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BACKGROUND: Telemedicine has the advantage of expanding access to care for patients with Parkinson’s Disease (PD). However, rigidity and postural instability in PD are difficult to measure remotely, and are important measures of functional impairment and fall risk. RESEARCH QUESTION: Can measures from wearable sensors be used as future surrogates for the MDS-UPDRS rigidity and Postural Instability and Gait Difficulty (PIGD) subscores? METHODS: Thirty-one individuals with mild to moderate PD wore 3 inertial sensors at home for one week to measure quantity and quality of gait and turning in daily life. Separately, we performed a clinical assessement and balance characterization of postural sway with the same wearable sensors in the laboratory (On medication). We then first performed a traditional correlation analysis between clinical scores and objective measures of gait and balance followed by multivariable linear regression employing a best subset selection strategy. RESULTS: The number of walking bouts and turns correlated significantly with the rigidity subscore, while the number of turns, foot pitch angle, and sway area while standing correlated significantly with the PIGD subscore (p

Background: Persons with Huntington’s disease (HD) are at increased risk for subdural hematomas (SDH) because of underlying brain atrophy and increased frequency of falls and head trauma. SDH can cause serious disability, but there is little information about the association of SDH with HD in the medical literature. Objective: To review the occurrence and characteristics of SDH seen in clinics specializing in HD. Methods: A retrospective review identifying the occurrence and manifestations of SDH in HD patients attending three HDSA Centers of Excellence. Results: Twenty-five HD patients (16F/9M) were identified with SDH. Twelve (44%) SDH were bilateral, 16 (60%) required surgical intervention, and 2 resulted in death. Mean age at the time of SDH was 60 years, mean duration of HD symptoms prior to event was 8 years, mean CAG repeat expansion size was 43 and mean UHDRS motor score obtained closest to time of SDH was 51 (16 patients). Most SDH occurred in the context of ground level falls or using stairs although 5 patients had no history of head trauma. Additional brain injury may occur along with the SDH. The most common symptoms were altered mental status, hemiparesis and loss of consciousness. The over-representation of females in this study requires replication and further investigation. Conclusion: Patients with HD are at increased risk for SDH. An increased suspicion for SDH in HD patients should be considered, as this phenomenon may be initially unrecognized, may require extensive utilization of medical resources and is a potential cause of death.

Effective student selection methods are needed to identify applicants who are expected to complete their studies and succeed professionally. The assessment of emotional intelligence has recently be...

Aim Mesenchymal stem cell (MSC) therapies are emerging as a promising strategy to promote tissue repair, and may extend their utility to burn care. This comprehensive review of the extant literature, evaluated all in vivo studies, to elucidate the potential protective and therapeutic effect of MSCs in acute thermal skin burns. Methods PubMed was systematically searched, according to PRISMA guidelines, and all relevant preclinical and clinical studies were included according to pre-specified eligibility criteria. Results Forty-two studies were included in a qualitative synthesis, of which three were human and 39 were animal studies. The preclinical studies showed that MSCs can significantly reduce inflammation, burn wound progression and accelerate healing rate of acute burns. The underlying mechanisms are complex and not fully understood but paracrine modulators, such as immunomodulatory, antioxidative and trophic factors, seem to play important roles. Allogeneic MSC therapy has proved feasible in humans, and could allow for prompt treatment of acute burns in a clinical setting. Conclusion MSC therapy show positive results, regarding improved burn wound healing and immunologic response. However, most findings are based on small animal studies. Randomized clinical trials are warranted to investigate the regenerative effects in human burns before translating the findings into clinical practice.

Amyotrophic lateral sclerosis (ALS) results in progressive impairment of upper and lower motor neurons. Increasing evidence from both in vivo and ex vivo studies suggest that iron accumulation in the motor cortex is a neuropathological hallmark in ALS. An in vivo neuroimaging marker of iron dysregulation in ALS would be useful in disease diagnosis and prognosis. Magnetic resonance imaging (MRI), with its unique capability to generate a variety of soft tissue contrasts, provides opportunities to image iron distribution in the human brain with millimeter to sub-millimeter anatomical resolution. Conventionally, MRI T1-weighted, T2-weighted, and T2*-weighted images have been used to investigate iron dysregulation in the brain in vivo. Susceptibility weighted imaging has enhanced contrast for para-magnetic materials that provides superior sensitivity to iron in vivo. Recently, the development of quantitative susceptibility mapping (QSM) has realized the possibility of using quantitative assessments of magnetic susceptibility measures in brain tissues as a surrogate measurement of in vivo brain iron. In this review, we provide an overview of MRI techniques that have been used to investigate iron dysregulation in ALS in vivo. The potential uses, strengths, and limitations of these techniques in clinical trials, disease diagnosis, and prognosis are presented and discussed. We recommend further longitudinal studies with appropriate cohort characterization to validate the efficacy of these techniques. We conclude that quantitative iron assessment using recent advances in MRI including QSM holds great potential to be a sensitive diagnostic and prognostic marker in ALS. The use of multimodal neuroimaging markers in combination with iron imaging may also offer improved sensitivity in ALS diagnosis and prognosis that could make a major contribution to clinical care and treatment trials. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

ObjectiveDysregulation of iron in the cerebral motor areas has been hypothesized to occur in individuals with Amyotrophic Lateral Sclerosis (ALS). There is still limited knowledge regarding iron dysregulation in the progression of ALS pathology. Our objectives were to use magnetic resonance based Quantitative Susceptibility Mapping (QSM) to investigate the association between iron dysregulation in the motor cortex and clinical manifestations in patients with limb-onset ALS, and to examine changes in the iron concentration in the motor cortex in these patients over a six-month period.MethodsIron concentration was investigated using magnetic resonance based -QSM in the primary motor cortex and the pre-motor area in thirteen limb-onset ALS patients (including five lumbar onset, six cervical onset and two flail arm patients), and eleven age and sex-matched healthy controls. Nine ALS patients underwent follow-up scans at six months.ResultsSignificantly increased QSM was observed in the left posterior primary motor area (p = 0.02, Cohen’s d = 0.9) and right anterior primary motor area (p = 0.02, Cohen’s d = 0.92) in all individuals with limb-onset ALS compared to healthy controls. Increased QSM was observed in the primary motor and pre-motor area at baseline in patients with lumbar onset ALS patients, but not cervical limb-onset ALS patients, compared to healthy controls. No significant change in QSM was observed at the six-month follow-up scans in the ALS patients.ConclusionsThe findings suggest that iron dysregulation can be detected in the motor cortex in limb-onset ALS, which does not appreciably change over a further 6 months. Individuals with lumbar onset ALS appear to be more susceptible to motor cortex iron dysregulation compared to the individuals with cervical onset ALS. Importantly, this study highlights the potential use of QSM as a radiological indicator in disease diagnosis, and in clinical trials in limb-onset ALS and its subtypes.HighlightsSerial measurement of QSM in the motor cortex in limb-onset ALS was performedQSM changes in the motor cortex in ALS sub-groups were investigatedHigher QSM was observed in the motor cortex in Lumbar ALS relative to controlsQSM is sensitive to iron dysregulation in the motor cortex in limb-onset ALS

Reasoning skills are needed in the future work life. As such, it is important that reasoning skills be assessed in higher education, both in the selection phase and during education. This study aim...

Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1–3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity. Electronic supplementary material The online version of this article (10.1007/s00204-020-02711-8) contains supplementary material, which is available to authorized users.

Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. Another hallucinogenic drug, esketamine, has recently been U.S. Food and Drug Administration (FDA)-approved as a rapid-acting antidepressant. The mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. The efficacy of these two medications has not, however, been directly compared either clinically or preclinically. Further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. To address these questions, we tested psilocybin, lysergic acid diethylamide (LSD), and ketamine in a rat model for depression. As in humans, a single administration of psilocybin or LSD produced persistent antidepressant-like effects in our model. In contrast, ketamine produced only a transient antidepressant-like effect. Our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.

ObjectiveTo establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts.MethodsWe generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population.ResultsWe identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r2 = 0.99, Japan r2 = 0.99, South Korea r2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8–5.5) in Japanese, 5.4 (95% CI, 5.2–5.7) in Australian, and 4.4 (95% CI, 4.2–4.8) in South Korean patients.ConclusionsThe linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.

Aim: To use available electronic administrative records to identify data reliability, predict discharge destination, and identify risk factors associated with specific outcomes following hospital admission with stroke, compared to stroke specific clinical factors, using machine learning techniques.Method: The study included 2,531 patients having at least one admission with a confirmed diagnosis of stroke, collected from a regional hospital in Australia within 2009–2013. Using machine learning (penalized regression with Lasso) techniques, patients having their index admission between June 2009 and July 2012 were used to derive predictive models, and patients having their index admission between July 2012 and June 2013 were used for validation. Three different stroke types [intracerebral hemorrhage (ICH), ischemic stroke, transient ischemic attack (TIA)] were considered and five different comparison outcome settings were considered. Our electronic administrative record based predictive model was compared with a predictive model composed of “baseline” clinical features, more specific for stroke, such as age, gender, smoking habits, co-morbidities (high cholesterol, hypertension, atrial fibrillation, and ischemic heart disease), types of imaging done (CT scan, MRI, etc.), and occurrence of in-hospital pneumonia. Risk factors associated with likelihood of negative outcomes were identified.Results: The data was highly reliable at predicting discharge to rehabilitation and all other outcomes vs. death for ICH (AUC 0.85 and 0.825, respectively), all discharge outcomes except home vs. rehabilitation for ischemic stroke, and discharge home vs. others and home vs. rehabilitation for TIA (AUC 0.948 and 0.873, respectively). Electronic health record data appeared to provide improved prediction of outcomes over stroke specific clinical factors from the machine learning models. Common risk factors associated with a negative impact on expected outcomes appeared clinically intuitive, and included older age groups, prior ventilatory support, urinary incontinence, need for imaging, and need for allied health input.Conclusion: Electronic administrative records from this cohort produced reliable outcome prediction and identified clinically appropriate factors negatively impacting most outcome variables following hospital admission with stroke. This presents a means of future identification of modifiable factors associated with patient discharge destination. This may potentially aid in patient selection for certain interventions and aid in better patient and clinician education regarding expected discharge outcomes.

Three-dimensional (3D) printing has recently emerged as a cost-effective alternative for rapid prototyping of microfluidic devices. The feature resolution of stereolithography-based 3D printing is particularly well suited for manufacturing of continuous flow cell culture platforms. Poor cell adhesion or material-induced cell death may, however, limit the introduction of new materials to microfluidic cell culture. In this work, we characterized four commercially available materials commonly used in stereolithography-based 3D printing with respect to long-term (2 month) cell survival on native 3D printed surfaces. Cell proliferation rates, along with material-induced effects on apoptosis and cell survival, were examined in mouse embryonic fibroblasts. Additionally, the feasibility of Dental SG (material with the most favored properties) for culturing of human hepatocytes and human-induced pluripotent stem cells was evaluated. The strength of cell adhesion to Dental SG was further examined over a shear force gradient of 1–89 dyne per cm² by using a custom-designed microfluidic shear force assay incorporating a 3D printed, tilted and tapered microchannel sealed with a polydimethylsiloxane lid. According to our results, autoclavation of the devices prior to cell seeding played the most important role in facilitating long-term cell survival on the native 3D printed surfaces with the shear force threshold in the range of 3–8 dyne per cm². Three-dimensional (3D) printing has recently emerged as a cost-effective alternative for rapid prototyping of microfluidic devices. The feature resolution of stereolithography-based 3D printing is particularly well suited for manufacturing of continuous flow cell culture platforms. Poor cell adhesion or material-induced cell death may, however, limit the introduction of new materials to microfluidic cell culture. In this work, we characterized four commercially available materials commonly used in stereolithography-based 3D printing with respect to long-term (2 month) cell survival on native 3D printed surfaces. Cell proliferation rates, along with material-induced effects on apoptosis and cell survival, were examined in mouse embryonic fibroblasts. Additionally, the feasibility of Dental SG (material with the most favored properties) for culturing of human hepatocytes and human-induced pluripotent stem cells was evaluated. The strength of cell adhesion to Dental SG was further examined over a shear force gradient of 1-89 dyne per cm(2)by using a custom-designed microfluidic shear force assay incorporating a 3D printed, tilted and tapered microchannel sealed with a polydimethylsiloxane lid. According to our results, autoclavation of the devices prior to cell seeding played the most important role in facilitating long-term cell survival on the native 3D printed surfaces with the shear force threshold in the range of 3-8 dyne per cm(2).

Higher education student selection has significant societal, institutional and individual impacts. Thousands of applicants apply only for nursing, one of the major higher education disciplines. As ...

Cell-enrichment of fat grafts has produced encouraging results, but the optimal concentrations and types of added cells are unknown. The authors investigated the effects of enrichment with various concentrations of ex vivo-expanded adipose-derived stem/stromal cells and stromal vascular fraction on graft retention in a porcine model.Adipose-derived stem/stromal cells were culture-expanded, and six fat grafts (30 ml) were prepared for each minipig (n = 13). The authors investigated grafts enriched with 2.5 × 10 to 20 × 10 adipose-derived stem cells/ml and stromal vascular fraction and nonenriched control grafts. Each pig served as its own control. Magnetic resonance imaging was performed immediately after grafting and 120 days postoperatively before the pigs were euthanized, and histologic samples were collected.The authors recorded an enhanced relative graft retention rate of 41 percent in a pool of all cell-enriched grafts compared to the nonenriched control (13.0 percent versus 9.2 percent; p = 0.0045). A comparison of all individual groups showed significantly higher graft retention in the 10 × 10-adipose-derived stem/stromal cells per milliliter group compared with the control group (p = 0.022). No significant differences were observed between the cell-enriched groups (p = 0.66). All fat grafts showed a significantly better resemblance to normal fat tissue in the periphery than in the center (p0.009), but no differences in overall graft morphology were observed between groups (p0.17).Cell-enriched fat grafting improved graft retention and was feasible in this porcine model. No significant differences in graft retention were observed among the various adipose-derived stem/stromal cell concentrations or between adipose-derived stem/stromal cell and stromal vascular fraction enrichment. Future studies using this model can help improve understanding of the role of adipose-derived stem/stromal cells in cell-enriched fat grafting.

Sentence-level representations are necessary for various NLP tasks. Recurrent neural networks have proven to be very effective in learning distributed representations and can be trained efficiently on natural language inference tasks. We build on top of one such model and propose a hierarchy of BiLSTM and max pooling layers that implements an iterative refinement strategy and yields state of the art results on the SciTail dataset as well as strong results for SNLI and MultiNLI. We can show that the sentence embeddings learned in this way can be utilized in a wide variety of transfer learning tasks, outperforming InferSent on 7 out of 10 and SkipThought on 8 out of 9 SentEval sentence embedding evaluation tasks. Furthermore, our model beats the InferSent model in 8 out of 10 recently published SentEval probing tasks designed to evaluate sentence embeddings' ability to capture some of the important linguistic properties of sentences., To appear in JNLE

Phyllodes tumors (PTs) are rare fibroepithelial neoplasms of the breast and constitute 0.3–1% of all primary breast tumors. They should be characterized in to a benign, borderline or malignant category based on a combination of histological features. PTs can show heterologous components, typically sarcomatous, including osteosarcomatous and chondrosarcomatous. Benign heterologous components are exceedingly rare with only one prior reported case in the English literature. This case emphasizes how difficult establishing a correct diagnosis in PTs with heterologous components can be, especially when the tumor consists mainly of a benign heterologous component. We report the case of a 65 year old woman with a recurrent breast tumor initially misdiagnosed as benign osseous metaplasia. The tumor re-occurred as a malignant PT dominated by benign osseous and chondroid metaplasia. Multiple metastases consisting of primarily mature bone and cartilage were seen in the lungs. On microscopic revision and considering the clinical course the primary breast tumor was re-classified as a borderline PT.

Objective Emerging evidences suggest that the trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS. Methods We measured degeneration in limb-onset ALS patients (n = 14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n = 12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. In order to investigate whether network spread on the brain connectome derived from healthy individuals were significant findings, we compared our findings against network spread simulated on random networks. Results The cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Network spread simulated on the random networks showed that the findings using healthy brain connectomes are significantly different from null models. Interpretation Our findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.

Disturbances of gait occur in all stages of Huntington’s disease (HD) including the premanifest and prodromal stages. Individuals with HD demonstrate the slower speed of gait, shorter stride length, and increased variability of gait parameters as compared to controls; cognitive disturbances in HD often compound these differences. Abnormalities of gait and recurrent falls lead to decreased quality of life for individuals with HD throughout the disease. This scoping review aims to outline the cross-disciplinary approach to gait evaluation in HD and will highlight the utility of objective measures in defining gait abnormalities in this patient population.

Sander Talman,1 Sevim Uzun,2 Remco S Djamin,1 Sara J Baart,3 Marco JJH Grootenboers,1 Joachim Aerts,2 Menno van der Eerden2 1Amphia Hospital Breda, Department of Pulmonary Medicine, Breda, 4800RK, the Netherlands; 2Erasmus Medical Centre Rotterdam, Department of Pulmonary Medicine, Rotterdam, 3015 CE, the Netherlands; 3Erasmuc Medical Centre Rotterdam, Department of Biostatistics, Rotterdam, 3015 CE, the NetherlandsCorrespondence: Sander Talman Tel +31 76 595 5351Email STalman@amphia.nlAbstract: Macrolides are effective in reducing the number of exacerbations in COPD patients with the frequent exacerbator phenotype. Our study did not show a persistent effect of azithromycin on exacerbation frequencies after more than one year of usage.Keywords: Macrolide, long-term, exacerbations, COPD, COLUMBUS

Some subgroups of breast cancer patients receiving neoadjuvant chemotherapy (NACT) show high rates of pathologic complete response (pCR) in the breast, proposing the possibility of omitting surgery. Prediction of pCR is dependent on accurate imaging methods. This study investigated whether magnetic resonance imaging (MRI) is better than ultrasound (US) in predicting pCR in breast cancer patients receiving NACT. This institutional, retrospective study enrolled breast cancer patients receiving NACT who were examined by either MRI or combined US and mammography before surgery from 2016 to 2019. Imaging findings were compared with pathologic response evaluation of the tumor. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for prediction of pCR were calculated and compared between MRI and US. Among 307 patients, 151 were examined by MRI and 156 by US. In the MRI group, 37 patients (24.5 %) had a pCR compared with 51 patients (32.7 %) in the US group. Radiologic complete response (rCR) was found in 35 patients (23.2 %) in the MRI group and 26 patients (16.7 %) in the US group. In the MRI and US groups, estimates were calculated respectively for sensitivity (87.7 % vs 91.4 %), specificity (56.8 % vs 33.3 %), PPV (86.2 % vs 73.8 %), NPV (60.0 % vs 65.4 %), and accuracy (80.1 % vs 72.4 %). In predicting pCR, MRI was more specific than US, but not sufficiently specific enough to be a valid predictor of pCR for omission of surgery. As an imaging method, MRI should be preferred when future studies investigating prediction of pCR in NACT patients are planned.

Axillary lymph node status is an important prognostic factor for breast cancer patients and sentinel lymph node biopsy (SLNB) is a less invasive surgical proxy. We examined if consecutively derived molecular subtypes from primary breast cancers provide additional predictive value for SLNB status. 1556 patients with a breast cancer > 10 mm underwent primary surgical procedure including SLNB and tumor specimens were assigned with a transcriptomics-based molecular subtype. 1020 patients had a negative sentinel node (SN) and 536 a positive. A significant association between tumor size and SN status (p p = 0.14) was found for BasL tumors. A BasL subtype was a predictor of an SN-negative status (p = 0.001, OR 0.58, 95% CI 0.38;0.90) and among the BasL, postmenopausal status was a predictor for SN-negative status (p = 0.01). Overall survival was significantly lower (p = 0.02) in patients with BasL tumors and a positive SN. Interestingly, we identified a significant correlation between hormone receptor activity and SN status within the BasL subtype. Taken together, molecular subtypes and hormone receptor activity of breast cancers add predictive value for SLNB status.

Cardiovascular diseases are one of the leading causes of mortality in the western world. Myocardial infarction is among the most prevalent and results in significant cell loss within the myocardium. Similarly, numerous drugs have been identified as having cardiotoxic side effects. The adult human heart is however unable to instigate an effective repair mechanism and regenerate the myocardium in response to such damage. This is in large part due to the withdrawal of cardiomyocytes (CMs) from the cell cycle. Thus, identifying, screening, and developing agents that could enhance the proliferative capacity of CMs holds great potential in cardiac regeneration. Human induced pluripotent stem cells (hiPSCs) and their cardiovascular derivatives are excellent tools in the search for such agents. This chapter outlines state-of-the art techniques for the two-dimensional differentiation and attainment of hiPSC-derived CMs and endothelial cells (ECs). Bioreactor systems and three-dimensional spheroids derived from hiPSC-cardiovascular derivatives are explored as platforms for drug discovery before focusing on relevant assays that can be employed to assess cell proliferation and viability.

Aims To develop and psychometrically test the Reasoning Skills (ReSki) test assessing undergraduate nursing applicants' reasoning skills for student selection purposes. Design A methodological cross-sectional design was applied for the psychometric testing. Methods The ReSki test was developed as part of a wider electronic entrance examination. The ReSki test included a case followed by three question sections assessing nursing applicants' reasoning skills according to the reasoning process. Item response theory was used for psychometric testing to assess item discrimination, difficulty and pseudoguessing parameters. The ReSki test was taken by 1056 nursing applicants in six Finnish Universities of Applied Sciences (28 May 2019). Results In the development process, the expert evaluations indicated acceptable content validity. In the psychometric testing, the test reliability was supported by item variance, the theoretical structure was supported by the correlation coefficients and the applicant mean performance supported an acceptable overall test difficulty. The item response theory indicated variance between the items' difficulty and discrimination ranges. However, most of the wrong items failed at being functional distractors. Conclusion The ReSki test is a new and valid objective assessment of undergraduate nursing applicants' reasoning skills. The item response theory provided item-level information that can be used for further development of the test, especially related to the revisions needed for the distractor items to achieve the desired level of difficulty. Impact What problem did the study address? The assessment of nursing applicants' reasoning skills is suggested, but there is a lack of admission tools. What were the main findings? The results provided support for the reliability and validity of the ReSki test. Item response theory indicated the need for further item-level improvement. Where and on whom will the research have an impact? The results may benefit higher education institutions and researchers when developing a test and/or student selection processes.

Background. The COVID-19 pandemic has led to many cases of pneumonia with extensive lung abnormalities on CT-scans. The consequences of COVID-19 pneumonia on survivors’ pulmonary function and quality of life are unknown. The purpose of this study is to examine the impact of COVID-19 pneumonia on pulmonary function, health-related quality of life (HRQoL) and perceived dyspnoea. Methods. A prospective longitudinal cohort study regarding patients discharged from our hospital after PCR-proven, non-critical COVID-19 pneumonia was conducted. Cases were classified as moderate or severe pneumonia according to WHO definitions. Six weeks post-discharge subjects underwent interviews and pulmonary function tests, and completed questionnaires to assess their HRQoL, perceived dyspnoea (Borgscale and mMRC), and symptoms of depression and anxiety (HADS). Results. 101 patients were included. Twenty-eight (27.7%) pneumonias were classified as moderate cases of COVID-19 pneumonia and 73 (72.3%) were classified as severe cases. Diffusion limitation (DLCOc, Highlights • Diffusion capacity is often abnormal six weeks after non-severe COVID 19 pneumonia. • Restriction is found in a minority (21%) of non-severe COVID 19 pneumonia survivors. • Quality of life is reduced in COVID19 pneumonia survivors six weeks after discharge.

Objectives Maintenance treatment with macrolide antibiotics has shown to be effective in reducing exacerbations in COPD patients. A major concern with prolonged treatment with antibiotics is the development of bacterial resistance. In this study we determined the effect of azithromycin on the development and acquisition of resistance to macrolides in the nasopharyngeal flora in COPD patients. Methods This study was part of the COLUMBUS trial, a randomised, double-blind, placebo-controlled trial to measure the effect of maintenance treatment with azithromycin in 92 COPD patients on the exacerbation rates during a 12-month period. In order to determine resistance to macrolides, we used a targeted metagenomic approach to measure the presence and relative abundance of specific macrolide resistance genes ermB, ermF and mefA in throat samples collected at different time-points during this 12-month period. Results There was no increased risk for acquisition of macrolide resistance genes in the azithromycin group compared to the placebo group in COPD patients. However, loss of the macrolide resistance gene ermB was increased overtime in the placebo treated group compared to the azithromycin group (n = 5 for the placebo group versus n = 0 for the azithromycin group at 12 months; p = 0.012). The change in relative abundance of the three macrolide-resistance genes showed that all but one (ermF) increased during treatment with azithromycin. Conclusions The acquisition rate of macrolide resistance genes in COPD patients treated with azithromycin maintenance therapy was limited, but the relative abundance of macrolide resistance genes increased significantly over time compared to placebo. This study was part of the COLUMBUS trial (Clinicaltrials.gov, NCT00985244).

A previous publication has shown that the in-plane polarization (IPP) component of a polarized 0.97-GeV/c deuteron beam in the COSY storage ring may acquire a polarization half-life in excess of 1000 s through a combination of beam bunching, electron cooling (prior to any spin manipulation), sextupole field adjustment, and a limitation of the beam intensity. This paper documents further tests pointing to additional gains in the IPP lifetime if cooling is active throughout the beam store., 11 pages, 6 figures Submitted to Physical Review Accelerators and Beams

Papillomas of the female breast is a relatively frequent lesion, and the majority are benign when excised. However, some may host malignant or premalignant areas. Consequently, it is a worldwide accepted principle to excise the lesion whenever diagnosed. However, this leads to a large number of patients having an unnecessary operation. The present study was designed to investigate whether we could find clinical, radiological and pathological factors in the preoperative, diagnostic setting that could identify patients hosting a benign papilloma in order to avoid operation. The patient material consisted of 260 patients, all with a preoperative diagnosis of a papillomatous process in core biopsy. The lesion was excised, and 71% had a benign lesion. The rest had lesions ranging from premalignant to malignant. In the clinical, radiological and histopathological investigations conducted, we were not able to identify factors that statistically significant could predict whether the lesion was benign or malignant. However, our data showed a higher prevalence of malignant and premalignant lesions for older patient, larger lesions, and lesions found at a longer distance from the papilla. We conclude that, since almost 30% of the patients in our study ended up with a premalignant or malignant diagnosis, where no statistically significant preoperative factors could indicate a benign outcome, operation is warranted in all patients with a preoperative diagnosis of a papillomatous lesion.

Developing alternative materials and methods of production and recycling is crucial to achieving more sustainable, circular textile practices. In addition to these, a shift in how textiles are perc...

In this paper, we present the University of Helsinki submissions to the WMT 2019 shared task on news translation in three language pairs: English-German, English-Finnish and Finnish-English. This year, we focused first on cleaning and filtering the training data using multiple data-filtering approaches, resulting in much smaller and cleaner training sets. For English-German, we trained both sentence-level transformer models and compared different document-level translation approaches. For Finnish-English and English-Finnish we focused on different segmentation approaches, and we also included a rule-based system for English-Finnish., To appear in WMT19

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples. We performed supervised and unsupervised approaches to proteomic data analysis to identify groups of samples sharing common characteristics that could be amenable to existing therapies. We found the heterogenous activation of multiple pathways, with PI3 K/AKT/mTOR signaling being the most common event. Some specific individualized therapeutic possibilities include the expression of oncogenic KIT in association with cytokeratin 15 and Erk1/2 positive tumors, both of which may have clinical value.

Axillary lymph node status has for long been the most important prognostic factor in patients with primary breast cancer [1]. Axillary lymph node dissection (ALND) provides the most accurate stagin...

Transcriptome analysis enables classification of breast tumors into molecular subtypes. BRCA1/2 predisposed patients are more likely to suffer from a basal-like subtype and this group of patients displays a more distinct phenotype and genotype. Hence, in-depth characterization of this separate entity is needed.Molecular subtyping was performed on a consecutive and unselected series of 1560 tumors from patients with primary breast cancer. Tumors were classified by the 256 gene expression signature (CIT) and associated with basic clinical characteristics and aggregated expression levels in the hallmark gene sets.Of the 1560 samples, 168 were classified basal-like and 120 patients were screened for BRCA1/2 mutations, resulting in 19 BRCA1/2 carriers, 95 non-carriers and six patients carried variants of unknown significance. The BRCA1/2 carriers were significantly younger and there were no carriers above 60 years of age. The tumors showed a loss in DNA-repair profile, as well as an upregulation in proliferative cancer signaling pathways. A robust molecular signature for identification of the BRCA1/2 - carriers was infeasible in the current cohort. Patients with a basal like breast cancer had the lowest median age and the largest median tumor size. They were almost exclusively diagnosed in disease stage III.Basal-like subtype is indeed a separate entity compared with other molecular breast cancer subtypes and the clinical course for this patient group should reflect the aggressiveness of this cancer. Taken together, patients being diagnosed with a basal-like breast cancer are in the youngest segment of breast cancer patients and are mainly diagnosed in stage III disease.

Drug resistance is a recurrent problem in the fight against malaria. Genetic and epidemiological surveillance of antimalarial resistant parasite alleles is crucial to guide drug therapies and clinical management. New antimalarial compounds are currently at various stages of clinical trials and regulatory evaluation. Using ∼2000 Plasmodium falciparum genome sequences, we investigated the genetic diversity of eleven gene-targets of promising antimalarial compounds and assessed their potential efficiency across malaria endemic regions. We determined if the loci are under selection prior to the introduction of new drugs and established a baseline of genetic variance, including potential resistant alleles, for future surveillance programmes., Graphical abstract Image 1, Highlights • Genetic diversity of 11gene-targets of new antimalarial compounds was investigated. • Genetic data was analysed for 18 malaria endemic countries. • No signals of selective pressure was observed. • A mutation linked to resistance to a new antimalarial was found in African parasites. • Amino-acid changes close to reported antimalarial resistant mutations were detected.

Background: The current standard method for locating nonpalpable breast lesions is wire guided localization (WGL) despite several methodological difficulties. Radioactive Seed Localization (RSL) has been developed to reduce these difficulties. The aim of this randomized trial was to compare the rate of positive resection margins between RSL and WGL in patients with nonpalpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS). Material and Methods: Patients with nonpalpable IBC or DCIS visible on ultrasound were randomized to either of the two localization methods. Primary outcome was margin status at the final pathological evaluation. According to Danish standard in the study period margins were defined positive if cancer cells were found < 2mm from the inked margin. Secondary outcomes were duration of the surgical procedure, weight of the excised specimen and patient's pain perception. χ2-test, Fisher's exact test and Wilcoxon rank-sum test, respectively, were used to test differences between groups. Level of statistical significance was set to 5%. The average activity of seeds used in the trial was 1.70 MBq (range 0.7-3.27). Results: 413 cases representing 409 patients were randomized; 207 were allocated to RSL and 206 to WGL. 23 cases, who did not meet inclusion criteria, chose to withdraw, or had a change in surgical management, were excluded. The remaining 390 were included in the analysis. Patient, surgical and pathological characteristics between the two groups were alike, except for significantly more patients with DCIS in the WGL group (5.1% vs 0.5%). Significantly more cases in the WGL group (9.7%) needed additional localization compared to the RSL group (2.1%) (p=0.0014). In all cases but one in the RSL group, the index lesion was removed. Margins were positive in 23 cases (11.8%) in the RSL group compared to 26 cases (13.3%) in the WGL group. We were not able to detect a difference in margin status between the two groups (p=0.65). For IBC only, the number of positive margins was 22 (11.3%) in the RSL group and 21 (11.4%) in the WGL group (p=0.997). There was no difference between the two groups in the amount of tissue removed whether the analysis was done on the primary excision (p=0.18) or the total weight including intraoperative re-excisions (p=0.33). There was no difference in pain perception between the two groups whether patients who received local anesthesia were kept in the analysis (p=0.28) or excluded (p=0.91). Local anesthesia was used more frequently in the RSL group. Finally, there was no difference in the duration of the surgical procedure (p=0.12), the complication rate (p=0.89) or the identification rate for SN (p=1.0). Conclusions: We were not able to detect any differences considering positive margins, patient's pain perception or duration of the surgical procedure between the two localization methods. However, RSL offers a major logistic advantage, as the seed localization can be done several days before surgery without any risk or discomfort for the patient, with a low proportion of patients needing additional localization. So the RSL procedure has now been found preferable at our institutions. Citation Format: Langhans L, Tvedskov TF, Klausen TL, Jensen M-B, Talman M-L, Vejborg I, Benian C, Roslind A, Hermansen J, Oturai PS, Bentzon N, Kroman N. Radioactive seed localization versus wire guided localization of nonpalpable invasive and in situ breast cancer: A Danish multicenter randomized controlled trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-08.

The annual image competition, Reflections of Research, provides a glimpse into the cutting-edge heart and circulatory research funded by the British Heart Foundation

All work done in this paper covers the analysis on the plate scale, which will be a reference to the composite radome shell. This study presents the effects of a cutout on the buckling behavior of symmetric cross-ply (0,90)s and symmetric angle-ply (45,- 45)s types laminated composite square plates using Finite Element Method (FEM) based on Equivalent Single-Layer Theory (ESLT). These special orthotropic laminated composite plates were examined under the uniaxial compressive loading using Composite Materials Module of COMSOL Multiphysics Software. Structural analyses were performed in order to predict the effects of a circular cutout size, location of cutout, plate thickness (t), aspect ratio (proportion of hole diameter-(d) to edge length-(b) of plate), and various boundary conditions (simply supported and clamped). Convergence study has been carried out by comparing the results obtained from the numerical results of previous work available in the literature. Some general results have been obtained depending on the variables examined. In the buckling load results of three different mesh sizes, it was seen that the critical buckling load converged more as the mesh size decreased. We found that the plates which were simply supported against the reduction in the critical buckling load on the square plates containing cutouts were more sensitive than the clamped plates. In cases where the cutout diameter was constant, it was seen that the increase in the edge length of the square plate caused a decrease in the buckling load.

Doxorubicin (DOX) is a widely used anticancer drug which, unfortunately, induces dose-related cardiotoxicity. A deep understanding of DOX’s toxicity is still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose DOX treatments. Thus, a more precise model of DOX cardiotoxicity is needed to more accurately simulate clinical scenario. The first aim of this study was to establish an in vitro model of long-term low-dose administration of DOX utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The second aim was to investigate if novel GATA4-targeted compounds can protect CMs from DOX toxicity. Acute toxicity was studied in both primary neonatal rat ventricular cardiomyocytes (NRVCs) and hiPSC-CMs. The cells were exposed to 0.1-3 μM DOX for 48 h, after which the lactate dehydrogenase and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were carried out. To study long-term toxicity, hiPSC-CMs were exposed to 100 nM DOX for up to 14 days. MTT assay and high-content analysis were carried out after 4, 7 and 14-day exposures. The effect of the test compound was studied by exposing the cells simultaneously to DOX and the compound. A 48-hour exposure to DOX at 1 and 3 μM concentrations induced more than 62% reductions in both NRVC and hiPSC-CM viability, whereas a 14-day exposure to 100 nM DOX induced a 26% reduction in hiPSC-CM viability. A 4-day exposure to 100 nM DOX induced a 3.1-fold increase in the percentage of cells positive for pro-B-type natriuretic peptide (proBNP) compared to control. When the cells were exposed simultaneously to 100 nM DOX and the test compound (10 μM), the percentage of proBNP+ cells increased only 1.4-fold compared to control. However, over 14-day exposure the compound at 10 μM concentration reduced hiPSC-CM viability 50% compared to control. A long-term exposure of hiPSC-CMs can be utilized as an in vitro model to investigate the mechanisms of delayed DOX-induced cardiotoxicity. The GATA4-targeted test compound exhibited cardioprotective potential against subacute DOX toxicity. Over chronic exposure the compound was, however, toxic to CMs, indicating that further structural optimization is required to develop non-toxic derivatives.

Objective: This study sought to investigate whether a multistep process was also evident in an Australian amyotrophic lateral sclerosis (ALS) population. Methods: Mortality rates for ALS patients (years 2007-2016) were obtained from the Australian Institute of Health and Welfare (AIHW). The log incidence of ALS, as reflected by crude mortality rates, was regressed against log of age disease onset. Results: From a total population of 24 million, 6524 cases of ALS were identified. A linear relation between the log incidence and log age was identified, with r2 value of 0.99, indicating that ALS is a multistep process. The linear slope estimate was 5.0, suggesting that six steps were required for development of ALS. Conclusions: This study established a linear relationship between log incidence and log age onset in an Australia ALS population, consistent with a multistep process. Identification of these steps will likely be of therapeutic benefit in ALS.