First Constraints on the Epoch of Reionization Using the Non-Gaussianity of the Kinematic Sunyaev-Zel'dovich Effect from the South Pole Telescope and Herschel-SPIRE Observations.

We report results from an analysis aimed at detecting the trispectrum of the kinematic Sunyaev-Zel'dovich (kSZ) effect by combining data from the South Pole Telescope (SPT) and Herschel-SPIRE experiments over a 100 deg^{2} field. The SPT observations combine data from the previous and current surveys, namely SPTpol and SPT-3G, to achieve depths of 4.5, 3, and 16 µK-arcmin in bands centered at 95, 150, and 220 GHz. For SPIRE, we include data from the 600 and 857 GHz bands. We reconstruct the velocity-induced large-scale correlation of the small-scale kSZ signal with a quadratic estimator that uses two cosmic microwave background (CMB) temperature maps, constructed by optimally combining data from all the frequency bands. We reject the null hypothesis of a zero trispectrum at 10.3σ level. However, the measured trispectrum contains contributions from both the kSZ and other undesired components, such as CMB lensing and astrophysical foregrounds, with kSZ being sub-dominant. We use the agora simulations to estimate the expected signal from CMB lensing and astrophysical foregrounds. After accounting for the contributions from CMB lensing and foreground signals, we do not detect an excess kSZ-only trispectrum and use this nondetection to set constraints on reionization. By applying a prior based on observations of the Gunn-Peterson trough, we obtain an upper limit on the duration of reionization of Δz_{re,50}<4.5 (95% confidence level). We find these constraints are fairly robust to foregrounds assumptions. This trispectrum measurement is independent of, but consistent with, Planck's optical depth measurement. This result is the first constraint on the epoch of reionization using the non-Gaussian nature of the kSZ signal.

Reconstruction of occluded pelvis markers during marker-based motion capture with industrial exoskeletons.

Industrial back support exoskeletons are a promising solution to alleviate lumbar musculoskeletal strain. Due to the complexity of spinal loading, evaluation of EMG data alone has been considered insufficient to assess their support effects, and complementary kinematic and dynamic data are required. However, the acquisition of marker-based kinematics is challenging with exoskeletons, as anatomical reference points, particularly on the pelvis, are occluded by exoskeleton structures. The aim of this study was therefore to develop and validate a method to reliably reconstruct the occluded pelvic markers. The movement data of six subjects, for whom pelvic markers could be placed while wearing an exoskeleton, were used to test the reconstructions and compare them to anatomical landmarks during lifting, holding and walking. Two separate approaches were used for the reconstruction. One used a reference coordinate system based on only exoskeleton markers (EXO), as has been suggested in the literature, while our proposed method adds a technical marker in the lumbar region (LUMB) to compensate for any shifting between exoskeleton and pelvis. Reconstruction with EXO yielded on average an absolute linear deviation of 54 mm ± 16 mm (mean ± 1SD) compared to anatomical markers. The additional marker in LUMB reduced mean deviations to 14 mm ± 7 mm (mean ± 1SD). Both methods were compared to reference values from the literature for expected variances due to marker placement and soft tissue artifacts. For LUMB 99% of reconstructions were within the defined threshold of 24 mm ±9 mm while for EXO 91% were outside.

Effect of robotic tilt table verticalization on recovery in patients with disorders of consciousness: a randomized controlled trial.

Verticalization is a common therapeutic intervention during rehabilitation of patients with disorders of consciousness (DoC). The Erigo®Pro is a robotic tilt-table (RTT) with built-in stepping unit for the lower extremities to prevent orthostatic hypotension during verticalization. In addition, the system also provides functional electrical stimulation (FES) of muscles of the lower extremities. In this randomized controlled clinical trial (RCT), 47 patients with subacute DoC received a 4-week verticalization regime (16 verticalization sessions) and were allocated to one of three experimental groups: (1) verticalization by means of RTT with FES, (2) by means of RTT without FES, or (3) by conventional physiotherapy (CPT). Level of consciousness (LoC), spasticity, functional independence in daily activities, and functional brain connectivity measured by means of high-density quantitative EEG were assessed at baseline, directly after the verticalization program and after 6 months. There was a similar clinical improvement in all three experimental groups. RTT was not associated with an effect on any of the clinical outcomes. Verticalization or mobilization time during the study period was significantly positively correlated with recovery of consciousness (rho = 0.494, p < 0.001) in the short term and showed a statistical trend at the 6 months follow-up (rho = 0.244, p = 0.078). In conclusion, RTT treatment is not more effective in promoting recovery of consciousness than CPT in subacute DoC patients. Yet, our data suggest, that verticalization may be an important and feasible rehabilitation intervention in this group of patients. ClinicalTrials.gov NCT Number NCT02639481, registered on December 24, 2015.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

PerBrain: a multimodal approach to personalized tracking of evolving state-of-consciousness in brain-injured patients: protocol of an international, multicentric, observational study.

BACKGROUND: Disorders of consciousness (DoC) are severe neurological conditions in which consciousness is impaired to various degrees. They are caused by injury or malfunction of neural systems regulating arousal and awareness. Over the last decades, major efforts in improving and individualizing diagnostic and prognostic accuracy for patients affected by DoC have been made, mainly focusing on introducing multimodal assessments to complement behavioral examination. The present EU-funded multicentric research project "PerBrain" is aimed at developing an individualized diagnostic hierarchical pathway guided by both behavior and multimodal neurodiagnostics for DoC patients. METHODS: In this project, each enrolled patient undergoes repetitive behavioral, clinical, and neurodiagnostic assessments according to a patient-tailored multi-layer workflow. Multimodal diagnostic acquisitions using state-of-the-art techniques at different stages of the patients' clinical evolution are performed. The techniques applied comprise well-established behavioral scales, innovative neurophysiological techniques (such as quantitative electroencephalography and transcranial magnetic stimulation combined with electroencephalography), structural and resting-state functional magnetic resonance imaging, and measurements of physiological activity (i.e. nasal airflow respiration). In addition, the well-being and treatment decision attitudes of patients' informal caregivers (primarily family members) are investigated. Patient and caregiver assessments are performed at multiple time points within one year after acquired brain injury, starting at the acute disease phase. DISCUSSION: Accurate classification and outcome prediction of DoC are of crucial importance for affected patients as well as their caregivers, as individual rehabilitation strategies and treatment decisions are critically dependent on the latter. The PerBrain project aims at optimizing individual DoC diagnosis and accuracy of outcome prediction by integrating data from the suggested multimodal examination methods into a personalized hierarchical diagnosis and prognosis procedure. Using the parallel tracking of both patients' neurological status and their caregivers' mental situation, well-being, and treatment decision attitudes from the acute to the chronic phase of the disease and across different countries, this project aims at significantly contributing to the current clinical routine of DoC patients and their family members. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04798456 . Registered 15 March 2021 - Retrospectively registered.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

Dataset for multidimensional assessment to incentivise decentralised energy investments in Sub-Saharan Africa.

In this data article, we present datasets from the construction of a composite indicator, the Photovoltaic Decentralised Energy Investment (PV-DEI) index, presented in detail in [1]. This article consists of a comprehensive energy-related data collected in practice from several sources, and from the outputs of the methodology described in [1]. The PV-DEI was designed and developed to measure the multidimensional factors that currently direct decentralised renewable energy investments. The PV-DEI index includes 52 indicators and was constructed because factors stimulating investment cannot be captured by a single indicator, e.g. competitiveness, affordability, or governance [1]. The PV-DEI index was built in alignment with a theoretical framework guided by an extensive review of the literature surrounding investment in decentralised Photovoltaic (PV), which led to the selection of its indicators. The structure of the PV-DEI was evaluated for its soundness using correlational assessments and principal component analyses (PCA). The raw data provided in this article can enable stakeholders to focus on specific country indicators, and how scores on these indicators contributed to a countries overall rank within the PV-DEI index. The data can be used to weight indicators depending on the specifications of several different stakeholders (such as NGOs, private sector or international institutions).

Broadband, millimeter-wave antireflection coatings for large-format, cryogenic aluminum oxide optics.

We present two prescriptions for broadband ($ {\sim} 77 - 252\;{\rm GHz} $), millimeter-wave antireflection coatings for cryogenic, sintered polycrystalline aluminum oxide optics: one for large-format (700 mm diameter) planar and plano-convex elements, the other for densely packed arrays of quasi-optical elements-in our case, 5 mm diameter half-spheres (called "lenslets"). The coatings comprise three layers of commercially available, polytetrafluoroethylene-based, dielectric sheet material. The lenslet coating is molded to fit the 150 mm diameter arrays directly, while the large-diameter lenses are coated using a tiled approach. We review the fabrication processes for both prescriptions, then discuss laboratory measurements of their transmittance and reflectance. In addition, we present the inferred refractive indices and loss tangents for the coating materials and the aluminum oxide substrate. We find that at 150 GHz and 300 K the large-format coating sample achieves $ (97 \pm 2)\% $ transmittance, and the lenslet coating sample achieves $ (94 \pm 3)\% $ transmittance.

European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

QSAR-derived affinity fingerprints (part 1): fingerprint construction and modeling performance for similarity searching, bioactivity classification and scaffold hopping.

An affinity fingerprint is the vector consisting of compound's affinity or potency against the reference panel of protein targets. Here, we present the QAFFP fingerprint, 440 elements long in silico QSAR-based affinity fingerprint, components of which are predicted by Random Forest regression models trained on bioactivity data from the ChEMBL database. Both real-valued (rv-QAFFP) and binary (b-QAFFP) versions of the QAFFP fingerprint were implemented and their performance in similarity searching, biological activity classification and scaffold hopping was assessed and compared to that of the 1024 bits long Morgan2 fingerprint (the RDKit implementation of the ECFP4 fingerprint). In both similarity searching and biological activity classification, the QAFFP fingerprint yields retrieval rates, measured by AUC (~ 0.65 and ~ 0.70 for similarity searching depending on data sets, and ~ 0.85 for classification) and EF5 (~ 4.67 and ~ 5.82 for similarity searching depending on data sets, and ~ 2.10 for classification), comparable to that of the Morgan2 fingerprint (similarity searching AUC of ~ 0.57 and ~ 0.66, and EF5 of ~ 4.09 and ~ 6.41, depending on data sets, classification AUC of ~ 0.87, and EF5 of ~ 2.16). However, the QAFFP fingerprint outperforms the Morgan2 fingerprint in scaffold hopping as it is able to retrieve 1146 out of existing 1749 scaffolds, while the Morgan2 fingerprint reveals only 864 scaffolds.

Detection of CMB-Cluster Lensing using Polarization Data from SPTpol.

We report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg^{2} survey at the locations of roughly 18 000 clusters with richness λ≥10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43±0.40)×10^{14}M_{⊙} which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.

[Cost analysis as a tool for assessing the efficacy of intensive care units]. / Kosten als Instrument zur Effizienzbeurteilung intensivmedizinischer Funktionseinheiten.

BACKGROUND: The German "Hospital Structure Act" intends to align the state hospital planning on quality criteria. Within this process cost-utility analyses (CUAs) shall be used to assess the efficacy of medical care. To be objective, CUAs of intensive care units (ICUs) require standardization (adjustment) of costs. The present study analyzed the extent to which treatment costs are related to patient-specific baseline variables (such as type and severity of the primary disease). METHODS: From 2000-2004, a bottom-up procedure was used to quantify total costs on 14 ICUs in nine German university hospitals. Results were combined with demographic data, and data indicating type (ICD-10 codes) and severity (ICU scoring systems) of the primary disease at ICU admission. Various statistical models were tested to identify that which best described the associations between baseline variables and costs. RESULTS: In all, 3803 critically ill patients could be examined. The median of treatment costs per patient was 3199 € (IQR 1768-6659 €). No model allowed an acceptably precise adjustment of costs; the estimated mean absolute prognostic error was at least 3860 € (mean relative prognostic error 66%), when we tested an Extreme Gradient Boosting Model. CONCLUSION: Instruments which are currently available (cost adjustment based on patient-specific baseline variables) do not allow a standardization of costs, and an objective CUA of ICUs. Factors unknown at baseline may cause a large portion of treatment costs.

In vivo hip joint loads and pedal forces during ergometer cycling.

The rising prevalence of osteoarthritis and an increase in total hip replacements calls for attention to potential therapeutic activities. Cycling is considered as a low impact exercise for the hip joint and hence recommended. However, there are limited data about hip joint loading to support this claim. The aim of this study was to measure synchronously the in vivo hip joint loads and pedal forces during cycling. The in vivo hip joint loads were measured in 5 patients with instrumented hip implants. Data were collected at several combinations of power and cadence, at two saddle heights. Joint loads and pedal forces showed strong linear correlation with power. So the relationship between the external pedal forces and internal joint forces was shown. While cycling at different cadences the minimum joint loads were acquired at 60RPM. The lower saddle height configuration results in an approximately 15% increase compared to normal saddle height. The results offered new insights into the actual effects of cycling on the hip joint and can serve as useful tools while developing an optimum cycling regimen for individuals with coxarthrosis or following total hip arthroplasty. Due to the relatively low contact forces, cycling at a moderate power level of 90W at a normal saddle height is suitable for patients.

Mediolateral force distribution at the knee joint shifts across activities and is driven by tibiofemoral alignment.

AIMS: Tibiofemoral alignment is important to determine the rate of progression of osteoarthritis and implant survival after total knee arthroplasty (TKA). Normally, surgeons aim for neutral tibiofemoral alignment following TKA, but this has been questioned in recent years. The aim of this study was to evaluate whether varus or valgus alignment indeed leads to increased medial or lateral tibiofemoral forces during static and dynamic weight-bearing activities. PATIENTS AND METHODS: Tibiofemoral contact forces and moments were measured in nine patients with instrumented knee implants. Medial force ratios were analysed during nine daily activities, including activities with single-limb support (e.g. walking) and double-limb support (e.g. knee bend). Hip-knee-ankle angles in the frontal plane were analysed using full-leg coronal radiographs. RESULTS: The medial force ratio strongly correlated with the tibiofemoral alignment in the static condition of one-legged stance (R² = 0.88) and dynamic single-limb loading (R² = 0.59) with varus malalignment leading to increased medial force ratios of up to 88%. In contrast, the correlation between leg alignment and magnitude of medial compartment force was much less pronounced. A lateral shift of force occurred during activities with double-limb support and higher knee flexion angles. CONCLUSION: The medial force ratio depends on both the tibiofemoral alignment and the nature of the activity involved. It cannot be generalised to a single value. Higher medial ratios during single-limb loading are associated with varus malalignment in TKA. The current trend towards a 'constitutional varus' after joint replacement, in terms of overall tibiofemoral alignment, should be considered carefully with respect to the increased medial force ratio. Cite this article: Bone Joint J 2017;99-B:779-87.

Do high participation rates improve effects of population-based general health checks?

The aim is to investigate if the effect of a health check differs between areas with different participation rates. The Inter99 population-based randomized lifestyle intervention study covered 73 areas within the suburbs of Copenhagen, Denmark. Adults aged 30-60years were randomly drawn from a population and were randomized to intervention group (n=11,483) or control group (n=47,122). Participation rates in the health check varied considerably between areas (mean 52%; range 35-85%). In separate survival analyses, area participation rate was included both as a continuous exposure variable and as a categorical variable (tertiles; low: 35-49%, meddle: 50-54%, high: 55-84%). All persons in the intervention and control group were followed in registers for 10-year total mortality and combined events (ischemic heart disease, stroke, or both). In adjusted models (including sociodemographic variables, ethnicity, number of children and comorbidity), among men, there was no difference in risk of death between areas with varying participation rates. Surprisingly, among women living in high-participation areas a significantly higher risk of all-cause mortality (HR: 1.32 [1.03-1.69]) was found in the intervention group (ref=controls). For both men and women, in no areas there was any difference between intervention and control group in incident IHD/stroke. Higher participation rates in population based health checks is probably unlikely to improve the effects of these, and may in worst case be harmful in subgroups of the population. Further well-designed studies within non-participation research should have high priority and are required to establish link between health checks and risk of death in subgroups of the population.

Meaningful use of the electronic patient portal - Virginia Mason's journey to create the perfect online patient experience.

We present a case study of Virginia Mason Medical Center's successful implementation of the online patient portal. The organization exceeded its Meaningful Use 2 View/Download/Transmit targets and national benchmarks, with over 70% of unique patient encounters being provided timely online access to their health information, over 50% viewing, downloading, and transmitting health information electronically, and potential cost savings to the institution. Key lessons learned in our implementation process were.

Systematic selection of small molecules to promote differentiation of embryonic stem cells and experimental validation for generating cardiomyocytes.

Small molecules are being increasingly used for inducing the targeted differentiation of stem cells to different cell types. However, until now no systematic method for selecting suitable small molecules for this purpose has been presented. In this work, we propose an integrated and general bioinformatics- and cheminformatics-based approach for selecting small molecules which direct cellular differentiation in the desired way. The approach was successfully experimentally validated for differentiating stem cells into cardiomyocytes. All predicted compounds enhanced expression of cardiac progenitor (Gata4, Nkx2-5 and Mef2c) and mature cardiac markers (Actc1, myh6) significantly during and post-cardiac progenitor formation. The best-performing compound, Famotidine, increased the percentage of Myh6-positive cells from 33 to 56%, and enhanced the expression of Nkx2.5 and Tnnt2 cardiac progenitor and cardiac markers in protein level. The approach employed in the study is applicable to all other stem cell differentiation settings where gene expression data are available.

DNMT3A(R882H) mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice.

TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.