"Schöne Welt, du gingst in Fransen!" : Auf der Suche nach dem authentischen deutschen Tango

Voluntary motor deficits are a common feature in Huntington's disease (HD), characterised by movement slowing and performance inaccuracies. This deficit may be exacerbated when visual cues are restricted.To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets.Nine premanifest HD (pre-HD), nine early symptomatic HD (symp-HD) and nine matched controls completed a motor task incorporating Fitts' law, a model of human movement enabling the quantification of movement timing, via the manipulation of task difficulty (i.e., target size, and distance between targets). The task required participants to make reciprocal movements under cued and blind conditions. Dwell times (time stationary between movements), speed, accuracy and variability of movements were compared between groups.Symp-HD showed significantly prolonged and less consistent movement times, compared with controls and pre-HD. Furthermore, movement planning and online control were significantly impaired in symp-HD, compared with controls and pre-HD, evidenced by prolonged dwell times and deceleration times. Speed and accuracy were comparable across groups, suggesting that group differences observed in movement time, variability, dwell time and deceleration time were evident over and above simple performance measures. The presence of cues resulted in greater movement time variability in symp-HD, compared with pre-HD and controls, suggesting that the deficit in movement consistency manifested only in response to targeted movements.Collectively, these findings provide evidence of a deficiency in both motor planning, particularly in relation to movement timing and online control, which became exacerbated as a function of task difficulty during symp-HD stages. These variables may provide a more sensitive measure of motor dysfunction than speed and/or accuracy alone in symp-HD

Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir

<p>Abstract</p> <p>Background</p> <p>Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available.</p> <p>Materials and methods</p> <p>The <it>integrase </it>coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against the ROD (group A) or EHO (group B) reference strains and polymorphic or conserved positions were analyzed.</p> <p>To select for raltegravir (RAL)-resistant variants <it>in vitro</it>, the ROD strain was cultured under increasing sub-optimal RAL concentrations for successive rounds. The phenotype of the selected variants was assessed using an MTT assay.</p> <p>Results</p> <p>We describe <it>integrase </it>gene polymorphisms in HIV-2 clinical isolates from 45 patients. Sixty-seven percent of the integrase residues were conserved. The HHCC Zinc coordination motif, the catalytic triad DDE motif, and AA involved in IN-DNA binding and correct positioning were highly conserved and unchanged with respect to HIV-1 whereas the connecting residues of the N-terminal domain, the dimer interface and C-terminal LEDGF binding domain were highly conserved but differed from HIV-1. The N155 H INI resistance-associated mutation (RAM) was detected in the virus population from one ARV-treated, INI-naïve patient, and the 72I and 201I polymorphisms were detected in samples from 36 and 38 patients respectively. No other known INI RAM was detected.</p> <p>Under RAL selective pressure <it>in vitro</it>, a ROD variant carrying the Q91R+I175M mutations was selected. The Q91R and I175M mutations emerged simultaneously and conferred phenotypic resistance (13-fold increase in IC₅₀). The Q91R+I175M combination was absent from all clinical isolates. Three-dimensional modeling indicated that residue 91 lies on the enzyme surface, at the entry of a pocket containing the DDE catalytic triad and that adding a positive charge (Gln to Arg) might compromise IN-RAL affinity.</p> <p>Conclusions</p> <p>HIV-2 polymorphisms from 45 INI-naïve patients are described. Conserved regions as well as frequencies of HIV-2 IN polymorphisms were comparable to HIV-1. Two new mutations (Q91R and I175M) that conferred high resistance to RAL were selected <it>in vitro</it>, which might affect therapeutic outcome.</p

Identity, accent aim, and motivation in second language users:new Scottish Gaelic speakers’ use of phonetic variation

This paper examines the use of phonetic variation in word-final rhotics among nineteen adult new speakers of Scottish Gaelic, i.e. speakers who did not acquire the language through intergenerational transmission. Our speakers learned Gaelic as adults and are now highly advanced users of the language. We consider variation in their rhotic productions compared to the productions of six older traditional speakers. Previous approaches to variation in second language users have either focussed on how variable production will eventually result in native-like ‘target’ forms (Type 1 study), or have investigated the extent to which second language users reproduce patterns of variation similar to ‘native speakers’ (Type 2 study). We additionally draw on sociocultural approaches to Second Language Acquisition and apply notions of accent aim, identity construction and learning motivation in order to fully explore the data. In doing so, we advocate a ‘Type 3’ approach to variation in second language users

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

The utility of new motor control paradigms in multiple sclerosis: an investigation of motor overflow and reciprocal aiming

Multiple Sclerosis (MS) is a neurological disease marked by widespread inflammation, demyelination and neurodegeneration in both white and gray matter structures of the brain and spinal cord. The widespread networks which mediate motor control are commonly damaged in MS, with up to 80% of MS patients experiencing motor symptoms such as muscle weakness, poor fine motor control and gait abnormalities. Despite the high prevalence of motor symptoms in MS, commonly used assessments overlook subtle, yet potentially important, aspects of motor control, such as the presence of involuntary movements, movement kinematics, movement planning, and online control of movement. This thesis investigates motor overflow and reciprocal aiming in MS to provide new insights into these subtle and unobservable aspects of MS-related motor dysfunction. This research provides preliminary data which may lead to the development of new assessments of motor symptoms in MS which are not only capable of capturing a broad range of motor symptoms in; but that may be sensitive to neuropathological changes, disease progression and therapeutic intervention. Motor overflow refers to involuntary movement that can accompany production of voluntary movement. The neurophysiological origins of motor overflow are not fully understood though it is evident that the corpus callosum (CC) is an important structure in the production and suppression of this phenomenon. Being the largest white matter tract in the central nervous system, the CC is commonly damaged in MS. Therefore it was considered conceivable that overflow may be exacerbated in MS and measurement of overflow might provide an index of MS-related CC pathology. Reciprocal aiming involves a two-stage process: 1) an initial planned ballistic movement which brings the limb close to the target, and 2) accurate movement of the limb to the target. These stages of movement require functional movement planning and online control respectively. By objectively measuring reciprocal aiming, unobservable aspects of movement planning, online control and movement accuracy can be measured. Studies 1 and 2 (Chapters 4 and 5) of this thesis used a motor overflow task to characterise voluntary force control and involuntary motor overflow in MS and control participants. Study 1 (Chapter 4) found that motor overflow levels did not differ between MS and control participants. However motor overflow was related to disease progression. These findings suggest that motor overflow may be exacerbated in more advanced stages of the disease. Motor overflow did not correlate with MRI measures of CC damage suggesting that structures other than the CC play an important role in its production and suppression. Study 2 (Chapter 5) demonstrated that motor overflow was significantly exacerbated in MS participants compared with controls which is likely a consequence of the inclusion of an MS sample with more advanced disease compared to the sample in Study 1 (Chapter 4). Similarly to Study 1 (Chapter 4), overflow was related to disease progression. The study also found that voluntary motor stability was significantly compromised in MS and poorer motor stability correlated with disease progression. Incorporating a concurrent cognitive test in conjunction with the overflow task did not differentially influence motor overflow or motor stability in MS compared to controls. These findings suggest that while exacerbated motor overflow and poorer motor stability may be features of MS, concurrent tasking is preserved. Studies 3 and 4 (Chapters 6 and 7) used a reciprocal aiming task to characterise movement planning, online control and accuracy in MS and control participants. Study 3 (Chapter 6) found that MS participants’ movements were equally as accurate as controls, however they displayed significant deficits in movement planning and online control of movement. MS participants were also disproportionately affected by changes in task difficulty compared with controls. Study 4 (Chapter 7) incorporated a concurrent cognitive task with the reciprocal aiming task. As found in Study 2 (Chapter 5), MS participants were not differentially affected by a concurrent task compared with controls; confirming the preserved dual tasking ability observed in these individuals. Several important conclusions can be drawn from this research. Firstly, it is clear that MS patients experience a range of motor symptoms over and above those that are clinically evident and commonly measured using traditional motor assessments. These symptoms affect both voluntary (movement planning, accuracy, online control, stability) and involuntary (motor overflow) motor functions. However these deficits do not impact on their ability to perform motor and cognitive tasks concurrently. Secondly, the motor overflow task did not consistently differentiate MS and control participants and was not reflective of CC damage. Therefore, with current data, the motor overflow task is unlikely to possess clinical utility in the detection of early and subtle changes in MS. Thirdly, the Fitts’ law reciprocal aiming task is capable of detecting subtle changes across a range of movement variables. Given its ability to capture these subtle changes, and that it is quick and easy to administer, it is proposed that the Fitts’ law reciprocal aiming task possesses clinical utility. The research presented in this thesis provides important preliminary data for the development of more sensitive and objective motor assessments in MS. Such assessments have the potential to provide supplementary measures of disease status, progression, and efficacy of novel treatments, particularly in proof of concept studies

The utility of new motor control paradigms in multiple sclerosis: an investigation of motor overflow and reciprocal aiming

Multiple Sclerosis (MS) is a neurological disease marked by widespread inflammation, demyelination and neurodegeneration in both white and gray matter structures of the brain and spinal cord. The widespread networks which mediate motor control are commonly damaged in MS, with up to 80% of MS patients experiencing motor symptoms such as muscle weakness, poor fine motor control and gait abnormalities. Despite the high prevalence of motor symptoms in MS, commonly used assessments overlook subtle, yet potentially important, aspects of motor control, such as the presence of involuntary movements, movement kinematics, movement planning, and online control of movement. This thesis investigates motor overflow and reciprocal aiming in MS to provide new insights into these subtle and unobservable aspects of MS-related motor dysfunction. This research provides preliminary data which may lead to the development of new assessments of motor symptoms in MS which are not only capable of capturing a broad range of motor symptoms in; but that may be sensitive to neuropathological changes, disease progression and therapeutic intervention. Motor overflow refers to involuntary movement that can accompany production of voluntary movement. The neurophysiological origins of motor overflow are not fully understood though it is evident that the corpus callosum (CC) is an important structure in the production and suppression of this phenomenon. Being the largest white matter tract in the central nervous system, the CC is commonly damaged in MS. Therefore it was considered conceivable that overflow may be exacerbated in MS and measurement of overflow might provide an index of MS-related CC pathology. Reciprocal aiming involves a two-stage process: 1) an initial planned ballistic movement which brings the limb close to the target, and 2) accurate movement of the limb to the target. These stages of movement require functional movement planning and online control respectively. By objectively measuring reciprocal aiming, unobservable aspects of movement planning, online control and movement accuracy can be measured. Studies 1 and 2 (Chapters 4 and 5) of this thesis used a motor overflow task to characterise voluntary force control and involuntary motor overflow in MS and control participants. Study 1 (Chapter 4) found that motor overflow levels did not differ between MS and control participants. However motor overflow was related to disease progression. These findings suggest that motor overflow may be exacerbated in more advanced stages of the disease. Motor overflow did not correlate with MRI measures of CC damage suggesting that structures other than the CC play an important role in its production and suppression. Study 2 (Chapter 5) demonstrated that motor overflow was significantly exacerbated in MS participants compared with controls which is likely a consequence of the inclusion of an MS sample with more advanced disease compared to the sample in Study 1 (Chapter 4). Similarly to Study 1 (Chapter 4), overflow was related to disease progression. The study also found that voluntary motor stability was significantly compromised in MS and poorer motor stability correlated with disease progression. Incorporating a concurrent cognitive test in conjunction with the overflow task did not differentially influence motor overflow or motor stability in MS compared to controls. These findings suggest that while exacerbated motor overflow and poorer motor stability may be features of MS, concurrent tasking is preserved. Studies 3 and 4 (Chapters 6 and 7) used a reciprocal aiming task to characterise movement planning, online control and accuracy in MS and control participants. Study 3 (Chapter 6) found that MS participants’ movements were equally as accurate as controls, however they displayed significant deficits in movement planning and online control of movement. MS participants were also disproportionately affected by changes in task difficulty compared with controls. Study 4 (Chapter 7) incorporated a concurrent cognitive task with the reciprocal aiming task. As found in Study 2 (Chapter 5), MS participants were not differentially affected by a concurrent task compared with controls; confirming the preserved dual tasking ability observed in these individuals. Several important conclusions can be drawn from this research. Firstly, it is clear that MS patients experience a range of motor symptoms over and above those that are clinically evident and commonly measured using traditional motor assessments. These symptoms affect both voluntary (movement planning, accuracy, online control, stability) and involuntary (motor overflow) motor functions. However these deficits do not impact on their ability to perform motor and cognitive tasks concurrently. Secondly, the motor overflow task did not consistently differentiate MS and control participants and was not reflective of CC damage. Therefore, with current data, the motor overflow task is unlikely to possess clinical utility in the detection of early and subtle changes in MS. Thirdly, the Fitts’ law reciprocal aiming task is capable of detecting subtle changes across a range of movement variables. Given its ability to capture these subtle changes, and that it is quick and easy to administer, it is proposed that the Fitts’ law reciprocal aiming task possesses clinical utility. The research presented in this thesis provides important preliminary data for the development of more sensitive and objective motor assessments in MS. Such assessments have the potential to provide supplementary measures of disease status, progression, and efficacy of novel treatments, particularly in proof of concept studies

Evaluation of saliva as an alternative matrix for monitoring plasma Zidovudine, Lamivudine and nevirapine concentrations in Rwanda

Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland-Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follow: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result to non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration