Real-world keystroke dynamics are a potentially valid biomarker for clinical disability in multiple sclerosis

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps < 0.001. Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS

Aerobic degradation of phytoplankton debris dominated by Phaeocystis sp in different physiological stages of growth

The aerobic degradation of phytoplankton debris collected in Dutch coastal waters on 2 days in 1991 (15 April and 8 May), representing 2 physiological stages of a phytoplankton spring bloom dominated by Phaeocystis sp., was studied in batch culture experiments. The bacterial production and the concentrations of particulate organic carbon (POC) and dissolved organic carbon (DOG) were monitored over a period of 102 d. Bacterial numbers and biomass were followed for 35 d. All experiments showed a rapid metabolic response of bacteria and a sharp decrease in the concentration of POC and DOC during the first days of the experiments. Thereafter bacterial production rates remained constant, and POC and DOC decreased slowly. Apparently, the phytoplankton debris consisted of a labile, rapidly degradable fraction and a refractory, slowly degradable fraction. The labile fraction comprised approximately 50 % of the debris, and was degraded with a bacterial carbon conversion efficiency of between 10 and 20%. There were no indications that antibiotic compounds present in the algal debris inhibited the degradation. Acrylate, a proposed antibiotic compound which was present in the algal debris, was rapidly degraded in a control experiment. The percentage of the material that had been degraded after 102 d was highest in the experiment with material collected in May. It was concluded that during the early phase of the bloom, more refractory compounds are produced

Two-channel Kondo effect and renormalization flow with macroscopic quantum charge states

Many-body correlations and macroscopic quantum behaviors are fascinating condensed matter problems. A powerful test-bed for the many-body concepts and methods is the Kondo model which entails the coupling of a quantum impurity to a continuum of states. It is central in highly correlated systems and can be explored with tunable nanostructures. Although Kondo physics is usually associated with the hybridization of itinerant electrons with microscopic magnetic moments, theory predicts that it can arise whenever degenerate quantum states are coupled to a continuum. Here we demonstrate the previously elusive `charge' Kondo effect in a hybrid metal-semiconductor implementation of a single-electron transistor, with a quantum pseudospin-1/2 constituted by two degenerate macroscopic charge states of a metallic island. In contrast to other Kondo nanostructures, each conduction channel connecting the island to an electrode constitutes a distinct and fully tunable Kondo channel, thereby providing an unprecedented access to the two-channel Kondo effect and a clear path to multi-channel Kondo physics. Using a weakly coupled probe, we reveal the renormalization flow, as temperature is reduced, of two Kondo channels competing to screen the charge pseudospin. This provides a direct view of how the predicted quantum phase transition develops across the symmetric quantum critical point. Detuning the pseudospin away from degeneracy, we demonstrate, on a fully characterized device, quantitative agreement with the predictions for the finite-temperature crossover from quantum criticality.Comment: Letter (5 pages, 4 figures) and Methods (10 pages, 6 figures

The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5(+) malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5(+)-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies

Clostridium difficile ribotypes in Austria: a multicenter, hospital-based survey

A prospective, noninterventional survey was conducted among Clostridium difficile positive patients identified in the time period of July until October 2012 in 18 hospitals distributed across all nine Austrian provinces. Participating hospitals were asked to send stool samples or isolates from ten successive patients with C.difficile infection to the National Clostridium difficile Reference Laboratory at the Austrian Agency for Health and Food Safety for PCR-ribotyping and in vitro susceptibility testing. A total of 171 eligible patients were identified, including 73 patients with toxin-positive stool specimens and 98 patients from which C. difficile isolates were provided. Of the 159 patients with known age, 127 (74.3 %) were 65 years or older, the median age was 76 years (range: 9–97 years), and the male to female ratio 2.2. Among these patients, 73 % had health care-associated and 20 % community-acquired C. difficile infection (indeterminable 7 %). The all-cause, 30-day mortality was 8.8 % (15/171). Stool samples yielded 46 different PCR-ribotypes, of which ribotypes 027 (20 %), 014 (15.8 %), 053 (10.5 %), 078 (5.3 %), and 002 (4.7 %) were the five most prevalent. Ribotype 027 was found only in the provinces Vienna, Burgenland, and Lower Austria. Severe outcome of C. difficile infection was found to be associated with ribotype 053 (prevalence ratio: 3.04; 95 % CI: 1.24, 7.44), not with the so-called hypervirulent ribotypes 027 and 078. All 027 and 053 isolates exhibited in vitro resistance against moxifloxacin. Fluoroquinolone use in the health care setting must be considered as a factor favoring the spread of these fluoroquinolone resistant C. difficile clones

An accurate and efficient identification of children with psychosocial problems by means of computerized adaptive testing

Background: Questionnaires used by health services to identify children with psychosocial problems are often rather short. The psychometric properties of such short questionnaires are mostly less than needed for an accurate distinction between children with and without problems. We aimed to assess whether a short Computerized Adaptive Test (CAT) can overcome the weaknesses of short written questionnaires when identifying children with psychosocial problems. Method: We used a Dutch national data set obtained from parents of children invited for a routine health examination by Preventive Child Healthcare with 205 items on behavioral and emotional problems (n = 2,041, response 84%). In a random subsample we determined which items met the requirements of an Item Response Theory (IRT) model to a sufficient degree. Using those items, item parameters necessary for a CAT were calculated and a cut-off point was defined. In the remaining subsample we determined the validity and efficiency of a Computerized Adaptive Test using simulation techniques, with current treatment status and a clinical score on the Total Problem Scale (TPS) of the Child Behavior Checklist as criteria. Results: Out of 205 items available 190 sufficiently met the criteria of the underlying IRT model. For 90% of the children a score above or below cut-off point could be determined with 95% accuracy. The mean number of items needed to achieve this was 12. Sensitivity and specificity with the TPS as a criterion were 0.89 and 0.91, respectively. Conclusion: An IRT-based CAT is a very promising option for the identification of psychosocial problems in children, as it can lead to an efficient, yet high-quality identification. The results of our simulation study need to be replicated in a real-life administration of this CAT