a primary tumor in 34/110 patients (31%). Forty-seven patients underwent palatine tonsillectomy, which identified 17 primaries (36%), yielding a cumulative primary tumor identification of 51/110 (46%). Fourteen patients underwent TORS lingual tonsillectomy, which identified eight primaries (57%), resulting in a cumulative identification of 59/110 (53%). The detection rate increased from 28/63 (44%) to 31/47 (66%) after the addition of TORS lingual tonsillectomy to our institutional approach. Detection rates varied by HPV status. Primary tumor identification altered subsequent radiation planning, as patients with an identified primary tumor received radiation to a smaller volume of tissue than did those without an identified primary tumor. However, there was no significant association between primary tumor identification and OS or PFS., Conclusions: A stepwise approach to primary tumor identification identifies a primary tumor in a majority of patients., Level of Evidence: 4 Laryngoscope, 129:1610-1616, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Biological therapy is currently widely used to treat IBD. Infliximab, adalimumab and golimumab are currently licensed anti-TNF therapies. Biosimilar anti-TNF monoclonal antibodies are increasingly used. Anti-TNF therapies are widely used and their adverse effects are well characterised, and may cause significant morbidity and mortality in a small proportion of exposed patients. Gastroenterologists need to understand the mechanisms for these effects, recognise these swiftly and manage such events appropriately., Aim: To cover the range of potential adverse reactions as a result of biologic therapy and specifically management of these events., Methods: A Medline and Pubmed search was undertaken. Search terms included were "anti-TNF," "infliximab" or "adalimumab" or "golimumab" combined with the keywords "ulcerative colitis" or "Crohn's disease" or "inflammatory bowel disease" and then narrowed to articles containing the keywords "complications," "side effects" or "adverse events" or "safety profile." International guidelines were also reviewed where relevant., Results: Adverse events discussed in this review include infusion reactions, blood disorders and infections (including bacterial, viral, fungal and opportunistic infections) as well as autoimmune, dermatological disorders, cardiac and neurological conditions. Malignancies including solid organ, haematological and those linked to viral disease are discussed., Conclusions: Anti-TNF therapy has wide-ranging effects on the immune system resulting in a spectrum of potential adverse events in a small proportion of patients. Research advances are improving the understanding, recognition and management of these adverse events., (© 2019 John Wiley & Sons Ltd.)

Aims: To assess the prevalence of elevated liver enzymes in adults with type 1 diabetes mellitus (T1DM) in routine clinical care and the association with cardiovascular risk profile in the Diabetes-Prospective-Documentation (DPV) network in Germany and Austria., Subjects and Methods: This cross sectional observational study from the DPV registry includes data from 45 519 adults with T1DM at 478 centres up to September 2016. Liver enzyme measurements were available in 9226 (29%) patients at 270 centres and were analysed for increased alanine aminotransferase (ALT; men >50 U/L, women >35U/L) and/or aspartate aminotransferase (AST; men >50 U/L, women >35U/L) and/or gamma-glutamyltransferase (GGT; men >60U/L, women >40 U/L). A subgroup analysis in patients for whom 2 or more ALT measurements were available (n = 2335, 25%) and whose ALT was increased at least twice (men >30 U/L, women >19U/L) was performed. Associations with glycaemic control, cardiovascular risk factors and late complications were investigated with multiple regression analyses., Results: Twenty percent (19.8%, n = 1824) had increased liver enzyme(s) on one or more occasions. Increased liver enzymes were associated with worse glycaemic control and higher BMI (both P < .0001), dyslipidemia (OR, 1.75; 95% CI, 1.54-2.0), hypertension (OR, 1.48; 95% CI: 1.31-1.68), myocardial infarction (OR, 1.49; 95% CI, 1.17-1.91) and end stage renal disease (OR, 1.59; 95% CI, 1.17-2.17). ALT was increased twice in 29% and was associated with worse glycaemic control (P < .0001), higher BMI (P < .0001), hypertension (OR, 1.58; 95% CI, 1.26-1.97) and dyslipidemia (OR, 1.89; 95% CI, 1.51-2.37)., Conclusions: In this clinical audit in adults with T1DM, elevated liver enzymes on routine assessment were associated with a less favourable cardiovascular risk profile and with poorer glycaemic control., (© 2017 John Wiley & Sons Ltd.)

Aim: Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices., Methods: Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed., Results: Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10 000 persons for HandiHaler® and between 1.5 and 9.3 per 10 000 persons for Respimat®. Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler® 32.1%, Respimat® 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial., Conclusions: Comparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data., (© 2015 The British Pharmacological Society.)

Objectives: Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB-NFIB fusion gene, but the clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB-NFIB fusion., Study Design: Case series., Methods: Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB-NFIB fusion., Results: One hundred fifty-eight patients were included, with median follow-up 75.1 months. Median overall survival was 171.5 months (95% confidence interval [CI] = 131.9-191.6), and median disease-free survival was 112.0 months (95% CI = 88.7-180.4). Advanced stage was associated with decreased overall survival (adjusted ptrend  < 0.001), and positive margins were associated with decreased disease-free survival (adjusted hazard ratio [aHR] = 8.80, 95% CI = 1.25-62.12, P = 0.029). Ninety-one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB-NFIB fusion. MYB-NFIB positive tumors were more likely than MYB-NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios = 1.51, 95% CI = 1.07-2.12, P = 0.019). MYB-NFIB tumor status was not significantly associated with disease-free or overall survival (hazard ratio [HR] = 1.53, 95% CI = 0.77-3.02, P = 0.22 and HR = 0.91, 95% CI = 0.46-1.83, P = 0.80, respectively, for MYB-NFIB positive compared with MYB-NFIB negative tumors)., Conclusion: Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB-NFIB fusion were more likely to originate in minor salivary glands, but MYB-NFIB tumor status was not significantly associated with prognosis., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress. PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was found expressed in only 1/1000 FSHD myoblasts. We have now shown it was induced upon differentiation and detected in about 1/200 myotube nuclei. The DUX4 and PITX1 proteins presented staining gradients in consecutive myonuclei which suggested a diffusion as known for other muscle nuclear proteins. Both protein half-lifes were regulated by the ubiquitin-proteasome pathway. In addition, we could immunodetect the DUX4 protein in FSHD muscle extracts. As a model, we propose the DUX4 gene is stochastically activated in a small number of FSHD myonuclei. The resulting mRNAs are translated in the cytoplasm around an activated nucleus and the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. The PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4. Together the diffusion and the deregulation cascade would explain how a rare protein could cause the muscle defects observed in FSHD., (© 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

The authors of J. Immunol. 184, 725-735 respond to the article by Rupp (2012), Acta Cryst. F68, 366-376.

We investigated whether capuchin monkeys (Cebus apella) would choose to observe a high- or low-status adult female from their group during experimental foraging tests. The subject was located in the center of a test chamber, with a low- and high-ranking demonstrator on either side of two partitions. A peephole allowed the subject to observe the models by looking through either respective partition. Each model was trained on one of the two different methods, lift or pull, for retrieving food from a foraging apparatus. There were 22 subjects and four models. During the 40-trial test sessions, subjects could choose which model they would watch in each trial. It was predicted that subjects would prefer observing the model with whom it was closer in rank, and therefore share greater affiliation with. Results showed that only half the subjects showed a preference and that preference was not linked to status. Relatedness played a larger role in determining if a subject showed a preference for a model, and a correlation was found for relatedness and observer preference. After the observer preference tests, subjects were presented with the foraging apparatus to determine if they displayed a preference for one of the two tasks. The majority of subjects (17/22) showed a preference for the pull method, suggesting that this method may have been more salient to the monkeys in this study., (© 2011 Wiley-Liss, Inc.)

Background: Sometimes, cytological lung cancer diagnosis is challenging because equivocal diagnoses are common. To enhance diagnostic accuracy, fluorescent in situ hybridization (FISH), DNA-image cytometry, and quantitative promoter hypermethylation analysis have been proposed as adjuncts., Methods: Bronchial washings and/or brushings or transbronchial fine-needle aspiration biopsies were prospectively collected from patients who were clinically suspected of having lung carcinoma. After routine cytological diagnosis, 70 consecutive specimens, each cytologically diagnosed as negative, equivocal, or positive for cancer cells, were investigated with adjuvant methods. Suspicious areas on the smears were restained with the LAVysion multicolor FISH probe set (Abbott Molecular, Des Plaines, Illinois) or according to the Feulgen Staining Method for DNA-image cytometry analysis. DNA was extracted from residual liquid material, and frequencies of aberrant methylation of APC, p16(INK4A) , and RASSF1A gene promoters were determined with quantitative methylation-specific polymerase chain reaction (QMSP) after bisulfite conversion. Clinical and histological follow-up according to a reference standard, defined in advance, were available for 198 of 210 patients., Results: In the whole cohort, cytology, FISH, DNA-image cytometry, and QMSP achieved sensitivities of 83.7%, 78%, 79%, and 49.6%, respectively (specificities of 69.8%, 98.2%, 98.2%, and 98.4%, respectively). Subsequent to cytologically equivocal diagnoses, FISH, DNA-image cytometry, and QMSP definitely identified malignancy in 79%, 83%, and 49%, respectively. With QMSP, 4 of 22 cancer patients with cytologically negative diagnoses were correctly identified., Conclusions: Thus, adjuvant FISH or DNA-image cytometry in cytologically equivocal diagnoses improves diagnostic accuracy at comparable rates. Adjuvant QMSP in cytologically negative cases with persistent suspicion of lung cancer would enhance sensitivity., (Copyright © 2011 American Cancer Society.)

Facioscapulohumeral dystrophy (FSHD) is a muscular hereditary disease with a prevalence of 1 in 20,000 caused by a partial deletion of a subtelomeric repeat array on chromosome 4q. However, very little is known about the pathogenesis as well as the molecular and biochemical changes linked to the progressive muscle degeneration observed in these patients. Several studies have investigated possible pathophysiological pathways in FSHD myoblasts and mature muscle cells but some of these reports were apparently in contradiction. The discrepancy between these studies may be explained by differences between the sources of myoblasts. Therefore, we decided to thoroughly analyze affected and unaffected muscles from patients with FSHD in terms of vulnerability to oxidative stress, differentiation capacity and morphological abnormalities. We have established a panel of primary myoblast cell cultures from patients affected with FSHD and matched healthy individuals. Our results show that primary myoblasts are more susceptible to an induced oxidative stress than control myoblasts. Moreover, we demonstrate that both types of FSHD primary myoblasts differentiate into multi-nucleated myotubes, which present morphological abnormalities. Whereas control myoblasts fuse to form branched myotubes with aligned nuclei, FSHD myoblasts fuse to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution. In conclusion, we postulate that these abnormalities could be responsible for muscle weakness in patients with FSHD and provide an important marker for FSHD myoblasts.

Objectives/hypothesis: To assess trends in the management of unilateral vestibular schwannomas over an 11-year period and to identify disease- and provider-related influences., Study Design: Retrospective chart review., Methods: Subjects presented to the Department of Otolaryngology-Head and Neck Surgery and the Department of Neurosurgery for management of unilateral vestibular schwannoma from 1997 through 2007, with at least two visits within the first year of presentation. The proportion of patients for whom initial management consisted of observation, surgical resection, or radiation therapy was determined, and the relative influence of study year, patient age, hearing status, and tumor size was analyzed., Results: Over the study period there was an increase in the proportion of cases that were observed with follow-up scanning (10.5% to 28.0%) and recommended for radiation (0% to 4.0%), whereas the proportion of operated cases declined (89.5% to 68.0%). There were no changes in mean age or hearing status at diagnosis, but mean tumor size declined significantly. Compared to those undergoing surgery, patients choosing observation and radiation therapy were on average 11.7 and 4.5 years older, respectively. Tumors that were surgically removed were on average 11.6 mm larger than those that were observed. The increasing frequency over time of observation relative to surgery was significant even after controlling for age, hearing status, and tumor size., Conclusions: Among patients managed by our center, there has been a significant shift in management of vestibular schwannomas over the last decade, with increasing tendency towards observation. This trend implies changing provider philosophy and patient expectations.

Much of the research on animal social learning focuses on complex cognitive functions such as imitation and emulation. When compelling evidence for such processes is not forthcoming, simpler processes are often assumed but rarely directly tested for. In this study we address the phenomenon of social facilitation, whereby the presence of a feeding conspecific is hypothesized to affect the motivation and behavior of the subject, elevating the likelihood of exploration and discovery in relation to the task at hand. Using a novel foraging task, sufficiently challenging that only just over half the subjects successfully gained food from it, we compared the performance of capuchin monkeys working either alone, or in a "social" condition where an actively feeding conspecific was in an adjacent chamber. Although similar numbers of subjects in these conditions were eventually successful during the 20 trials presented, the latency to successful solution of the task was over three times faster for monkeys in the social condition. The minority of monkeys that failed to learn (9/23) were then exposed to a proficient model. Only those older than 5 years provided evidence of learning from this. Accordingly, we obtained evidence for the social facilitation the study was designed to test for, and limited supplementary evidence for social learning in the older individuals who had not learned individually. These results are discussed in relation to other recent evidence for social learning in monkeys., ((c) 2009 Wiley-Liss, Inc.)

It has been claimed that capuchin monkeys (Cebus apella) show inequity aversion in relation to food rewards for a simple exchange task. However, other factors may affect the willingness of a monkey to consume foods of high or low value in the presence of a conspecific. In this study, pairs of monkeys were presented with unequally valued foods, but without any task-performance: they simply received the food under four experimental conditions. By looking at the rate of collection and consumption of low-valued cucumber slices we expected to see variation dependent on whether the partner either had 1) cucumber (equity), 2) grape (inequity), 3) inaccessible cucumber or 4) inaccessible grape. Testing 12 adult capuchin monkeys, our findings differed from those of other authors in that the monkeys failed to show negative reactions to inequity, but rather responded with scramble competition (i.e., fast food collection) in the presence of a conspecific without access to food. They also showed facilitated consumption in the presence of a conspecific consuming high-valued food. Possibly, (in)equity plays a different role if food serves as a reward for a task rather than if it is simply made available for consumption.

Activation of coagulation during hemodialysis (HD) is a relevant clinical problem, especially when patients at risk of bleeding are treated. However, little is known about the relative contribution of the various components of the circuit to the thrombotic process. Thus, an experimental model was developed that is aimed at evaluating biochemical markers of coagulation activation at different times and sites throughout the HD circuit. A HD blood-tubing set with integrated arterial and venous chambers (cartridge-line set) was used, which was added with the following sampling points: at the beginning of the arterial line (P1), before the blood pump (P2), after the blood pump (P3), and at the end of the venous line (P4). A bypass system allowed us to circulate the blood only into the blood lines for the first 20 min of the extracorporeal circulation. The extracorporeal circuit was rinsed with 1.7 L of heparinized saline (2,500 IU/L) that was completely discarded before patient connection. A continuous administration of unfractionated heparin (500-800 IU/h) without a starting bolus was adopted as a low heparin extracorporeal treatment. Samples were collected before the start of the extracorporeal circulation from the fistula needle (T0P0), after 5 (T1), 10 (T2), and 20 min (T3) from P1, P2, P3, and P4. After 20 min, the blood was returned to the patient using only saline and HD was then started, circulating the blood through the dialyzer. Further samples were obtained from P1 and P4 after 5 (T4) and 210 min (T5). Plasma levels of coagulation activation markers-thrombin-antithrombin complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2)-were evaluated in all the samples in 12 stable HD patients. In each patient, the activated partial thromboplastin time (APTT) was measured at T0P0 and T1-T5 from P1. No significant changes were found at any time as far as F1 + 2 is concerned. However, TAT levels increased over time only after the start of HD, suggesting that the latter test could be more useful in order to detect coagulation activation during HD. The same experiments performed with nonheparin-primed extracorporeal circuit showed similar results. The blood lines used did not significantly activate coagulation during the first 20 min, whereas only 5 min of blood circulation throughout the whole circuit increased TAT values, which still remained lower than previous reports, even after 210 min of treatment.

Aim: The inflammatory response induced by perinatal infections and asphyxia is considered to participate in neonatal brain damage. Inflammatory responses are characterized by the expression of chemokines. Although chemokine levels have been investigated in healthy newborns, their role during neonatal pathological conditions has not been studied. The aim of our study was to examine chemokine serum levels in asphyxiated and infected neonates., Methods: Peripheral blood samples were obtained from perinatally asphyxiated and infected neonates during the first days of life and from neonates who developed nosocomial infections. Serum levels of interleukin-8 (IL-8), interferon-gamma-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and regulated upon activation, normal T cells expressed and secreted (RANTES) were determined., Results: In perinatally asphyxiated neonates, IL-8 levels were significantly elevated on the 1st day of life. In perinatally infected neonates, IL-8 and IP-10 levels were significantly increased on the 1st day of life, while RANTES levels were significantly lower and remained so until the 4th day. In nosocomially infected neonates, IL-8, IP-10 and MIP-1alpha levels were significantly increased on diagnosis of infection., Conclusion: The neonatal immune system is able to produce chemokines for the induction of an inflammatory response during perinatal asphyxia and perinatal or nosocomial infections. Blockade of inflammatory chemokines could possibly contribute to the prevention of brain damage.