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Cardiovascular lability is common after cardiac arrest. We investigated whether altered endothelial function is present in cerebral and mesenteric arteries 2 and 4 h after resuscitation. Male Sprague-Dawley rats were anesthetized, intubated, ventilated, and intravascularly catheterized whereupon rats were randomized into four groups. Following 7 min of asphyxial cardiac arrest and subsequent resuscitation, cardiac arrest and sham rats were observed for either 2 or 4 h. Neuron-specific enolase levels were measured in blood samples. Middle cerebral artery segments and small mesenteric arteries were isolated and examined in microvascular myographs. qPCR and immunofluorescence analysis were performed on cerebral arteries. In cerebral arteries, bradykinin- induced vasodilation was inhibited in the presence of either calcium-activated K+ channel blockers (UCL1684 and senicapoc) or the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), whereas the combination abolished bradykinin-induced vasodilation across groups. Neuron-specific enolase levels were significantly increased in cardiac arrest rats. Cerebral vasodilation was comparable between the 2-h groups, but markedly enhanced in response to bradykinin, NS309 (an opener of small and intermediate calcium-activated K+ channels), and sodium nitroprusside 4 h after cardiac arrest. Endothelial NO synthase and guanylyl cyclase subunit a-1 mRNA expression was unaltered after 2 h, but significantly decreased 4 h after resuscitation. In mesenteric arteries, the endothelium-dependent vasodilation was comparable between corresponding groups at both 2 and 4 h. Our findings show enhanced cerebral endothelium-dependent vasodilation 4 h after cardiac arrest mediated by potentiated endothelial-derived hyperpolarization and NO pathways. Altered cerebral endotheliumdependent vasodilation may contribute to disturbed cerebral perfusion after cardiac arrest.

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Background Differences in cardiac remodeling after mitral valve (MV) surgery between the sexes is poorly understood. Inferior outcomes for females undergoing MV surgery compared with males have been suggested in the literature, although causative factors behind this discrepancy have not been identified. MATERIALS AND METHODS: In this propensity-matched, retrospective, single-center study, we sought to identify the impact that sex may have on cardiac remodeling and long-term outcomes to better inform clinical decision-making in MV surgical intervention. Outcomes were compared between males and females undergoing MV replacement (MVR) between 2004 and 2018. The primary outcome was cardiac remodeling 1 year postoperatively. Secondary outcomes included mortality, stroke, myocardial infarction (MI), reoperation of the MV, and rehospitalization. Results A total of 311 males and 311 females were included after propensity matching. Both groups demonstrated significant improvement in left atrial remodeling, although only males demonstrated a significant degree of improved left ventricular remodeling while their female counterparts did not. Mortality rates were relatively equivalent between the two groups, although males were more likely to develop sepsis and require rehospitalization due to MI. Conclusions There has been little research exploring the differences in cardiac remodeling between the sexes after MVR. The results of this study have suggested that MVR is equally safe for both sexes and has demonstrated a difference in the heart's ability to remodel after MVR. The significance of this difference has the potential to result in largely different clinical outcomes for males and females. Further study is necessary to fully elucidate this relationship.

Heat stress is a major concern in animal reproduction, as testicular temperature must be 3–5 °C below body core temperature for production of motile and fertile sperm in mammals. Although recent studies concluded that increased temperature per se was the underlying pathophysiology of testicular impairment, more studies are required to better understand the mechanisms. Therefore, our objective was to investigate the impacts of mild acute heat stress on sperm and testes, and based on mRNA, elucidate involvement of StAR, Trp53 and Trp53-dependent intrinsic and extrinsic apoptotic pathways in pathophysiology of testicular heat stress. Forty-eight C57 BCL6 elite male mice were equally allocated into six groups, anesthetized and the distal third of their body immersed in a water-bath at 40 or 30 °C (heat treatment and control, respectively) for 20 min. Intervals from heat exposure (Day 0) to euthanasia were: 8 and 24 h and 7, 14 and 21 d (plus a control group at 14 d). The epididymides were excised, minced and placed in Tyrode albumin lactate pyruvate hepes (TALPH) at 37 °C for 15 min to recover sperm. Based on computer assisted sperm analysis (CASA), heat treatment reduced total and progressive motility ∼40% (P < 0.05) on Days 14 and 21. Furthermore, percentage morphologically normal sperm was significantly decreased on Day 7, with greater reductions on Days 14 and 21, mostly due to increased midpiece defects. Acrosome integrity (FITC PSA) was decreased ∼35% at 8 h (P < 0.05) and reached a nadir on Day 14. There were decreases (P < 0.05) in seminiferous tubule diameter and testicular weight (relative to body weight) on Day 14. Testicular RNA was extracted, reverse-transcribed and cDNA used for PCR. Expression of genes Hspa1b (Hsp70) and Gpx1 had 7- and 10-fold increases (P < 0.001 for each) at 8 and 24 h, respectively, with Hspa1b remaining upregulated at 24 h, whereas StAR peaked at Day 14 (15-fold, P < 0.0001) and had returned to baseline on Day 21. Both Trp53 and Casp8 were upregulated (P < 0.05) on Day 14, whereas Bcl-2 was decreased (P < 0.05) on Days 7 and 14. In conclusion, acute mild heat stress severely reduced sperm quality and based on mRNA, there was upregulation of chaperone and antioxidant systems and Trp53-dependent intrinsic and extrinsic apoptotic pathways, with deleterious effects on sperm, spermatocytes and spermatids. These findings provided insights into the pathophysiology of heat stress and should contribute to development of evidence-based approaches to mitigate effects of testicular heating.

Trait self-control is important for well-being and mental and physical health. Most extant measures of self-control are limited in that they do not account for the multidimensionality and specificity of the trait. The aim of this study was to develop and validate a multidimensional and hierarchical scale of self-control in a full and a short version. The development of the Multidimensional Self-Control Scale (MSCS) and the Brief Multidimensional Self-Control Scale (BMSCS) was based on focus groups, a pilot, a main, and a validation sample (total N = 2,409). The 29-item MSCS consists of 6 first-order factors (Procrastination, Attentional Control, Impulse Control, Emotional Control, Goal Orientation, and Self-Control Strategies), 2 second-order factors (Inhibition and Initiation), and a third-order self-control factor. The 8 items in BMSCS provides a general trait self-control score. Findings from exploratory and confirmatory factor analyses supported the structures across samples, and internal consistency was acceptable. Assessment for acquiescence and sex differences indicated no major impacts on the scales. Strong convergent validity was observed with the Self-Control Scale (SCS) and the Brief Self-Control Scale (BSCS), as well as to other similar concepts. The MSCS subscales discriminated well between each other. Assessment of incremental validity of the MSCS over SCS, when controlling for sex and personality, showed significant increases in explained variance when predicting habits, hardiness, and life satisfaction. Similar significant results were observed for the BMSCS over the BSCS. Overall, results indicate that the new scales are useful measures that integrate recent theoretical and empirical findings of trait self-control. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objectives To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis. Methods This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009–2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis. Results Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups. Conclusion In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.

Made available in DSpace on 2020-12-12T01:35:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-08-12 BACKGROUND: Twenty-five phenotypes were measured as indicators of bull fertility (1099 Brahman and 1719 Tropical Composite bulls). Measurements included sperm morphology, scrotal circumference, and sperm chromatin phenotypes such as DNA fragmentation and protamine deficiency. We estimated the heritability of these phenotypes and carried out genome-wide association studies (GWAS) within breed, using the bovine high-density chip, to detect quantitative trait loci (QTL). RESULTS: Our analyses suggested that both sperm DNA fragmentation and sperm protamine deficiency are heritable (h2 from 0.10 to 0.22). To confirm these first estimates of heritability, further studies on sperm chromatin traits, with larger datasets are necessary. Our GWAS identified 12 QTL for bull fertility traits, based on at least five polymorphisms (P

Research question: Which early-diagnosed Klinefelter syndrome patients have been offered cryopreservation of testicular tissue as part of fertility preservation before spermatogonial stem cell (SSC) loss? Do these Klinefelter syndrome patients present with behavioural, cognitive and/or psychological problems? Does a testicular biopsy procedure have long-term effects on the gonadal development of Klinefelter syndrome patients? Design: Early-diagnosed Klinefelter syndrome patients followed between 2009 and 2020 and offered testicular tissue banking in an experimental context at the Universitair Ziekenhuis Brussel were included. The prevalence of behavioural, cognitive and/or psychological problems was determined. Changes in testicular volume and in gonadal function (LH, FSH, testosterone and inhibin B [INHB]) were studied. Results: Of the 48 Klinefelter syndrome patients included, 22 had testicular tissue removed (biopsy group) and 26 had no surgical intervention (control group). The need for specialized education was significantly higher in prenatally (P = 0.0159) and prepubertally (P = 0.0002) diagnosed Klinefelter syndrome patients. Psychological problems were significantly more prevalent in Klinefelter syndrome patients who did not opt for fertility preservation (P = 0.0447). In the first 4.2 (1.9–9.1) years after testicular biopsy, no difference in testicular volume was observed between the biopsied and the contralateral non-biopsied testes (P > 0.9999). After pubertal onset, no differences in LH, FSH, testosterone and INHB were found between the biopsy and the control groups (P = 0.1324 for LH, P > 0.9999 for FSH, P = 0.5433 for testosterone, P > 0.9999 for INHB). Conclusion: Early-diagnosed Klinefelter syndrome patients presented with behavioural, cognitive and/or psychological problems. Only psychological problems seemed to influence the decision towards fertility preservation. Follow-up data confirm that harvesting testicular tissue does not have a long-term impact on the gonadal development of Klinefeltersyndrome patients.

Bovine trichomoniasis, caused by the protozoal parasite Tritrichomonas foetus, is a highly contagious venereal disease characterised by early pregnancy loss, abortion and pyometra. Persistently infected bulls and cows are the primary reservoirs of infection in infected herds. This research investigated the prevalence of T. foetus infection in bulls from properties located across northern Australia and New South Wales. Preputial samples were collected from 606 bulls at slaughter and tested for T. foetus using the VetMAX-Gold Trich Detection Kit (Thermo Fisher Scientific). The apparent prevalence of T. foetus infection varied between regions, with northern regions in the Northern Territory, Queensland and Western Australia showing a prevalence of 15.4%, 13.8% and 11.4%, respectively. There was some evidence of an association between infection and postcode (P = 0.06) and increasing bull age (P = 0.054). This study confirms that T. foetus infection is likely to be present in many beef breeding herds and contributing to lower than expected reproductive performance, particularly across northern Australia.

Mantle cell lymphoma (MCL) is a malignancy arising from naive B lymphocytes with common bone marrow (BM) involvement. Although t(11;14) is a primary event in MCL development, the highly diverse molecular etiology and causal genomic events are still being explored. We investigated the transcriptome of CD19+ BM cells from eight MCL patients at single-cell level. The transcriptomes revealed marked heterogeneity across patients, while general homogeneity and clonal continuity was observed within the patients with no clear evidence of subclonal involvement. All patients were SOX11+CCND1+CD20+. Despite monotypic surface immunoglobulin (Ig) κ or λ protein expression in MCL, 10.9% of the SOX11 + malignant cells expressed both light chain transcripts. The early lymphocyte transcription factor SOX4 was expressed in a fraction of SOX11 + cells in two patients and co-expressed with the precursor lymphoblastic marker, FAT1, in a blastoid case, suggesting a potential prognostic role. Additionally, SOX4 was found to identify non-malignant SOX11– pro-/pre-B cell populations. Altogether, the observed expression of markers such as SOX4, CD27, IgA and IgG in the SOX11+ MCL cells, may suggest that the malignant cells are not fixed in the differentiation state of naïve mature B cells, but instead the patients carry B lymphocytes of different differentiation stages.

Environmental temperature has effects on sperm quality with differences in susceptibility between cattle subspecies and breeds, but very little is known about the seminal plasma protein (SPP) changes resulting from testicular heat stress. Scrotal insulation (SI) for 48 hr was applied to Brahman (Bos indicus) bulls. Semen was collected at 3-day intervals from before, until 74 days post-SI. The changes in sperm morphology and motility following SI were comparable to previously reported and differences were detected in measures of sperm chromatin conformation as early as 8 days post-SI. New proteins spots, in the SPP two-dimensional (2-D) gels, were apparent when comparing pre-SI with 74 days post-SI, and SPP identified as associated with mechanisms of cellular repair and protection. Similar trends between 2-D gel and Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) data was observed, with SWATH-MS able to quantify individual SPP that otherwise were not resolved on 2-D gel. The SPP assessment at peak sperm damage (21-24 days) showed a significant difference in 29 SPP (adjusted p < .05), and identified six proteins with change in abundance in the SI group. In conclusion both spermatozoa and SPP composition of bulls are susceptible to temperature change incurred by SI, and SPP markers for testicular heat insults may be detected.

Background: Transplant ureter obstruction is an important cause of graft loss after kidney transplantation. Most cases occur early after transplantation and are related to surgical causes or ischaemic strictures. Underlying mechanisms of late ureteral obstruction are less well understood.Case report: We present the case of a 61-year-old man who showed gradual decline in renal allograft function and hydronephrosis nine years after transplantation, due to an inguinal herniation of the transplant ureter. After urinary diversion using a percutaneous nephrostomy, graft function restored and the patient underwent surgery. The ureter was reduced from the inguinal hernia and re-implanted in the bladder, with primary closure of the abdominal wall defect. Postoperative course was uneventful and serum creatinine returned to baseline levels.Discussion: Search of relevant literature revealed a number of similar cases, which allowed identification of risk factors associated to the development of uretero-inguinal herniation leading to obstructive nephropathy. Diagnosis of this rare cause of transplant dysfunction and operative treatment strategies are discussed.Conclusions: Inguinal herniation of the transplant ureter leading to ureteral obstruction is a rare, probably underreported, cause graft of dysfunction. Therefore, we advocate elective repair of inguinal or incisional hernias in renal transplant recipients.

Objective: Examine the feasibility and acceptability of an electrocardiogram (ECG) attached to a mobile phone (iECG) screening device for atrial fibrillation (AF) in Aboriginal Controlled Community Health Services (ACCHS) and other community settings. Methods: Semi‐structured interviews were conducted with ACCHS staff in urban, rural and remote communities in three Australian states/territories. Quantitative and qualitative questions identified the enabling factors and barriers for staff and Aboriginal patients' receptiveness to the device. Mean quantitative scores and their standard deviation were calculated in Microsoft Excel and qualitative questions were thematically analysed. Results: Eighteen interviews were conducted with 23 staff across 11 ACCHS. Quantitative data found staff were confident in providing iECG screening and managing the referral pathway, and thought the process was beneficial for patients. Qualitative data highlighted the usefulness of the device to undertake opportunistic screening and acceptability in routine practice, and provided opportunities to engage patients in education around AF. Conclusion: The iECG device was well accepted within ACCHSs and was feasible to use to screen for AF among Aboriginal patients. Implications for public health: The device can be used in clinical and community settings to screen Aboriginal people for atrial fibrillation to help reduce rates of stroke and other cardiovascular diseases.

Aerobic exercise (AE) modulates cortical excitability. It can alter both corticospinal excitability and intra-cortical networks, which has implications for its use as a tool to facilitate processes such as motor learning, where increased levels of excitability are conducive to the induction of neural plasticity. Little is known about how different intensities of AE modulate cortical excitability or how individual-level characteristics impact on it. Therefore, we investigated whether AE intensities, lower than those previously employed, would be effective in increasing cortical excitability. We also examined whether the aerobic fitness of individual participants was related to the magnitude of change in AE-induced cortical excitability. In both experiments we employed transcranial magnetic stimulation to probe corticospinal excitability before and after AE. We show that 20 min of continuous moderate- (40% and 50% of heart rate reserve, HRR), but not low- (30% HRR) intensity AE was effective at increasing corticospinal excitability. We also found that while we observed increased corticospinal excitability following 20 min of continuous moderate-intensity (50% HRR) AE, aerobic fitness was not related to the magnitude of change. Our results suggest that there is a lower bound intensity of AE that is effective at driving changes in cortical excitability, and that while individual-level characteristics are important predictors of response to AE, aerobic fitness is not. Overall these findings have implication for the way that AE is used to facilitate processes such as motor learning, where increased levels of cortical excitability and plasticity are favourable.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal–Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach–Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

This study sought to investigate the hypothesis that patients with left bundle branch block (LBBB) are hypersensitive to elevated afterload.Epidemiological data suggest that LBBB can provoke heart failure in patients with hypertension.In 11 asymptomatic patients with isolated LBBB and 11 age-matched control subjects, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured by echocardiography. Systolic arterial pressure was increased by combining pneumatic extremity constrictors and handgrip exercise. To obtain more insight into mechanisms of afterload response, 8 anesthetized dogs with left ventricular (LV) micromanometer and dimension crystals were studied during acutely induced LBBB and aortic constriction. Regional myocardial work was assessed by LV pressure-dimension analysis.Consistent with normal afterload dependency, elevation of systolic arterial pressure by 38 ± 12 mm Hg moderately reduced LVEF from 60 ± 4% to 54 ± 6% (p 0.01) in control subjects. In LBBB patients, however, a similar blood pressure increase caused substantially larger reduction in LVEF (p 0.01), from 56 ± 6% to 42 ± 7% (p 0.01). There were similar findings for GLS. In the dog model, aortic constriction abolished septal shortening (p 0.02), and septal work decreased to negative values (p 0.01). Therefore, during elevated systolic pressure, the septum made no contribution to global LV work, as indicated by net negative work, and instead absorbed energy from work done by the LV lateral wall.Moderate elevation of arterial pressure caused marked reductions in LVEF and GLS in patients with LBBB. This reflects a cardiodepressive effect of elevated afterload in the dyssynchronous ventricle and was attributed to loss of septal function.

Adequate protein intake is necessary to maintain muscle mass and function. Nutritionally dense(r) products are increasingly sought after by consumers that need a heightened protein intake, such as active young and elderly individuals. This paper focuses on functional snack sausages enriched with umami-tasting meat protein hydrolysates (MPH), developed by systematically varying in recipe, meat type and MPH content. A consumer study (N = 100) was conducted where young and elderly consumers evaluated perceived acceptability and sensory quality of samples. Additionally, textural (Warner–Braztler shear test) and chemical (amino acids) analyses on the same samples were conducted to give a complete characterization of the functionality of the hydrolysates. Both the consumer test and the instrumental analyses consistently indicated that the enrichment with MPH had minor or no influence on the perceptual quality of the sausages, suggesting that this ingredient can be added to increase the nutritional density of a reference meat product without negatively affecting consumer acceptability.

Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

Background and aims Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC. Methods We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up. Results In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients. Conclusion Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

OBJECTIVES Motor imagery can be used as an adjunct to traditional stroke rehabilitation therapies for individuals who have hand and arm impairment resulting from their stroke. The provision of neurofeedback during motor imagery allows individuals to receive real time information regarding their motor imagery-related brain activity. However, the equipment required to administer this feedback is expensive and largely inaccessible to many of the individuals who could benefit from it. Available EEG-based technology provides an accessible, low-cost, wireless alternative to traditional neurofeedback methods, with the tradeoff of lower gain and channel count resulting in reduced signal quality. This study investigated the efficacy of this wireless technology for the provision of motor imagery-related neurofeedback. APPROACH Twenty-eight healthy individuals participated in a 2-group, double-blinded study which involved imagining performing a unimanual button pressing task while receiving neurofeedback that is either a direct transform of their motor imagery-related brain activity (i.e., real) or is related to someone else's brain activity (i.e., sham). The change in amplitude of 15-30 Hz (beta) rhythmic brain activity elicited during the task blocks was calculated and analyzed across sessions and groups. MAIN RESULTS We found that individuals who received real neurofeedback showed a statistically significant positive trajectory in modulating the amplitude of the beta rhythm across sessions, while those who received sham feedback showed a negative trajectory. Our results did not indicate a trend of increased lateralization across sessions, as has been shown in previous studies. SIGNIFICANCE Our main findings replicated previous results with research-grade equipment indicating that there is potential for introducing this wireless technology for the provision of neurofeedback. Given the marginal longitudinal effect of neurofeedback in our study, further study is required to address the limitations associated with this technology before our protocol can be implemented in a clinical setting.

Background To investigate the effectiveness of chiropractic spinal manipulation versus sham manipulation in children aged 7–14 with recurrent headaches. Methods Design: A two-arm, single-blind, superiority randomised controlled trial. Setting: One chiropractic clinic and one paediatric specialty practice in Denmark, November 2015 to August 2020. Participants: 199 children aged 7 to 14 years, with at least one episode of headache per week for the previous 6 months and at least one musculoskeletal dysfunction identified. Interventions: All participants received standard oral and written advice to reduce headaches. In addition, children in the active treatment group received chiropractic spinal manipulation and children in the control group received sham manipulation for a period of 4 months. Number and frequency of treatments were based on the chiropractor’s individual evaluation in the active treatment group; the children in the control group received approximately eight visits during the treatment period. Primary outcome measures: ‘Number of days with headache’, ‘pain intensity’ and ‘medication’ were reported weekly by text messages, and global perceived effect by text message after 4 months. A planned fixed sequence strategy based on an initial outcome data analysis was used to prioritize outcomes. ‘Number of days with headache’ and ‘pain intensity’ were chosen as equally important outcomes of highest priority, followed by global perceived effect and medication. The significance level for the first two outcomes was fixed to 0.025 to take multiplicity into account. Results Chiropractic spinal manipulation resulted in significantly fewer days with headaches (reduction of 0.81 vs. 0.41, p = 0.019, NNT = 7 for 20% improvement) and better global perceived effect (dichotomized into improved/not improved, OR = 2.8 (95% CI: 1.5–5.3), NNT = 5) compared with a sham manipulation procedure. There was no difference between groups for pain intensity during headache episodes. Due to methodological shortcomings, no conclusions could be drawn about medication use. Conclusions Chiropractic spinal manipulation resulted in fewer headaches and higher global perceived effect, with only minor side effects. It did not lower the intensity of the headaches. Since the treatment is easily applicable, of low cost and minor side effects, chiropractic spinal manipulation might be considered as a valuable treatment option for children with recurrent headaches. Trial registration ClinicalTrials.gov, identifier NCT02684916, registered 02/18/2016 – retrospectively registered.

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation., A full list of the investigators who contributed to the generation of the WTCCC data is available from the WTCCC website, funding for which was provided by The Wellcome Trust under award 07611. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The KORA Study Group consists of A. Peters (speaker), J. Heinrich, R. Holle, R. Leidl, C. Meisinger, K. Strauch, and their co-workers, who are responsible for the design and conduct of the KORA studies. We gratefully acknowledge the contribution of all members of field staff conducting the KORA study, and we are grateful to all study participants of KORA for their invaluable contributions to this study. The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (263 MD 9164 and 263 MD 821336). The Spanish mastocytosis cohort and the Spanish National DNA Bank were supported by grants from the Instituto de Salud Carlos III and FEDER (PI16/00642 and PT17/0015/0044). The Italian cohort of mastocytosis-affected individuals was funded by the Associazione Italiana per la Ricerca sul cancro, Mynerva project, 21267. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. A.A.Z.D. was supported by a Lady Tata International Award; G.G., N.C.P.C., Y.H., A.J.C., and W.J.T. were supported by Blood Cancer UK (13002 and 18007).

Previous literature has demonstrated equivalent or improved survival post mitral valve (MV) surgery amongst patients with obesity when compared to their normal-weight counterparts. This relationship is poorly understood and the impact of body mass index (BMI) on cardiac remodeling has not been established.In this retrospective, single-center study, we sought to identify the impact that BMI may have on long-term outcomes and cardiac remodeling post-MV repair. Outcomes were compared between patients of varying BMI undergoing MV repair between 2004 and 2018. The primary outcome was mortality and secondary outcomes included stroke, myocardial infarction, reoperation of the MV, rehospitalization, and cardiac remodeling.A total of 32 underweight, 249 normal weight, 249 overweight, 121 obese, and 50 morbidly obese patients were included in this study. Underweight patients had increased mortality at longest follow-up. Patients with morbid obesity were found to have higher rates of readmission for heart failure. Only underweight patients did not demonstrate a significant reduction in LVEF. Patients with normal weight and overweight had a significant reduction in left atrial size, and patients with obesity had a significant reduction in MV area.An obesity paradox has been identified in cardiac surgery. While patients with obesity have higher rates of comorbidities preoperatively, their rates of mortality are equivalent or even superior to those with lower BMI. The results of our study confirm this finding with patients of high BMI undergoing MV repair demonstrating equivalent rates of morbidity to their normal BMI counterparts. While the obesity paradox has been relatively consistent in the literature, the understanding of its cause and long-term impacts are not well understood. Further focused investigation is necessary to elucidate the cause of this relationship.

Background The Mental Health Continuum–Short Form (MHC-SF) is a measure of positive mental health and flourishing, which is widely used in several countries but has not yet been validated in Denmark. This study aimed to examine its qualitative and quantitative properties in a Danish population sample and compare scores with Canada and the Netherlands. Methods Three thousand five hundred eight participants aged 16–95 filled out an electronic survey. Both the unidimensional and multidimensional aspects of the Danish MHC-SF were studied through bifactor modelling. Cognitive interviews examined face validity and usability. Results The general score of the Danish MHC-SF was reliable for computing unit-weighted composite scores, as well as using a bifactor model to compute general factor scores or measurement models in an SEM context. Nonetheless, subscale scores were unreliable, explaining very low variance beyond that explained by the general factor. The participants of the qualitative interviews observed problems with wording and content of the items, especially from the social subscale. The general score correlated with other scales as expected. We found substantial variation in flourishing prevalence rates between the three cultural settings. Conclusions The Danish MHC-SF produced reliable general scores of well-being. Most of the issues observed regarding the subscale scores have been shown in previous research in other contexts. The further analysis of indices of the bifactor model and the inclusion of qualitative interviews allowed for a better understanding of the possible sources of problems with the questionnaire’s subscales. The use of subscales, the substantive understanding of the general score, as well as the operationalization of the state of flourishing, require further study.

Background Experiencing parental stress is common among parents of children of all ages and is elevated in families characterized by stressors such as poverty, mental health problems, and developmental problems. The Parental Stress Scale (PSS) is a short measure for the assessment of perceived stress resulting from being a parent. Methods This study examines the construct validity and psychometric properties of the Danish PSS using Rasch and graphical loglinear Rasch models in a sample of parents of 2–18-year-old children with and without known behavior problems. We emphasized analyses of differential item functioning, to ascertain whether the scale yields unbiased scores for subgroups of parents. Results The 18-item PSS did not fit the Rasch model or a graphical loglinear Rasch model. After dichotomizing item responses and eliminating items 2 and 11, we found the PSS to consist of two distinct subscales measuring parental stress and lack of parental satisfaction. For the total sample, the Parental Stress subscale fit a very complex graphical loglinear Rasch model with differential item functioning relative to parental education and whether children had behavior problems or not. The Lack of Parental Satisfaction subscale fit a simple graphical loglinear Rasch model with differential item functioning only relative to subsample. When dividing into subsamples of parents of children with and without behavior problems, the Parental Stress subscale fit a simple graphical loglinear Rasch model, though still with differential item functioning, while the Lack of Parental Satisfaction subscale fit the Rasch model in each subsample of parents. Both subscales performed best for parents of children with behavior problems. Conclusions The PSS should be used in a 16-item version and scored as two subscales. The PSS appears better suited for use among parents of children with behavior problems than within a sample without any known difficulties.

Background Knowledge about the occurrence and distribution of musculoskeletal problems in early life is needed. The objectives were to group children aged 8 to 16 according to their distribution of pain in the spine, lower- and upper extremity, determine the proportion of children in each subgroup, and describe these in relation to sex, age, number- and length of episodes with pain. Method Data on musculoskeletal pain from about 1,000 Danish schoolchildren was collected over 3 school years (2011 to 2014) using weekly mobile phone text message responses from parents, indicating whether their child had pain in the spine, lower extremity and/or upper extremity. Result are presented for each school year individually. Results When pain was defined as at least 1 week with pain during a school year, Danish schoolchildren could be divided into three almost equally large groups for all three school years: Around 30% reporting no pain, around 40% reporting pain in one region, and around 30% reporting pain in two or three regions. Most commonly children experienced pain from the lower extremities (~ 60%), followed by the spine (~ 30%) and the upper extremities (~ 23%). Twice as many girls reported pain in all three sites compared to boys (10% vs. 5%) with no other statistically significant sex or age differences observed. When pain was defined as at least 3 weeks with pain during a schoolyear, 40% reported pain with similar patterns to those for the more lenient pain definition of 1 week. Conclusion Danish schoolchildren often experienced pain at more than one pain site during a schoolyear, and a significantly larger proportion of girls than boys reported pain in all three regions. This could indicate that, at least in some instances, the musculoskeletal system should be regarded as one entity, both for clinical and research purposes.

Sensory feedback has traditionally been considered critical for motor learning. While it has been shown that motor learning can occur in the absence of visual or somatosensory feedback, it is thought that at least one must be present. This assumption contrasts with literature demonstrating that motor imagery (MI) - the mental rehearsal of a movement - is capable of driving motor learning even though the lack of actual execution precludes sensory feedback related to movement. However, studies of MI typically employ simple tasks that do not require improvements in motor execution per se, suggesting that MI might improve task performance primarily through perceptual mechanisms. To avoid this limitation, we designed a novel motor task requiring the repeated execution of unfamiliar kinematic trajectories where learning was assessed through changes in the speed-accuracy function (SAF) across five sessions. General task performance was controlled for by assessing performance on randomly generated trajectories. Groups included physical practice (PP; with and without added visual feedback), MI, and perceptual control (PC), the latter of which only observed the trajectories. All groups performed physically on the final session. Upon the final session, the MI group performed better than the PC group, and better than initial session PP performance. These results suggest that motor learning occurred in the MI group despite the lack of sensory feedback related to the movement, and that this learning was not simply the result of perceptual learning. Our results question long-standing assumptions about MI based learning and the necessity of feedback in motor learning generally.

OBJECTIVES: Tyrosine kinase inhibitors (TKIs) are first line treatment choices for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, responses vary among patients, therefore good biomarkers predicting better responses are required. EGFR mutations are detected in the blood from patients as circulating tumour DNA (ctDNA). Studies have shown that clearing ctDNA during first line TKI treatment predicts outcomes for first and second generation TKI treatments. We aimed to investigate the effects on outcome measures of ctDNA clearing in subsequent treatment lines to treatment with the third generation TKI osimertinib.METHODS: In total, 225 patients were included in a prospective, multicentre study, where consecutive blood samples were monitored for EGFR mutations during systemic treatment lines, using the Cobas® EGFR mutation test v2. This study focused on EGFR mutations in ctDNA of 82 systemically pre-treated patients receiving osimertinib.RESULTS: Clearing all EGFR mutations from the blood after osimertinib treatment, significantly predicted progression-free survival, objective response rates and disease control rates. Primary sensitising EGFR mutations were found in ctDNA in 70 % of patients, and were accompanied by the T790 M mutation in nearly two thirds of cases. The T790 M mutation was cleared in all cases, while the accompanying sensitising mutations did not necessarily clear. However, T790 M clearing without simultaneously clearing of the primary sensitising mutation did not predict clinical responses. Neither the detection of T790 M before osimertinib treatment, nor the presence of EGFR mutations at the time of osimertinib initiation predicted clinical outcomes.CONCLUSION: The clearing of EGFR mutations in ctDNA after osimertinib treatment initiation in patients with advanced NSCLC is useful as a positive predictor of clinical outcome.

Objectives: We aimed to evaluate the utility of computed tomography angiography (CTA) for coronary compression (CC) prediction in patients with congenital heart disease undergoing balloon-expandable transcatheter pulmonary valve replacement (TPVR). Background: Coronary compression is a serious complication of TPVR, but the value of preprocedural CTAs to assess CC risk is largely unexplored. Methods: In all, 586 patients underwent TPVR between January 2009 and July 2018. Adults with a pre-TPVR CTA and children with a CTA performed less than one year prior to TPVR were included. Patients with poor CTA image quality or with aborted cases due to reasons other than CC were excluded. Sixty-six patients were finally included. Cardiac anatomy was assessed via multiplanar reconstruction of CTAs. Results: Coronary compression occurred in 9 (14%) of the 66 patients who underwent TPVR. Most CC cases (seven of nine) occurred in patients with conduits. Proximity of the right ventricular outflow tract (RVOT) landing zone to the coronary arteries and to the chest wall was a significant risk factor for compression ( P < .001 and P = .019, respectively). Compression risk increased significantly if patients had an RVOT to coronary artery distance of ≤3 mm ( P < .001) and an RVOT to chest wall distance of ≤8 mm ( P = .026). Anomalous course of coronary arteries was another significant univariate risk factor ( P = .003). Conclusions: Right ventricular outflow tract landing zone distance of ≤3 mm to a coronary artery, landing zone distance of ≤8 mm to the chest wall, and anomalous coronary arteries are associated with increased CC risk. Electrocardiogram gating may not be necessary if coronary arteries are opacified on CTAs. Larger studies are needed to explore and confirm these coronary artery compression risk factors.

Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163

Objectives: Epidermal growth factor receptor (EGFR) mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, a subset of patients has limited or no response. We investigated the initial dynamics of EGFR mutations detected in circulating tumour DNA (ctDNA) during treatment as a predictive marker of outcome. Methods: A total of 225 patients with advanced EGFR mutated NSCLC were included for consecutive blood sampling in this prospective multicentre study. Out of these, 146 patients received first line TKI and had a baseline blood sample available for EGFR mutation testing with the Cobas® EGFR mutation test V2. For examinations on clearing and clinical outcome, 98 patients who had detectable ctDNA at baseline and at least one follow-up blood sample were included. Results: For patients with EGFR mutations present in plasma at baseline, clearing of mutations from the blood during first line TKI served as a positive predictor for objective response rate (p = 0.0008), progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001). This was seen both for patients who cleared the ctDNA within the first 7 weeks of treatment and patients who cleared the ctDNA at a slower pace. Baseline mutation presence was a negative predictor for PFS (p = 0.0069) and OS (p = 0.0340). Conclusion: The current study is the first to confirm, in a sizeable Caucasian cohort, that clearing of EGFR mutations predict outcome to first line TKI in patients with EGFR mutated NSCLC.

Objective We sought to describe the leaflet morphology variation in the Melody Transcatheter Pulmonary Valve (TPV) and evaluate associated outcomes. The Melody TPV is constructed from harvested bovine jugular venous valves which have been rigorously tested. Natural anatomic leaflet variations are seen in the Melody TPV but have not been evaluated. Design A Melody TPV leaflet morphology classification system was devised after reviewing a subset of photographed and implanted TPVs. All images were blindly reviewed by implanters and classified. Midterm hemodynamic outcomes and complications of the Melody TPVs were compared by leaflet morphology. Results Photographed Melody TPVs implanted between 2011 and 2016 (n = 62) were categorized into the following leaflet morphology types: A-symmetric trileaflet (47%); B-asymmetric trileaflet with a single small leaflet (32%); C-asymmetric trileaflet with a single large leaflet (16%); D-rudimentary leaflet with near bicuspid appearance (5%). Acceptable hemodynamic function at 6 months postimplantation was seen in 97.5% of valves. Over a median follow-up of 1.5 years (range 0-4.4 years), two TPVs (Type A) had > mild regurgitation. Nine TPVs developed complications (endocarditis, 3; stent fracture, 2; refractory arrhythmia, 1; conduit replacement, 2; death, 1), of which 6 required reintervention. There was no significant difference in outcomes based on Melody TPV leaflet morphology type. Conclusions The Melody TPV can be classified into one of four categories based on leaflet morphology. Study outcomes were not associated with leaflet morphology. Further documentation and evaluation of Melody TPV morphology may lead to better understanding of this technology.

Atrial switch operation in patients with transposition of the great arteries (TGA) leads to leftward shift and changes the geometry of the interventricular septum. By including the implications of regional work and septal curvature, this study investigates if changes in septal function and geometry contribute to reduced function of the systemic right ventricle (RV) in adult TGA patients. Regional myocardial work estimation has been possible by applying a recently developed method for noninvasive work calculation based on echocardiography. In 14 TGA patients (32 ± 6 yr, means ± SD) and 14 healthy controls, systemic ventricular systolic strains were measured by speckle tracking echocardiography and regional work was calculated by pressure-strain analysis. In TGA patients, septal longitudinal strain was reduced to −14 ± 2 vs. −20 ± 2% in controls ( P < 0.01) and septal work was reduced from 2,046 ± 318 to 1,146 ± 260 mmHg·% ( P < 0.01). Septal circumferential strain measured in a subgroup of patients was reduced to −11 ± 3 vs. −27 ± 3% in controls ( P < 0.01), and a reduction of septal work (540 ± 273 vs. 2,663 ± 459 mmHg·%) was seen ( P < 0.01). These reductions were in part attributed to elevated afterload due to increased radius of curvature of the leftward shifted septum. To conclude, in this mechanistic study we demonstrate that septal dysfunction contributes to failure of the systemic RV after atrial switch in TGA patients. This is potentially a long-term response to increased afterload due to a flatter septum and suggests that medical therapy that counteracts septal flattening may improve function of the systemic RV. NEW & NOTEWORTHY We have demonstrated that transposition of the great arteries patients with systemic right ventricles (RVs) have reduced function of the interventricular septum (IVS). Since the IVS is constructed to eject into the systemic circulation, it may seem unexpected that it does not maintain function when being part of the systemic RV. By applying the principles of regional work, wall tension, and geometry, we have identified unfavorable working conditions for the IVS when the RV adapts to systemic pressures.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) constitutes a heterogeneous category of lymphomas, which do not fit into any of the specifically defined T-cell lymphoma entities. Both the pathogenesis and tumor biology in PTCL-NOS are poorly understood. Protein expression in pretherapeutic PTCL-NOS tumors was analyzed by proteomics. Differentially expressed proteins were compared in 3 distinct scenarios: (A) PTCL-NOS tumor tissue (n = 18) vs benign lymphoid tissue (n = 8), (B) clusters defined by principal component analysis (PCA), and (C) tumors from patients with chemosensitive vs refractory PTCL-NOS. Selected differentially expressed proteins identified by proteomics were correlated with clinico-pathological features and outcome in a larger cohort of patients with PTCL-NOS (n = 87) by immunohistochemistry (IHC). Most proteins with altered expression were identified comparing PTCL-NOS vs benign lymphoid tissue. PCA of the protein profile defined 3 distinct clusters. All benign samples clustered together, whereas PTCL-NOS tumors separated into 2 clusters with different patient overall survival rates (P = .001). Differentially expressed proteins reflected large biological diversity among PTCL-NOS, particularly associated with alterations of “immunological” pathways. The 2 PTCL-NOS subclusters defined by PCA showed disturbance of “stress-related” and “protein metabolic” pathways. α-Enolase 1 (ENO1) was found differentially expressed in all 3 analyses, and high intratumoral ENO1 expression evaluated by IHC correlated with poor outcome (hazard ratio, 2.09; 95% confidence interval, 1.17-3.73; P = .013). High expression of triosephosphate isomerase (TPI1) also showed a tendency to correlate with poor survival (P = .057). In conclusion, proteomic profiling of PTCL-NOS provided evidence of markedly altered protein expression and identified ENO1 as a novel potential prognostic marker.

An analysis was conducted of 325 consecutive metacarpophalangeal arthroplasties prospectively collected using a single institution’s total joints registry over a 14-year time period to characterize long-term radiographic and functional outcomes. Patients were followed for a mean of 7.2 years (2–18) or until revision. The 5-, 10- and 15-year survival free from revision were 98%, 95% and 95%, respectively. The 5-, 10- and 15-year survival rates free from radiographic implant fracture were 93%, 58% and 35%, respectively. The 5-, 10- and 15-year survival rates free from coronal plane deformity greater than 10° were 81%, 37% and 17%, respectively. Patients had significant improvements in their postoperative pain levels and metacarpophalangeal arc of motion. Neither implant fracture, nor coronal plane deformity >10° had a significant association with worse function. Overall, pain relief and functional improvement are reliable, though silicone implants do not protect from progression of coronal plane deformity and have a high fracture rate. Level of evidence: IV

Whether or not brain activation during motor imagery (MI), the mental rehearsal of movement, is modulated by experience (i.e. skilled performance, achieved through long-term practice) remains unclear. Specifically, MI is generally associated with diffuse activation patterns that closely resemble novice physical performance, which may be attributable to a lack of experience with the task being imagined vs. being a distinguishing feature of MI. We sought to examine how experience modulates brain activity driven via MI, implementing a within- and between-group design to manipulate experience across tasks as well as expertise of the participants. Two groups of 'experts' (basketball/volleyball athletes) and 'novices' (recreational controls) underwent magnetoencephalography (MEG) while performing MI of four multi-articular tasks, selected to ensure that the degree of experience that participants had with each task varied. Source-level analysis was applied to MEG data and linear mixed effects modelling was conducted to examine task-related changes in activity. Within- and between-group comparisons were completed post hoc and difference maps were plotted. Brain activation patterns observed during MI of tasks for which participants had a low degree of experience were more widespread and bilateral (i.e. within-groups), with limited differences observed during MI of tasks for which participants had similar experience (i.e. between-groups). Thus, we show that brain activity during MI is modulated by experience; specifically, that novice performance is associated with the additional recruitment of regions across both hemispheres. Future investigations of the neural correlates of MI should consider prior experience when selecting the task to be performed.

Background Lung cancer patients with an activating mutation in the EGFR (epidermal growth factor receptor) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR. The difficulties in obtaining biopsies at progression make it challenging to investigate the appearance of the T790M mutation at progression in large patient cohorts. We have used cell free DNA (cfDNA) from patients treated with erlotinib to investigate if the development of a T790M mutation coincides with the presence of an activating EGFR mutation in the pre-treatment blood sample. Methods A cohort of 227 NSCLC (non-small cell lung cancer) adenocarcinoma patients was treated with erlotinib irrespective of EGFR-mutational status. Blood samples were drawn immediately before erlotinib treatment was initiated and again at progression. The cobas® EGFR Mutation Test v2 designed for cfDNA was used to identify 42 EGFR mutations. Results Of the 227 NSCLC patients, blood samples were available from 144 patients both before erlotinib treatment and at progression (within 1 month before or after clinical progression). One hundred and twenty-eight of the 144 were wild-type EGFR before treatment, and we demonstrate that the T790M mutation was not present at progression in any of these. In contrast, in the 16 patients with an activating EGFR mutation in the pre-treatment blood sample six patients (38%) were identified with a T790M mutation in the progression blood sample. Conclusion The T790M resistance mutation is only found in the cfDNA of erlotinib-treated NSCLC patients if they have an activating EGFR mutation before treatment. Electronic supplementary material The online version of this article (10.1186/s12885-018-4108-0) contains supplementary material, which is available to authorized users.

BACKGROUND: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited.OBJECTIVE: To assess the efficacy and safety of omalizumab in SM.METHODS: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored.RESULTS: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded.CONCLUSIONS: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.

In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.

Objective We sought to identify a time during cardiac ejection when the instantaneous pressure gradient (IPG) correlated best, and near unity, with peak-to-peak systolic ejection gradient (PPSG) in patients with congenital aortic stenosis. Noninvasive echocardiographic measurement of IPG has limited correlation with cardiac catheterization measured PPSG across the spectrum of disease severity of congenital aortic stenosis. A major contributor is the observation that these measures are inherently different with a variable relationship dependent on the degree of stenosis. Design Hemodynamic data from cardiac catheterizations utilizing simultaneous pressure measurements from the left ventricle (LV) and ascending aorta (AAo) in patients with congenital valvar aortic stenosis was retrospectively reviewed over the past 5 years. The cardiac cycle was standardized for all patients using the percentage of total LV ejection time (ET). Instantaneous gradient at 5% intervals of ET were compared to PPSG using linear regression and Bland-Altman analysis. Results A total of 22 patients underwent catheterization at a median age of 13.7 years (interquartile range [IQR] 10.3-18.0) and median weight of 51.1 kg (IQR 34.2-71.6). The PPSG was 46.5 ± 12.6 mm Hg (mean ± SD) and correlated suboptimally with the maximum and mean IPG. The midsystolic IPG (occurring at 50% of ET) had the strongest correlation with the PPSG ( PPSG = 0.97(IPG50%)–1.12, R2 = 0.88), while the IPG at 55% of ET was closest to unity ( PPSG = 0.997(IPG55%)–1.17, R2 = 0.87). Conclusions The commonly measured maximum and mean IPG are suboptimal estimates of the PPSG in congenital aortic stenosis. Using catheter-based data, IPG at 50%–55% of ejection correlates well with PPSG. This may allow for a more accurate estimation of PPSG via noninvasive assessment of IPG.

BACKGROUND: Mutated circulating cell-free DNA (cfDNA) has been suggested as a surrogate marker of tumour burden and aggressiveness of disease. We examined the association between the level of plasma mutant cfDNA and metabolic tumour burden (MTB) measured by (18)F-fluoro-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). Furthermore, the presence of mutant cfDNA was correlated with patient survival.METHODS: Forty-six advanced non-small cell lung cancer (NSCLC) patients were included. At the time of inclusion, blood sampling and a PET/CT scan were performed. cfDNA was isolated and next-generation sequencing (NGS) was performed (Ion AmpliSeq Colon and Lung Cancer panel v2). MTB was defined by a volumetric PET parameter.RESULTS: NGS succeeded in 41 patients. Mutations were detected in the blood of 24 patients. A significant correlation between the allele frequency of the most frequent mutation and MTB was found (P=0.001). Patients with detectable mutated cfDNA had a significantly shorter median overall survival compared with patients without (3.7 versus 10.6 months, P=0.019). This impact on survival was independent of the MTB.CONCLUSIONS: Level of mutated cfDNA tends to correlate with MTB in advanced-stage NSCLC patients. Patients with detectable mutant DNA in plasma had an inferior survival, indicating that this could be an important predictor of survival.

Implicit sequence learning (ISL) occurs without conscious awareness and is critical for skill acquisition. The extent to which ISL occurs is a function of exposure (i.e., total training time and/or sequence to noise ratio) to a repeated sequence, and thus the cognitive mechanism underlying ISL is the formation of stimulus-response associations. As the majority of ISL studies employ paradigms whereby individuals unknowingly physically practice a repeated sequence, the cognitive mechanism underlying ISL through motor imagery (MI), the mental rehearsal of movement, remains unknown. This study examined the cognitive mechanisms of MI-based ISL by probing the link between exposure and the resultant ISL. Seventy-two participants underwent MI-based practice of an ISL task following randomization to one of four conditions: 4 training blocks with a high (4-High) or low (4-Low) sequence to noise ratio, or 2 training blocks with a high (2-High) or low (2-Low) sequence to noise ratio. Reaction time differences (dRT) and effect sizes between repeated and random sequences assessed the extent of learning. All groups showed a degree of ISL, yet effect sizes indicated a greater degree of learning in groups with higher exposure (4-Low and 4-High). Findings indicate that the extent to which ISL occurs through MI is impacted by manipulations to total training time and the sequence to noise ratio. Overall, we show that the extent of ISL occurring through MI is a function of exposure, indicating that like physical practice, the cognitive mechanisms of MI-based ISL rely on the formation of stimulus response associations.

Preparation for postural instability engages cortical resources that serve to optimize compensatory balance responses. Engagement of these cortical resources in cognitive dual-task activities may impact the ability to appropriately prepare and optimize responses to instability. The purpose of this study was to determine whether cognitive dual-task activities influenced cortical activity preceding and following postural instability. Postural instability was induced using a lean-and-release paradigm in 10 healthy participants. Perturbations were either temporally predictable (PRED) or unpredictable (UNPRED) and presented with (COG) or without a cognitive dual-task, presented in blocks of trials. The electroencephalogram was recorded from multiple frontal electrode sites. EEG data were averaged over 25-35 trials across conditions. Area under the curve of pre-perturbation cortical activity and peak latency and amplitude of post-perturbation cortical activity were quantified at the Cz site and compared across conditions. Performance of the concurrent cognitive task reduced the mean (SE) magnitude of pre-perturbation cortical activity in advance of predictable bouts of postural instability (PRED: 18.7(3.0)mVms; PRED-COG; 14.0(2.3)mVms). While the level of cognitive load influenced the amplitude of the post-perturbation N1 potential in the predictable conditions, there were no changes in N1 with a cognitive dual task during unpredictable conditions (PRED: -32.1(3.2)µV; PRED-COG: -50.8(8.4)µV; UNPRED: -65.0(12.2)µV; UNPRED-COG: -64.2(12.7)µV). Performance of the cognitive task delayed and reduced the magnitude of the initial gastrocnemius response. The findings indicate that pre- and post-perturbation cortical activity is affected by a cognitive distractor when postural instability is temporally predictable. Distraction also influences associated muscle responses.

Cigarette smoke usage is prevalent in human immunodeficiency virus (HIV)-positive patients, and, despite highly active antiretroviral therapy, these individuals develop an accelerated form of chronic obstructive pulmonary disease (COPD). Studies investigating the mechanisms of COPD development in HIV have been limited by the lack of suitable mouse models. Here we describe a model of HIV-induced COPD in wild-type mice using EcoHIV, a chimeric HIV capable of establishing chronic infection in immunocompetent mice. A/J mice were infected with EcoHIV and subjected to whole body cigarette smoke exposure. EcoHIV was detected in alveolar macrophages of mice. Compared with uninfected mice, concomitant EcoHIV infection significantly reduced forced expiratory flow 50%/forced vital capacity and enhanced distal airspace enlargement following cigarette smoke exposure. Lung IL-6, granulocyte-macrophage colony-stimulating factor, neutrophil elastase, cathepsin G, and matrix metalloproteinase-9 expression was significantly enhanced in smoke-exposed EcoHIV-infected mice. These changes coincided with enhanced IκBα, ERK1/2, p38, and STAT3 phosphorylation and lung cell apoptosis. Thus, the EcoHIV smoke exposure mouse model reproduces several of the pathophysiological features of HIV-related COPD in humans, indicating that this murine model can be used to determine key parameters of HIV-related COPD and to test future therapies for this disorder.

Motor imagery (MI), the mental rehearsal of movement, facilitates learning by driving brain activation similar to that of physical practice (PP). However, a growing body of evidence suggests that learning via MI relies more on effector independent as opposed to effector dependent encoding. One approach to probing the nature of MI based learning is to study the primary motor cortex (MC), a brain region known to be critical to effector dependent encoding, but whose involvement in MI is debatable. The current study sought to inform on the nature of MI-based learning by examining the extent to which participants could learn via MI following inhibition of the MC using repetitive transcranial magnetic stimulation (TMS). Forty-seven participants completed an MI-based implicit sequence learning paradigm after receiving inhibitory TMS to the contralateral or ipsilateral MC (TMS groups), or with the coil angled away from the scalp (Sham). The extent to which participants learned was assessed via reaction time differences (dRT) and effect sizes between repeated and random sequences. Similar dRT values and moderate effect sizes were observed across all groups, providing evidence that inhibition of the MC did not disrupt MI-based learning. As the MC is critical to effector dependent encoding, the current findings suggest that MI-based learning does not rely on effector dependent encoding and unlike PP, is more effector independent in nature. Ultimately, these results inform on the nature of MI-based learning.

Student well-being is a growing issue in higher education, and assessment of the prevalence of conditions as loneliness is therefore important. In higher education and population surveys the Three-Item Loneliness Scale (T-ILS) is used increasingly. The T-ILS is attractive for large multi-subject surveys, as it consists of only three items (derived from the UCLA Loneliness Scale). Several ways of classifying persons as lonely based on T-ILS scores exist: dichotomous and trichotomous classification schemes and use of sum scores with rising levels indicating more loneliness. The question remains whether T-ILS scores are comparable across the different population groups where they are used or across groups of students in the higher education system. The aim was to investigate whether the T-ILS suffers from differential item functioning (DIF) that might change the loneliness classification among higher education students, using a large sample just admitted to 22 different academy profession degree programs in Denmark (N = 3,757). DIF was tested relative to degree program, age groups and gender. The framework of graphical loglinear Rasch models was applied, as this allows for adjustment of sum scores for uniform DIF, and thus for assessment of whether DIF might change the classification. Two items showed DIF relative to degree program and gender, and adjusting for this DIF changed the classification for some subgroups. The consequences were negligible when using a dichotomous classification and larger when using a trichotomous classification. Therefore, trichotomous classification should be used with caution unless suitable adjustments for DIF are done prior to classification.