Background: Use of antipsychotic medication is central in the treatment of psychotic disorders. However, there is limited knowledge about prescription practice of antipsychotics in the critical early phase of these disorders. Clinical guidelines recommend low dosages, but no discontinuation of antipsychotic medication during the first year of treatment in first episode patients. The main aim of this study was to identify clinical predictors for dosage change or discontinuation of antipsychotics during this period.Methods: A total of 426 antipsychotic-using patients with schizophrenia spectrum or bipolar disorder, including both a first treatment sample and a sample of patients with previous treated episodes (“multi-episode” sample) from the same diagnostic groups, underwent thorough clinical and sociodemographic assessment at study baseline and after 1 year. Prescribed dosage levels at baseline and follow-up and change in dosage or discontinuation of antipsychotics from baseline to follow-up were compared between groups, controlling for possible confounders.Results: We found reduced dosages over the first year in both first treatment groups across diagnoses, but not in multi-episode groups. Weight increase predicted dosage reduction in the schizophrenia group, while the level of psychotic symptoms at baseline predicted dosage reduction in the bipolar group. We found higher baseline levels of antipsychotic use in the schizophrenia group than in the bipolar group.Conclusion: We found indications of a trans-diagnostic reduction of prescribed dosages of antipsychotics over the first year in treatment, but with different predictors for this reduction in the two diagnostic groups. The findings increase the understanding of drivers of early medication change in psychotic disorder. Psychopharmacological agents are one of the main treatment approaches in clinical psychiatry. Antipsychotics (“neuroleptics”) were introduced for the treatment of schizophrenia in 1956, and have persisted as the cornerstone of treatment for schizophrenia and related psychotic disorders . They alProspective studies show beneficial effects of earlier adequate treatment in psychotic disorders, and treatments given in the early phases of illness seem to be of particular importance for short- and long-term outcome –14. StudThe efficacy of current antipsychotics is dependent on their effects on the dopamine neurotransmitter system in the central nervous system. Since drug uptake, first-pass metabolism and passage over the blood–brain barrier are highly individual there is no fixed dose–response , 23, andThe current study is based on a 1-year follow-up of comprehensively characterized patients with schizophrenia and bipolar disorder, including both first-treatment and multi-episode patients from the same catchment areas, and thus using the same treatment services. These services give treatment based on guidelines that recommend low dosages of antipsychotics for first-treatment schizophrenia for 2 years, but with no particular advice for the dosages and length of maintenance treatment in first-treatment bipolar disorder. The study had the following aims:Are there differences in the use of antipsychotics, between first-treatment and multi- episode patients in patients with schizophrenia spectrum and bipolar disorder at study baseline?What dosage changes or discontinuation rates of antipsychotic medication are there over the subsequent year? Do these predictors differ between patients with schizophrenia spectrum and bipolar disorder, or between first-treatment and multi- episode patients?What are the predictors of changes in the dosages or discontinuation of antipsychotics, and are there different predictors between patients with schizophrenia spectrum and bipolar disorder, and between first-treatment and multi-episode patients?The current study is a component of the TOP  Study, which is approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. Recruitment was done from 2003 until 2017 from major hospitals in the Oslo area, Norway. The TOP study comprises several smaller sub-studies. All first treatment patients are included in prospective cohorts with planned follow-up studies. Multi-episode patients were part of smaller follow-up studies, based on the focus of ongoing projects. The reasons for multi-episode patients to participate, or not to participate, in follow-up studies were thus administrative (based in project design and funding) with no identified selection bias involved. There were no significant differences in baseline demographic and clinical characteristics between multi-episode patients participating or not participating in follow-ups. For a more detailed description, see Faerden et al. , HellvinInclusion criteria at baseline: age 17 to 67 years and meeting the DSM-IV criteria for a diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, psychotic disorder NOS, delusional disorder or bipolar I, II or NOS disorder. Exclusion criteria were: presence of a diagnosis of a developmental disorder, IQ < 70 or acquired brain damage , and lack of fluency in a Scandinavian language. There were no exclusion criteria based on course of illness, history of treatment or substance use. Patients were recruited consecutively from in- and outpatient psychiatric units in the collaborating hospitals. There were no other treatment organizations serving these areas, allowing for a high degree of representation for participating patients. For details, see Ringen et al. . Each paDiagnosis, onset of illness and treatment history at baseline were established using the Structural Clinical Instrument of Diagnosis for DSM-IV axis I disorders (SCID – I), modules A–E, with the aid of medical charts . All intThe duration of untreated illness (DUI) was defined as the time (in weeks) from the onset of the first SCID verified illness episode to the start of use of adequate medication. For Bipolar disorder specifically, DUI was defined as time from first affective episode (regardless of polarity), to the start of adequate treatment, defined as either antipsychotic or mood-stabilizing medication for mania or mixed episodes (in appropriate dosages for minimum 6 weeks) according to available treatment guidelines for BD I .Data was collected on marital status, occupational status, and educational level. Four groups were defined: “First treatment patients” were defined based on treatment history as patients receiving their first adequate treatment of the disorder in question within the last 12 months. “Schizophrenia spectrum” (SS) included schizophrenia, schizophreniform disorder, schizoaffective disorder, psychotic disorder NOS and delusional disorder and was further divided into “First Treatment Schizophrenia Spectrum” and “Multi-episode Schizophrenia Spectrum” based on treatment history. “Bipolar disorder” (BD) included bipolar disorder I, II and NOS and was divided into “First Treatment Bipolar Disorder” and “Multi-episode Bipolar Disorder.”Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale (All patients were assessed at first recruitment (“Baseline”) and 12 months later. At both time points, information on type and dosage of all antipsychotic medication was collected. Defined daily doses (DDD) were defined according to the WHO criteria , 33. Forng scale  was usedInsight was measured by the Birchwood Insight scale  items 2 The inter-rater reliability of the symptom assessments in the TOP study have been shown to be good with an Intraclass Coefficient (ICC)  of 0.82 post hoc Bonferroni corrections and paired t-tests as appropriate. Significance level was set to 0.05, two-tailed.All analyses were performed using the Statistical Package for the Social Sciences . Differences between categorical variables were analyzed using chi square tests. Differences between normally distributed continuous variables were analyzed using univariate analyses of variance with A two-way between-groups analysis of variance was conducted to explore the impact of diagnostic group (schizophrenia spectrum or bipolar disorder spectrum) and treatment group (first treatment or multi-episode) on change in dosage of antipsychotics. To identify predictors for change in dosages of antipsychotics from first treatment we performed a series of follow-up multivariate analyses for each group. We here used multiple linear regression analyses for normally distributed dependent variables, with independents entered hierarchically in several blocks. Age and sex were selected as priori independent variables, in addition to baseline measures regarded as plausible predictive factors for inducing change, including measures of common side-effects, insight and reported compliance. Additional putative predictors were added based on findings of significant bivariate associations to changes in dosage of antipsychotic medication in the current sample. The assumption of a linear relationship was evaluated based on examinations of residual plots for each analysis, and on examination of influential observations based on leverages and Cox distances. The final model with the best fits is presented in the paper.A total of 426 patients were included in the current study, with assessments both at baseline and follow-up. Their demographic and clinical characteristics at baseline are described in 2 = 4.6, p = 0.032). Thirteen (68%) of those discontinuing antipsychotics in the First Treatment Bipolar Disorder group had however changed to mood stabilizers at follow-up.Use of antipsychotics and discontinuation rates for the different groups at baseline and follow-up are shown in 20.02). There was no significant main effect for diagnostic group and no significant interaction effects.There was a statistically significant reduction in antipsychotic dosage for both the First Treatment Schizophrenia Spectrum group and the First Treatment Bipolar Disorder group. There were no significant changes in antipsychotic use in the two multi-episode illness groups Figure 1Bivariate analyses showed the following group-wise significant associations with change in dosage of antipsychotics measured as PDD/DDD ratio: First Treatment Schizophrenia Spectrum: Age (+), PDD/DDD for all antipsychotics at baseline (−), UKU weight gain (−), UKU investigators’ assessment of global side effect load (−) and level of physical activity (−); First Treatment Bipolar Disorder: PDD/DDD for all antipsychotics at baseline (−), UKU hypokinesia (−), GAF-F (+), and PANSS-P scores (−). Since there were no changes for multi-episode patients, we did not do follow-up analyses for these groups.Final combined models for the multivariate linear regressions analyses are presented in The logistic regression analysis with discontinuation as the dependent variable showed significant contributions to the risk of discontinuation from higher GAF-F and alcohol use (AUDIT scores) at baseline in First Treatment Schizophrenia Spectrum, and from increased age in First Treatment Bipolar Disorder, significant odds ratios were in the range from 1.06 to 1.11  and the Research Council of Norway (Grant #223273).OA received speakers’ honoraria from Lundbeck.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Alterations to normal knee kinematics performed during conventional total knee arthroplasty (TKA) focus on the nonanatomic articular surface. Patient-specific TKA was introduced to provide better normal knee kinematics than conventional TKA. However, no study on tibiofemoral conformity has been performed after patient-specific TKA. The purpose of this study was to compare the biomechanical effect of cruciate-retaining (CR) implants after patient-specific TKA and conventional TKA under gait and deep-knee-bend conditions.The examples of patient-specific TKA were categorized into conforming patient-specific TKA, medial pivot patient-specific TKA and anatomy mimetic articular surface patient-specific TKA. We investigated kinematics and quadriceps force of three patient-specific TKA and conventional TKA using validated computational model. The femoral component designs in patient specific TKA were all identical.The anatomy mimetic articular surface patient-specific TKA provided knee kinematics that was closer to normal than the others under the gait and deep-knee-bend conditions. However, the other two patient-specific TKA designs could not preserve the normal knee kinematics. In addition, the closest normal quadriceps force was found for the anatomic articular surface patient-specific TKA.Our results showed that the anatomy mimetic articular surface patient-specific TKA provided close-to-normal knee mechanics. Other clinical and biomechanical studies are required to determine whether anatomy mimetic articular surface patient-specific TKA restores more normal knee mechanics and provides improved patient satisfaction. The treatment of severe knee joint arthritis with total knee arthroplasty (TKA) continues to grow and a wide range of implants based on various designs are available on the market Greene . AlthougTKA that returns proper functions tends to assuage the most common criticisms regarding pain and stiffness, leading to the belief that TKA should restore “normal-like” kinematic functions  and computer tomography (CT) scans are being used to provide data for manufacturing a patient-specific TKA or instrumentation. There are advantages to both methods, but each is better suited to a particular type of joint analysis (Slamin and Parsley The purpose of this study was to investigate the effect of the articular surface conformity on patient-specific posterior cruciate-retaining (CR) TKA, along with conventional CR TKA. The patient-specific TKA procedures were categorized into conforming patient-specific TKA, medial pivot patient-specific TKA and anatomy mimetic articular surface patient-specific TKA. We investigated four different types of TKA to compare the kinematics and quadriceps force with a normal model under gait and deep-knee-bend conditions using finite element (FE) simulation. We hypothesized that anatomic articular surface TKA provides the most normal-like mechanics.Patient-specific TKA was designed with a previously existing three-dimensional (3D) knee joint model  and medial pivot design Evolution Medial Pivot Total Knee Arthroplasty  were selected.To investigate the CR TKA conformity, they were scanned using a non-contact 3D laser scanner  with an accuracy of 50 μm. Scanned point data were converted to 3D models, and scanning was repeated until the 3D model dimensions had geometrical errors of < 100 μm  and medial pivot tibial insert with medial pivot conformity (Evolution) were developed by applying the curvature radius ratio in the coronal and sagittal planes to the patient-specific femoral component Fig. . In addiAs previously mentioned, the existing validated normal knee and TKA model was used in this study  is the current force, k is the stiffness, ε is the strain, and ε1 is assumed to be constant at 0.03. The ligament bundle slack length l0 can be calculated using the reference bundle length lr and reference strain εr in the upright reference position.where The interfaces between the articular cartilage and bones were assumed to be fully bonded. Six pairs of tibiofemoral contacts between the femoral cartilage and meniscus, the meniscus and tibial cartilage, and the femoral cartilage and tibial cartilage were modeled on both the medial and lateral sides  were virtually implanted in the bone geometry. Based on the dimensions of the femur and tibia, devices with sizes of 7 and 5–6 were selected for the femoral component and tibial insert, respectively. Conventional and patient-specific TKA models were implanted as shown below. In the neutral position, the femoral component was aligned so that the distal bone resection was perpendicular to the mechanical axis of the femur, and the anterior and posterior resections were parallel to the clinical epicondylar axis in the transverse plane. The tibial default alignment was rotated by 0° relative to the anterior-posterior axis, and the coronal alignment corresponded to 90° relative to the mechanical axis. Similarly, three different patient-specific TKA devices were virtually implanted in the bone geometry Fig. .Contact conditions were applied between the femoral component, tibial insert and patellar button during TKA. The coefficient of friction between the polyethylene (PE) and metal materials was assumed to be 0.04, for consistency with previous explicit FE models . We investigated the kinematics and quadriceps force to evaluate how effectively the generation of normal knee mechanics was achieved for different conformity after patient specific TKA compared to conventional TKA. A three-cylindrical knee joint model was developed with six degrees-of-freedom for the relative kinematics of the tibiofemoral and patellofemoral articulations (Grood and Suntay Figure Figure Figure The most important finding of this study was that the anatomy mimetic tibial articular surface APS TKA showed knee mechanics that were the closest to normal knee joint. Other patient-specific TKA designs also showed knee kinematics that was closer to normal than that with conventional TKA, but their tibial inserts were derived from the femoral component. Thus, they were not as effective as APS TKA in terms of normal knee kinematics.Patil et al. showed that patient-specific implants generated kinematics that more closely resembled normal knee kinematics than standard knee designs using an in-vitro cadaveric experiment (Patil et al. The objective in our study was to determine the effect of femoral and tibial conformity in patient-specific TKA using computational simulation. The advantage of computational simulation using a single subject, as used in this study, was the ability to determine the effects of conformity on the tibiofemoral articular surface for an identical subject, without the effect of variables such as the weight, height, bony geometry, ligament properties and component size (Thompson et al. We found that patient-specific TKA showed knee kinematics that was closer to normal than conventional TKA under gait and deep-knee-bend conditions (Thompson et al. An interesting finding was that it showed knee kinematics that was closer to normal compared to MPS TKA and CPS TKA. The traditional “medial pivot” implant on the medial side is designed to be a “ball-in-socket” articulation Blaha . PreviouTheoretically, a TKA design with the center of the flexion located relatively more posterior could result in additional lengthening of the quadriceps lever arm. A previous study showed that a longer lever arm reduces the tension on the quadriceps during knee extension, especially at flexion angles that typically generate high knee moments (D’Lima et al. In terms of biomechanical aspect, the APS TKA design showed the nearest normal knee biomechanics during gait and squat conditions. However, the APS TKA design did not fully implement normal knee biomechanics. The main reason could be the absence of anterior cruciate ligament. In addition, the development of materials of implants that implement real biomechanics of anatomical knee joints will be needed.There were several limitations to the current study. First, gait and deep-knee-bend simulations were performed, although simulations related to more demanding activities such as chair rising, sitting, stair climbing and stair descending are required for a more reliable investigation. Second, the implant kinematics and quadriceps force were evaluated using computational simulations, which did not fully represent in-vivo conditions. Third, the computational model was developed using data from a single subject because the time and computational cost associated with generating many subject-specific FE models made doing so inefficient. Additionally, although the FE model was well validated, it did not represent an in-vivo environment by considering anatomic variations and age-related changes in the ligament and cartilage. Thus, it is necessary to expand the number of subjects in future research. This approach is widely used in orthopedic biomechanics (Kang et al.  We evaluated conventional TKA and patient-specific TKA with respect to different conformity levels and determined the design that provided the most normal mechanics. We found that APS TKA with an anatomic articular geometry was able to more closely mimic the activity dependent kinematics of normal knees. Moreover, the quadriceps force was also most similar to that of a normal knee after APS TKA. Other clinical and biomechanical studies are required to determine whether anatomic articular surface patient-specific TKA restores more normal knee mechanics and improves patient satisfaction.


To achieve high direct current (DC) dielectric performance of crosslinked polyethylene (XLPE) applied for insulated cable, the auxiliary crosslinking agent of trimethylolpropane trimethacrylate (TMPTMA) is employed in photon-initiated crosslinking process to the present polar-molecular group which will introduce deep traps for charge carriers. The space-charge accumulation and electrical conductance of XLPE are observably suppressed due to the deep traps deriving from the TMPTMA crosslinkers that are chemically connecting (grafted onto) polyethylene molecules. Thermally stimulated depolarization current tests and first-principles calculations consistently demonstrate a trapping mechanism of impeding charge injection and carrier transport in XLPE with TMPTMA crosslinkers. The characteristic cyclic anhydrides with coupled carbonyl groups are used as auxiliary crosslinkers to promote crosslinking efficiency and provide polar groups to polyethylene molecules which can be effectively fulfilled in industrial cable production. The results of infrared spectroscopy show that the auxiliary crosslinkers have been successfully grated to polyethylene molecules through the UV-initiation process. The space-charge characteristics achieve a significant improvement consistent with the theoretical estimation that deeper electronic traps can be introduced by auxiliary crosslinker and will consequently suppress space-charge accumulation through a trapping mechanism. Meanwhile, the conductivity of XLPE observably increases after using TMPTMA auxiliary crosslinkers at various temperatures of cable operation. The first-principles calculations also demonstrate that substantial electronic bound states have been introduced at the band edge of polyethylene molecules crosslinked by TMPTMA, leading to reduction in electrical conductivity. On the advantage of ameliorating DC dielectric performance by way of UV-initiated crosslinking process, the present research suggests a substantial strategy in XLPE cable industrial productions. At present, the effective methods of modifying polymer insulation materials have been presented as by polymer dielectric nanocomposites (filling nanoparticles), ultra-clean process, blending, and chemical modification ,2,3. TheWith the development of the marine development strategy, the submarine cable manufacture of high-grade and super-long crosslinked polyethylene (XLPE) has become a focus in electrical insulation research. However, the peroxide chemical crosslinking technology commonly used in the production of high-voltage cables represents some unavoidable shortcomings, such as high production energy consumption, low heat-transfer rate, long reaction time, and so on. In addition, scorching is liable to occur at the dead angle of mold in chemical crosslinking processes, thus forming defects in the insulation layer of high-voltage cable, which will worsen electrical characteristics ,9. UltraIn the present paper, to develop the prospective molecular modification of polymer insulation materials, a strategic scheme of UV-initiated crosslinking reactions between the polyethylene molecules and the auxiliary crosslinking agent is employed to achieve XLPE materials with preferable dielectric performance, which can be practically used in industrial cable manufacture. We adopt TMPTMA with triple-carbonyl polar groups as an auxiliary crosslinking agent and benzophenone (BP) as the photon-initiator to accomplish crosslinking reactions of polyethylene molecules under UV irradiation, which will simultaneously introduce deep traps for charge carriers to ameliorate direct current (DC) dielectric properties. Linear low-density polyethylene (LLDPE) represents higher resistances to penetration, impact, and tear than ordinary low-density polyethylene, which makes it suitable to be processed into thin films. In particular, LLDPE is adapted to advanced plastic processes, such as film extrusion process, due to its excellent melting rheological property with a melt rheological index of 1.0 g/10 min. Furthermore, LLDPE shows remarkable endurance to environmental stress cracking, low temperature impact, and mechanical warping, which can be effectively applied in the extrusion and molding of pipe and sheet substances. Without long-chain branches on the molecular backbone, LLDPE molecules can easily form crosslinking and be grafted by functional molecular groups in crosslinking reactions, which facilitates the developments of a new crosslinking process and graft-modified polyethylene materials. Therefore, LLDPE is used as the pristine matrix material for preparing the modified XLPE materials in the present study. The first-principles electronic structure calculations are performed to consistently elucidate the electronic bound states with the energy level located in band-gap arising after polyethylene molecules are chemically connected by the auxiliary crosslinker of TMPTMA, which accounts for the underlying mechanism of inhibiting space-charge accumulation and reducing electrical conductivity.The melting blend and hot-pressing approaches are employed in synthesis of TMPTMA-crosslinked polyethylene with the original materials being adopted as follows: linear low-density polyethylene  as parent material, benzophenone  for initiating grafting reaction under photon irradiation, auxiliary crosslinking agent , all of which have purity higher than 95%. In the melting blend process of preparing the initial mixtures, the pristine LLDPE are melted uniformly in Torque Rheometer  at 160 °C for 3 min with stirring speed of 60 rpm, and then 2 wt. % BP photon-initiator and 1 wt. % auxiliary crosslinking agent are added and blended for 3 min then cooled to room temperature to obtain the uniform mixture materials. 1) BP and the partial fractures of carbon double bonds on TMPTMA molecules are simultaneously initiated by instantaneous UV irradiation, leading to considerable amounts of transient free radicals on both polyethylene and TMPTMA molecules which will eventually form chemical bonds to accomplish crosslinking reactions, as schematically illustrated in For photon-initiated crosslinking reactions, the prepared hot-pressed blend is first treated in a plate vulcanizer at 160 °C with the pressure being increased by 5 MPa per 5 min from 0 to 15 MPa so as to make the material melt, and then the melt material is irradiated by a light source array of UV LED units  for 2 s on an irradiation platform at normal pressure and room temperature in an air atmosphere. In this pivotal process, exploiting UV-transparency of the LLDPE fluid at the temperature higher than fusion point after being squeezed out from extruder, the UV lights are incident through the melting mixture of LLDPE, BP, and TMPTMA. Hydrogen abstractions from polyethylene molecules to UV-excited first-triplet  Spectroscopy  in spectral range of 500 ~ 4000 cm3 film samples with both sides being evaporated by aluminum electrode films in 25 mm diameter. Thermally stimulated depolarization currents  are tested to analyze the energy level distribution of charge traps, for which the samples in 0.1 mm thickness are first polarized under an electric field of 40 kV/mm for 30 min and then rapidly cooled by liquid nitrogen down to −50 °C being stabilized for 3 min. The depolarization currents are measured in short circuit when temperature is raised from −50 to 150 °C with a heating rate of 3 °C/min.Using a pulsed electro-acoustic system , the space-charge distributions are measured at ambient temperature of 25 °C by applying an electric field of 40 kV/mm in polarization for 30 min and then short-circuiting for 30 min, in which the tested materials are fabricated into 50 × 50 × 0.3 mmElectrical conductivity is measured by a three-electrode system at variable temperatures from 25 to 90 °C for the circular film samples of 50 mm diameter and 300 µm thickness with the evaporated aluminum electrodes on both sides. The protective electrode in annular shape  encircles the disc of the measuring electrode (50 mm in diameter) on one side of the film samples, and the circular electrode with a larger diameter of 78 mm on the other side is used for applying high voltage. After the samples are heated and stabilized at the testing temperature for 60 min, the electric field at each point covering the range of 3–40 kV/mm is applied for 60 min to measure the stable conductance current.−5 eV/atom, 0.03 eV/Å and 0.001 Å, respectively. The electronic structures are calculated for molecular orbitals and electronic density of states to investigate band-edge features and grafting-introduced trap states. The first-principles calculations are performed by employing the scheme of all-electron numerical atom-orbitals as implemented in DMol3 program of Materials studio 8.0 software package . The detailed schemes and parameters adopted in DMol3 calculations are listed in The model of polyethylene molecules in 20 polymerization degrees, being connected by an auxiliary crosslinker molecule near the middle position of polyethylene backbone chain, is initially constructed with random distributed torsion based on rotational isomeric state (RIS) model . The conThermal elongation and gel extraction experiments are carried out by referring to the standards of GB/T 2951.21-2008 and ASTMD 2765-2011, respectively. It is explicit that the XLPE crosslinking degrees being initiated by UV irradiation with TMPTMA have reached an adequate 25% in thermal elongation to be mechanically qualified for cable productions, implying the competent efficiency of UV-initiation crosslinking technique with TMPTMA as the auxiliary crosslinking agent. −1 in IR transmission spectra, which are engendered by UV irradiation and retain after hot-degassing treatment. Especially for the mixture of LLDPE and BP without auxiliary crosslinking agent, this characteristic peak does not arise even through UV irradiation process, confirming the definite correlation of this characteristic peak with the auxiliary crosslinker being chemically connected (grafted) between polyethylene molecules. The FT-IR results reasonably prove that TMPTMA have been successfully grafted to polyethylene molecules.The molecular structure of UV-XLPE-TMPTMA is characterized by IR spectroscopy in comparison to the homologous blend sample obtained though the similar preparation process without TMPTMA (LLDPE + BP), as the results shown in 3, implying the migration of negative space charges into LLDPE under the DC electric field. Meanwhile, a few homocharges are also injected into the surface of the LLDPE samples from the anode. In comparison, the crosslinked sample UV-XLPE-TMPTMA represents a gentle varying curve of space-charge distributions even after being polarized for 1800 s, but with a small amount of heterocharges accumulating near cathode with a peak value of 1.5 C/m3. The minimal quantity of positive space charges distributing inside UV-XLPE-TMPTMA and near the anode further demonstrates that the depth of space-charge injection and the density of space-charge accumulation can be substantially reduced by UV-initiated crosslinking with a TMPTMA auxiliary agent.Space-charge characteristics of LLDPE and UV-XLPE-TMPTMA are tested with pulsed electro-acoustic (PEA) method to reveal the underlying behavior of charge injections. Electric field distributions across samples in the polarization process are shown by the variation curves in the middle panels of 3. Many homocharges are observed to appear at cathode with a peak density of 1.5 C/m3 while a few heterocharges emerging at anode, with the accumulated charges being dissipated to a convergent state after short-circuiting for an adequately long time of 1200 s. Nevertheless, the peak value of charge density in UV-XLPE-TMPTMA is appreciably decreased to 3.5 C/m3 with a faster dissipating rate of short-circuit process, in which residual charge distribution remains unchanged after 300 s. Therefore, it can be reasonably suggested that the higher ability of suppressing space-charge accumulation has been acquired by UV-XLPE-TMPTMA, which is attributed to the deep traps deriving from the polar group of TMPTMA, as elucidated by the following TSDC analyses and first-principles calculations.Space-charge characteristics of LLDPE and UV-XLPE-TMPTMA in short-circuit process are exhibited in the bottom panels of The TSDC testing temperature range of −50–150 °C covers the thermal excitation energies of the charges captured by both intrinsic traps of XLPE and TMPTMA-introduced deep traps, in which the practical operating temperatures of high voltage DC cable are completely included. TSDC test characterizes the current produced by the thermally excited charges which have been trapped by bound states of electron or holes, in which the intensity and position of current peak signify the whole quantity of the trapped charges throughout the material and the trapping level depth respectively . Accordi21 eV−1·m−3) respectively. The homogeneously distributed deep traps fixed on the grafted TMPTMA will effectively capture the injected hetero-charges and thus form intensified electrostatic shielding layers near electrodes under applied DC electric field, which can eventually block charges being further injected from electrodes and impede carrier transport. Consequently, the space-charge accumulation in UV-XLPE-TMPTMA is remarkably suppressed due to the deep traps introduced by the TMPTMA connecting polyethylene molecules. Furthermore, auxiliary-introduced traps, being 0.13 eV deeper than intrinsic traps, can retain the highly efficient suppression mechanism of space accumulation at a temperature approaching to 118 °C, which is significantly higher than the 68 °C for LLDPE without auxiliary crosslinking. These results suggest that UV-XLPE-TMPTMA can persist in high DC dielectric performance when the cable working temperature increases to 118 °C.It is illustrated from the measured TSDC spectra and the derived trap level distributions of LLDPE and UV-XLPE-TMPTMA as shown in To establish a theoretical basis of accounting for the improved DC dielectric performance of UV-XLPE-TMPTMA, the first-principles electronic structure calculations are performed for the multiple polyethylene molecules being chemically connected by an auxiliary crosslinker (XLPE-TMPTMA), as the representative structural schematics of the relaxed molecule and the energetic distribution of electronic states , as shown in γ-E) varies with the archetypal operating temperature of DC insulated cable (25–90 °C) shown in γ-E curves also illustrate the evident increment of critical electric field caused by grafting auxiliary crosslinking agents onto polyethylene molecules. The density of states near the CBM and VBM of the polymer molecules directly determines the probability of carrier transition between the adjacent levels of electronic states at the band edge, and thus dominates the carrier mobility without consideration of impurity or defect scattering. As illustrated in The electrical conductance of XLPE materials is highly dependent on the temperature and electric field, as the conductivity-electric field (Exploiting auxiliary crosslinking agents in the photon-initiated crosslinking process, the DC dielectric performance of XLPE has been evidently improved with UV irradiation technology. The underlying mechanism of suppressing charge injection and restraining electrical conductance is elucidated by TSDC analysis and quantum mechanics calculations in combination with the conductivity field variation at various temperatures of cable operation. The auxiliary crosslinking efficiency of UV-XLPE-TMPTMA has been verified by thermal elongation test and IR transmission spectra. It has been demonstrated that UV irradiation technique can successfully initiate crosslinking reactions between polyethylene molecules and auxiliary crosslinking agents to achieve modified XLPE with sufficient crosslinking degree and excellent thermal elongation performance. The modified DC dielectric performance of UV-XLPE-TMPTMA is attributed to the deep traps engendered by the polar carbonyl of grafted TMPTMA which is testified by TSDC analysis and first-principles calculations. The charges, being captured by these deep traps in higher density, will form effective electrostatic shielding layers near electrodes to impede charge injections and thus remarkably inhibit space-charge accumulation inside XLPE materials. Compared with LLDPE, lower conductivity has been acquired by the XLPE with TMPTMA as an auxiliary crosslinker which represents prominent efficiency of ameliorating dielectric properties. The first-principles calculations also indicate that the multiple electronic bound states can be engendered by the grafted TMPTMA, which will decrease the density of state at the edges of both conduction and valance bands, consequently leading to decreased carrier mobility. The present study suggests a prospective strategic scheme of UV-initiated graft modification for realizing high-performance insulating materials in HVDC cable production. Nevertheless, this paper only presents the most important study on the DC dielectric performance of modified XLPE, concerning the improvement of space-charge accumulation and the suppression of electrical conductance. For practical applications in DC insulated cable, the other electrical properties, such as DC breakdown strength when the polarity reverses, and electric tree characteristics under impulse voltage or DC short circuit, should be further researched in future work.


To investigate the frequency and predictors of sustained 28-joint DAS (DAS28) remission and low disease activity (LDA) in patients receiving anti-TNF therapy and changes in responses over a 12 year period.Data from the British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis were used. Sustained remission and LDA were defined according to DAS28-ESR thresholds sustained for 6 months. The dataset was dichotomized into sequential chronological subgroups (2001–2010 and 2010–2013). Predictive variables were identified from a previous systematic review and modelled using multivariable logistic regression.vs etanercept), greater patient global assessment, never- and ex-smoker status (vs current smoking), greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription (except in the 2010–2013 subgroup). Negative predictors of sustained remission and LDA included poor baseline functional status (HAQ), female gender, older age at starting anti-TNF, infliximab use (vs etanercept), increasing BMI and greater baseline ESR. Increasing tender joint count was negatively associated with sustained LDA only. The overall proportion of patients achieving sustained remission and LDA has increased significantly over time.Overall, 2144 (14.9%) and 3802 (26.3%) patients achieved sustained remission or LDA, respectively. Positive predictors of sustained remission/LDA included adalimumab (Sustained remission/LDA on anti-TNF treatment remains uncommon. Adalimumab use, greater patient global assessment, never- and ex-smoker status, greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription are associated with achievement of sustained remission/LDA. However, co-prescription of MTX was not associated with an increased likelihood of achieving sustained remission or LDA in the analysis of more recent anti-TNF responses. The demographics of rheumatoid arthritis patients commencing their first anti-TNF has changed significantly since 2001.Sustained remission in anti-TNF-treated rheumatoid arthritis patients has increased significantly since 2001.Clinical predictors are associated with sustained DAS28 remission in anti-TNF-treated rheumatoid arthritis patients.Treat-to-target strategies and increased use of biologic agents over the past decade have improved outcomes for patients with RA , 2. InitAnti-TNFs form a routine part of clinical care for patients with RA. Understanding how often and in whom sustained remission/LDA occurs is essential to appreciate the likely success of treatment. With increasing availability and earlier initiation of anti-TNFs and other biologics, it is possible that both the frequency of sustained remission/LDA and predictors associated with these outcomes may have changed over time.This study investigates the frequency of sustained remission and LDA in patients receiving anti-TNF therapy, the predictors associated with achieving these outcomes and how these predictors and the frequency of these outcomes may have changed over 12 years.The British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis (BSRBR-RA) is a national, prospective, longitudinal, observational study examining the long-term safety of biologic agents in patients with RA in the UK. Ethical approval was obtained from the Multicentre Research Ethics Committee for the North-West of England. All patients enrolled provided written informed consent. The methods of the BSRBR-RA have been described previously .Biologics use in England and Wales is directed by National Institute for Health and Care Excellence guidance , which rRemission and LDA were defined according to DAS28-ESR thresholds . The BSRBR-RA collects DAS28 outcomes on a 6 month basis for the first 3 years. Thereafter, data collection is performed annually. Sustained remission or LDA was defined as any patient achieving the required DAS28-ESR thresholds on two sequential follow-ups during the first 3 years of data collection. Only one period of sustained remission/LDA was counted per individual and analysis included only individuals starting on an anti-TNF as their first biologic agent. Point remission was defined as any patients who had one or more recorded occurrences of non-consecutive episodes of remission. Patient data were censored at the time of switching to another anti-TNF or biologic agent or discontinuation of anti-TNF treatment. Possible clinical and demographic variables associated with response were identified from a systematic review  and assoTo examine changes in prescribing and patient characteristics over time, the dataset was split into two chronological subgroups (2001–2010 and 2010–2013). Recruitment for anti-TNF medications  to the BSRBR-RA was paused from 2007 until 2010 and then restarted in 2010 to include etanercept, infliximab, adalimumab and certolizumab (the recruitment of which was targeted). These factors made 2010 an appropriate time point to split the cohort. Only individuals enrolled up to 2013 were included in the analyses to allow for three complete years of data collection (up to a data censor date of 30 September 2016).t-tests and χ2. Univariable regression analysis  confirmed variables for inclusion in the final multivariable logistic regression model. Binary vector multiplication identified individuals in sustained remission/LDA. Uni- and multivariable regression modelling was performed on all imputed datasets [using the generalized linear model package in R ] and results combined using Ruben’s rules  achieving sustained LDA across the whole cohort also had at least one episode of point remission. Indeed, only 627 (16.5%) patients who achieved sustained LDA had no recorded episodes of remission .The proportion of sustained LDA patients achieving at least one episode of point remission has remained stable over time. However, the proportion of patients who never achieved remission in the sustained LDA group decreased from 4.4% in the 2001–2010 subgroup to 2.7% in the 2010–2013 subgroup, although the numbers are small .P < 0.05) confirmed the inclusion of all variables in the multivariable model except smoking. However, given the evidence of a link between smoking and RA pathogenesis and severity [Univariable analysis , baseline MTX, greater PGA and ex-smoker status (vs current smoker) were associated with an increased likelihood of sustained remission in the whole cohort and the 2001–2010 subgroup. Never-smoker status, greater swollen joint count (SJC) and more recent commencement of anti-TNF were also associated with an improved likelihood of achieving sustained remission in the 2001–2010 subgroup but not the whole cohort. Female gender, older age at starting anti-TNF, infliximab use (vs etanercept), increasing BMI and greater baseline ESR were all negatively associated with the likelihood of achieving sustained remission in the cohort as a whole and the 2001–2010 subgroup  ratio (i.e. more swollen than tender joints) was associated with a greater chance of achieving sustained LDA in the 2010–2013 subgroup only .vs etanercept) were all associated with reduced likelihoods of sustained LDA in all analyses. Increasing TJC, female gender and greater age at starting anti-TNF treatment were associated with a reduced likelihood of sustained LDA for the cohort as a whole and the 2001–2010 subgroup , increased anti-TNF switching (and thus being censored from these data) and earlier use of anti-TNFs. However, this study did not investigate switching or length of time on anti-TNF treatment, so it is not possible to quantify this from these data. It should also be noted that for this analysis, MTX use was defined as co-prescription at the time of commencement of an anti-TNF (i.e. baseline entry to the BSRBR-RA), not at subsequent follow-up visits. Therefore it is possible that some patients who were co-prescribed MTX at baseline subsequently stopped taking it and vice versa. Current evidence suggests combination biologic–MTX therapy is superior to biologic monotherapy , 25, altCompared with etanercept, adalimumab had better and infliximab worse rates of sustained remission and LDA. Adalimumab may truly be associated with higher rates of sustained remission and LDA. However, etanercept and infliximab were first-in-class anti-TNF agents given to patients with the worst disease activity, greatest disability and longest disease duration, all factors independently associated with a lower likelihood of achieving remission , 7 and iIn sustained LDA/remission analyses, a greater number of predictors were identified in the 2001–2010 subgroup compared with the 2010–2013 analysis, which may be due to different group sizes, although it is possible increasing treatment standardization has influenced the latter subgroup results.This analysis examines one of the most challenging clinical targets of treatment: sustained remission. Use of real-world data to examine this endpoint is important, as clinical trial data are lacking and results from routine clinical use are often not as favourable as those seen in clinical trial environments . FurtherRheumatology online). Remission was defined according to DAS28 criteria, which is known to be more lenient than contemporary definitions [This study has limitations. It is an observational study and, as such, causality cannot be demonstrated. Although recruitment to the BSRBR-RA is nationwide and has broad inclusion criteria, there may be unidentified selection biases. There is real-world variation in follow-up patterns that result in variable sequential follow-up data and there are different recruitment windows that may have influenced results  and is in line with most current standard public health advice. It also shows that clinically demonstrable evidence of inflammation (swollen joints) are a good predictor of future sustained response and supports the paradigm of aggressive treat-to-target clinical practice. Conversely however, it also suggests individuals with high TJCs in the absence of clinical inflammation are less likely to experience resolution of symptoms and is in keeping with findings from a recent Norwegian DMARD study .The finding that MTX does not increase the likelihood of achieving sustained remission or LDA in the most recent subgroup requires further investigation before any changes to guidance can be issued.These results challenge assumptions about the treatment of RA patients with anti-TNF and show that patients treated in clinical practice today and the associations with sustained remission and LDA are significantly different from when anti-TNF first became available. Additional work is required to examine if predictors identified in this study are generic to all biologic-class drugs or if nuances are observed between different biologic classes that could help tailor treatment to individual patients.kez188_Supplementary_DataClick here for additional data file.


We have shown previously that a feed-forward, back propagation neural network model based on composite n-grams can predictnormalized signal strengths of a microarray based DNA sequencing experiment. The microarray comprises a 4xN set of 25-basesingle-stranded DNA molecule ('oligos'), specific for each of the four possible bases  for Adenine, Cytosine,Guanine and Thymine respectively at each of N positions in the experimental DNA. Strength of binding between reference oligos andexperimental DNA varies according to base complementarity and the strongest signal in any quartet should `call the base` at that position.Variation in base composition of and (or) order within oligos can affect accuracy and (or) confidence of base calls. To evaluatethe effect of order, we present oligos as n-gram neural input vectors of degree 3 and measure their performance. Microarray signalintensity data were divided into training, validation and testing sets. Regression values obtained were >99.80% overall with very lowmean square errors that transform to high best validation performance values. Pattern recognition results showed high percentageconfusion matrix values along the diagonal and receiver operating characteristic curves were clustered in the upper left corner,both indices of good predictive performance. Higher order n-grams are expected to produce even better predictions. DNA sequences are strings of hundreds to millions of fournitrogenous bases represented by the letters A,C,G, and T respectively.Representation of these strings as numerical values enables theapplication of powerful dig- ital signal processing techniques.Desirable properties of a DNA numerical representations andsome examples are given in -yσ(y) = 1/1-ewhere y is the weighted sum of the inputs. The output ofthe sigmoid function ranges from 0 to 1, increasingmonotonically with its input and the weights of theinterconnections between the different neurons are adjustedduring the training process to achieve a desired input/outputmapping. Artificial neural networks studies have been used forcomputational analysis of human DNA sequence In This is a 2-dimensional matrix with a row and column for eachclass for training, validation, testing and all datasets. Each matrixelement shows the number of test examples for which the actualclass is the row and the predicted class is the column. Good resultscorrespond to large numbers down the main diagonal. Thediagonal (green cells) in each table show the number of casesthat were correctly classified. The off-diagonal (red cells) showthe misclassified cases. Blue cells in the bottom right show thetotal percent of correctly classified cases (in green text) and thetotal percent of misclassified cases (in red text). ROC curve shown in We adopt the same methods as in 1.Compute n-gram profiles of the DNA data set using Python programming language.2.Calculate the nucleotide, di nucleotide and tri nucleotide frequencies of these profiles..3.Do substitution of the nucleotides, di nucleotides and tri nucleotide strings with their respective frequencies. Do the following on the intensity profiles:4. Calculate the highest and lowest value along each row..5. Do normalization along each row using N(i) = (yi - min)/(max - min), where yi is the actual value of the attribute i, max and min are the maximum and minimum values along each row..6. Repeat step 5 for every row of intensity profile..7. Combine results obtained from step 1 to step 6..8. Extract every 26th line (to avoid subsequence overlap and possibility of random match) from the data set after the operations above..9. Use Matlab subroutines to get performance plots, regression values, confusion matrices and Receiver operating characteristic curves.The flowchart for the steps is shown in Neural network regression value R, determine how robust theprediction is. Higher R value and a smaller MSE in terms ofperformance imply good prediction. We compare theperformances of the networks with 1-3-gram, 2-3-gram and 1-2-3-gram with different number of neurons in the hidden layerusing the Matlab regression toolkit. These results are comparedwith those obtained in As noted in  We can predict the signal intensities via their normalized valuesfrom Affymetrix data using artificial neural network based n-grammodel. It seems the higher the n-gram value and appropriatecomposition, the better the predictive accuracy of the model. Theusage of higher n-gram values and their different compositions areconsidered in this paper. Efforts could be made to increase thenumber of n-grams to see if better results can be obtained whichwe envisage to be true. An effort could also be made to getoptimal number of neurons in the hidden layer that give maximalregression values and lower mean square error. An increase inregression value to say 0.999 is indicative of a much betterprediction with its attendant low mean square errors which is ameasure of performance. As we increase the n-grams, we canalso check which composition of the n-grams give better results.Greater confusion matrix values along the diagonal and ROCcurves points in the upper most left corner can also be achievedfor better classification.


Cervical cancer is almost entirely preventable through vaccination and screening, yet remains one of the ‘gravest threats to women’s lives’ according to the World Health Organization. Specific high-risk subtypes of human papillomavirus (HR-HPV) are well-established as the primary cause of cervical cancer. Uganda has one of the highest cervical cancer incidence rates in the world  as a result of limited screening access and infrastructure. The integration of a self-collected cervical cancer screening program using HPV testing within existing community-based primary health care services could increase access to screening and reduce cervical cancer rates among Ugandan women.Using a pragmatic, sequential, cluster randomized trial design; we will compare the effectiveness of two cervical cancer screening models for self-collected HPV testing: 1) community health worker recruitment (door-to-door); and 2) community health meetings. In Mayuge district, Uganda, 31 villages are randomized to one of two treatment arms. Due to the nature of this trial, blinding is not possible. Women are eligible to participate if they have no previous history of hysterectomy or treatment for cervical cancer or pre-cancer and are aged 25–49 years old. All participants receive an integrated package of cervical cancer screening and education. Samples are tested for HPV using GeneXpert point of care testing. All women who test positive for HR-HPV types are referred to a designated health centre for follow-up inspection by Visual Inspection with Acetic acid (VIA) and treatment with thermal ablation. The primary outcome for the trial is the number of women who attend follow-up for VIA screening at a designated Health Centre after a positive HR-HPV test out of all women screened per arm. Secondary outcomes include: cervical cancer screening knowledge; patient-reported experience measures for self-collected cervical cancer screening; and HPV incidence.Results from this study will inform the national scale-up of cervical cancer screening in Uganda, aligning with the World Health Organization’s target of achieving cervical cancer elimination through the pillar of increased HPV screening coverage., ISRCTN12767014. Registered 14 May 2019, 10.1186/ISRCTN12767014; clinicaltrials.gov, NCT04000503; Registered 27 June 2019, https://clinicaltrials.gov/ct2/show/NCT04000503ISRCTNJanuary 8, 2020, version 1. Although cervical cancer is almost entirely preventable through vaccination and screening, it continues to be responsible for unnecessary deaths among women around the world. The World Health Organization (WHO) has called cervical cancer one of the ‘gravest threats to women’s lives’  as it isSpecific high-risk subtypes of human papillomavirus (HR-HPV) are well-established as the cause of cervical cancer , 7. NearThe WHO recommends a screen-and-treat strategy to reduce incidence of cervical cancer. This strategy can include either screening with an HR-HPV test followed by visual inspection with acetic acid (VIA) and treatment with thermal ablation for women who test positive on both tests, or screening with an HR-HPV test and treatment for all HR-HPV positive cases . HR-HPV Self-collected HR-HPV testing is highly acceptable to women and care providers and has potential to be rapidly expanded through communities –15, partThe primary objective of this study is to compare cervical cancer screening follow-up completion using two implementation approaches for self-collected HR-HPV testing in a rural, low-resource setting: 1) community health workers recruiting women door-to-door and 2) community health meetings. Secondary objectives of the trial are to compare cost-effectiveness of each cervical cancer screening model measured by the incremental cost-effectiveness ratio (ICER) and reduction in lifetime cervical cancer risk for each study arm and to conduct a process evaluation guided by the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework  focused Advances in Screening and Prevention in Reproductive Cancers (ASPIRE) Mayuge is a pragmatic, sequential, two-arm cluster-randomized trial in Mayuge district, Eastern Uganda. The sequential nature of the study arms was chosen to prevent contamination between arms related to the enhanced community mobilization efforts included in arm 2. Ethics approval was granted from the University of British Columbia / Children’s and Women’s Health Centre of British Columbia Research Ethics Board (UBC C&W REB # H17–03332) and the Uganda Cancer Institute Research Ethics Committee (UCIREC REF-02-2018). All study participants have provided informed consent.Mayuge district in Eastern Uganda has an estimated population of 480,000 residents divided into 13 sub-counties . The majThe study involves task shifting self-collected CCS to CHWs, known locally as Village Health Teams (VHT). VHT are an existing element in Uganda’s community-based primary health care service model in rural areas and currently administer health education to communities through informal community health days. Topics for discussion at the community health days are determined through the demands of the local community or based on government defined priorities. For this trial, a total of 61 CHWs have completed a one-week training session guided by the WHO’s CHW training guidelines for CCS . TraininPrior to recruitment, all laboratory staff at the Kigandalo HCIV were trained on the use of the GeneXpert IV System for HPV sample analysis including clinical utility, reagents, sample collection, kit storage and handling, preparing the cartridge, quality controls, and results analysis. Concurrently, a group of 7 nurses who provide VIA screening at three designated health centres  were provided refresher training in cervical cancer screening, VIA, thermocoagulation, and quality monitoring.Women living in the Mayuge district are eligible to participate if they have no previous history of hysterectomy or treatment for cervical cancer or pre-cancer, are between the ages of 25 and 49 years, and have provided written informed consent. All women in the study villages who are approached and meet the inclusion criteria are invited to participate in a survey and self-collected HR-HPV testing. Women not meeting the inclusion criteria or those unable to provide informed consent are excluded. Any women who consent to the survey but decline self-collected CCS are referred to a HCIV in Kigandalo and are included in the study population but are not included in the primary analysis Fig. . For armThe ASPIRE Mayuge trial includes two sequential intervention arms. In both arms, participants are offered a package of self-collected cervical cancer screening and education that is integrated into community-based primary health care services, but interventions differ primarily by the model of delivery: door-to-door vs community health day. Participants who test positive for HR-HPV types follow the same pathway to care regardless of intervention allocation  described in Michie et al.’s Behaviour Change Techniques Taxonomy version 1(BCTTv1) . The BCTIn arm 1, participants receive one-to-one interaction with the CHW at their homes. A CHW goes door-to-door asking women to participate in a baseline survey, offers participants sexually transmitted infection (STI) and cervical cancer health education, and provides them with instructions on how to self-collect for CCS. The specimen is then dropped at a HCII or HCIII by the CHW and transported to a central laboratory at a local health centre for testing using GeneXpert point of care testing for HPV . SamplesIn arm 2, participants receive group interaction with a team of CHWs and other members of their community at a community health day meeting. Participants are asked to complete a baseline survey individually with a CHW. STI and cervical cancer health education and self-collected screening instructions are provided to participants in a group setting led by the CHW from their village. Participants choosing to complete self-collected CCS do so at a private location and a CHW drops the specimens at a HCIV at the end of the community health day. A follow-up community health day meeting is held to provide additional group education and CHWs deliver test results to participants in a one-on-one setting. Participants who test positive for HR-HPV are provided counselling and are invited to schedule their follow-up visit for VIA at an HCIII or HCIV.To describe the association between HPV and other STI, a small sub-sample of 100 participants from each arm are provided the opportunity to self-collect for chlamydia and gonorrhea testing in addition to HR-HPV testing. For those who test positive for either of the STIs, treatment is dispensed by a nurse at the Health Centre for the patient and their partner. Treatment is provided according to National guidelines in Uganda.Study outcomes were determined by applying RE-AIM framework  to interCervical cancer screening knowledge measured as the count of correct responses to knowledge questions per individual within 6 months of recruitment.Patient-reported experience measures for self-collected cervical cancer screening at intervention completion at the individual level within 6 months of recruitment.HPV incidence at baseline as a sensitivity analysis to test our assumption of equal distribution of HR-HPV among the study population.Secondary outcomes compared between arms include:A summary of objectives, outcomes and analysis plans can be found in Table A time line of study activities can be found in Table Sample size for the study was restricted to the 31 villages in the region available for randomization. Power was estimated using R statistical software across a range of plausible interclass correlation coefficients (ICCs) and absolute changes in follow-up rate from the baseline of 20% in one study arm. Power calculations assumed 15 clusters per study arm with an average size of 70 women per cluster. Power estimates were repeated using a cluster size of 50 women per village with negligible effect. Using these assumptions, we are adequately powered for a 20–30% absolute change in the outcome rate between the study arms, and up to 10% absolute change if low heterogeneity in clusters is found  using a 1:1 allocation. Stratification was performed to balance the clusters around the two sub-districts that each includes health centres where VIA follow-up is taking place. Blinding of study staff, outcome assessors, or participants is not possible due to the spatial and temporal nature of intervention arms.Primary trial data is captured through a survey of all participants at enrollment; a follow-up survey within 6 months of results; an audit of laboratory result logs; VIA screening logs; and referral and treatment logs at the participating facilities. All enrollment surveys are administered by a trained CHW in Lusoga or English based on the language of preference of the participant. The Core Plus module 1 (CPLUS1) from the Improving Data for Decision Making in Global Cervical Cancer Programs Toolkit-Part 2 (IDCCP)  is used After completion of CCS follow-up and within 6 months of baseline recruitment, an additional subgroup of 775 participants are recruited by a research assistant to complete a knowledge retention and patient-experience survey to better understand inhibitors and facilitators to self-collected CCS behaviour. The CCS knowledge and patient experience survey design was primarily informed by the IDCCP CPLUS1 module  and the A supplementary survey is distributed to approximately 300 men in the Mayuge district who attend the community health meetings for arm 2. The men’s survey was designed using the IDCCP CPLUS1 module  to captuCost and person-time data used for cost-effectiveness analysis is collected from the study’s financial records and by using customized survey tools completed at each health centre and through observations of both HPV and VIA screening during each study arm. An audit of the screening logs in each study designated health center is completed at the time of arm 1 recruitment start to estimate a cluster level measure of engagement in the VIA screening program prior to initiation of the study. Focus group discussions with participants who screen positive for HR-HPV and either complete or do not complete follow-up are conducted to evaluate the acceptability of screening and barriers and facilitators to engagement in care.A customized data management tool was developed using Research Electronic Data Capture (REDCap) software . Data isStatistical analysis will be performed in R Statistical software using the clusterPower package  with an Apparent prevalence of HPV and STIs will be estimated in the study regions using trial data. Population prevalence of CIN2+ will be estimated based on this apparent prevalence using the reported sensitivity and specificity of the GeneXpert HPV test for this disease status Table .Table 5Secondary outcomes compared between arms will be estimated in a similar manner. The effect of each study arm on HPV incidence is estimated using a multi-level logistic regression model as per the primary analysis. The effect of each study arm on CCS knowledge and patient experience will be estimated using a multi-level Poisson model, adjusted for the same individual and cluster level confounders with the addition of HPV status as an individual compounder and with person-time in follow-up as an offset.Planned secondary analyses include estimating the group by arm interaction of HIV and other STI status on effectiveness of each CCS model. This will be done by adding an interaction term for each comorbidity and arm in the primary model. Temporal trends in HPV incidence and follow-up will be presented graphically.Cost-effectiveness of the intervention will be estimated using a societal perspective and including all health system and out of pocket costs incurred for women participants in each arm. A decision tree model will be developed based on the patient pathway through care See Fig.  in each Process evaluation will be performed using a study specific logic model framework to define inputs, activities and outcomes See Fig. .. ProcesQualitative data will be analyzed using InVivo with initial open coding will be done based on the FGD guides to identify themes using a deductive approach.The ASPIRE Mayuge trial will provide evidence on the best model of delivery for integrated self-collected cervical cancer screening and follow-up in a rural low-resource setting. According to Mayuge District’s Development Plan II, a lack of skilled human resources and infrastructure are the main health system-related challenges faced by the district . To meetn = 43) reported ever being screened, 3.6% (n = 16) of whom were from Mayuge district [This approach aligns with the World Health Organization’s efforts towards achieving elimination within the twenty-first century through three key target areas: increased coverage of vaccination against human papillomavirus (HPV); increased screening coverage with an HPV test and appropriate management of women who have screened positive; and reduced mortality from cervical cancer . Ndejjo district . BarrierThe major challenges of implementation in real-world global health settings are unsustainable reliance on foreign donors, and the lack of infrastructure, commodities, and human resources . Models Additional file 1. Written Consent FormAdditional file 2. Verbal Consent Script: Baseline SurveyAdditional file 3. Verbal Consent Script: Follow-up Survey


Individuals with motor-incomplete SCI (m-iSCI) remain limited community ambulators, partly because they have difficulty with the skilled walking requirements of everyday life that require adaptations in inter-joint coordination and range of motion of the lower limbs. Following locomotor training, individuals with SCI show improvements in skilled walking and walking speed, however there is limited understanding of how adaptations in lower limb kinematics following training contribute to improvements in walking.To determine the relationship between changes in lower limb kinematics (range of motion and inter-joint coordination) and improvements in walking function  following locomotor training.Lower limb kinematics were recorded from 8 individuals with chronic m-iSCI during treadmill walking before and after a 3-month locomotor training program. Data were also collected from 5 able-bodied individuals to provide normative values. In individuals with SCI, muscle strength was used to define the stronger and weaker limb. Motion analysis was used to determine, hip, knee and ankle angles. Joint angle-angle plots (cyclograms) were used to quantify inter-joint coordination. Shape differences between pre-and post-training cyclograms were used to assess the changes in coordination and their relation to improvements in walking function. Walking function was assessed using the 10MWT for walking speed and the SCI-FAP for skilled walking. Comparing pre- and post-training cyclograms to the able-bodied pattern was used to understand the extent to which changes in coordination involved the recovery of normative motor patterns.ρ = − .833, p = 0.010) and knee range of motion  of the weaker limb. Inter-joint coordination tended to revert towards normative patterns, but not completely. No relationships were observed with walking speed.Following training, improvements in skilled walking were significantly related to changes in hip-ankle coordination (Larger changes in hip-ankle coordination and a decrease in knee range of motion in the weaker limb during treadmill walking were related to improvements in skilled walking following locomotor training in individuals with SCI. The changes in coordination seem to reflect some restoration of normative patterns and the adoption of compensatory strategies, depending on the participant. Rehabilitation and exercise training programs are important for individuals with spinal cord injury (SCI), not only to promote mobility, but also for minimizing the effects of secondary complications and improving quality of life –4. FolloMulti-joint movements, whether reaching for a cup or stepping over an obstacle, are essential components of everyday life. These skilled movements require concurrent rotations about several joints to guide the end-point along a desired trajectory towards or over a target. During walking, accurate control of foot trajectory during the swing phase is necessary for ensuring foot-floor or foot-object clearance to avoid tripping and falling. The precise control of foot trajectory requires simultaneous movement and coordination of multiple joints of the lower limb –26. FollInvestigating the association between lower limb kinematics and walking function provides insight into understanding how the nervous system adapts its motor control strategies to improve walking function after a locomotor intervention. Following locomotor training, improvements in hip  or ankleAs reviewed above, the regulation of multi-segmental control by the locomotor system is important for skilled walking tasks, such as obstacle crossing. In this study, we sought to contrast the relationship between changes in lower limb kinematics (joint range of motion and inter-joint coordination) and walking function  following locomotor training. Skilled walking was assessed using the Spinal Cord Injury Functional Ambulation Profile (SCI-FAP) and walking speed was assessed using the 10-m walk test (10MWT). We hypothesized that larger changes in lower limb inter-joint coordination control following training would be related to improvements in skilled walking, but not walking speed; and that greater joint range of motion following training would be related to improvements in both walking skill and speed.Kinematic data from individuals with m-iSCI who participated in a previously published pilot randomized control trial  were incWe were only able to include data from 8 of the original 13 participants who completed the pilot RCT. Data from the other 5 individuals from the previous study were excluded because of missing kinematic data, due to either technical difficulties or missed recording sessions. We also recruited five able-bodied (AB) controls to provide normative kinematic data.For individuals with SCI, kinematic data from the lower limbs were recorded during treadmill walking before and after a 3-month Lokomat-based training program. Details of the training program are described elsewhere , but briNormative data from the AB control participants were collected during a single session of treadmill walking. AB participants walked at different combinations of speed and body-weight support that matched the treadmill walking parameters of each SCI participant. Lower limb kinematics were collected as described above.10MWT) [SCI-FAP). The SCI-FAP is a series of seven timed walking tasks which include negotiating obstacles, curbs and stairs among other functionally relevant walking tasks [For individuals with SCI, the change in walking function was defined by skilled walking capacity and walking speed, which were measured pre- and post-training intervention. Walking speed was measured using the 10-m walk test (10MWT) . Particing tasks . Lower Sng tasks –42.The Lower Extremity Motor Score (LEMS) was also used to determine lower limb muscle strength in participants with SCI . This asKinematic data were analyzed offline using MATLAB . Data were filtered using a low-pass 4th order Butterworth filter with a cut off frequency of 6 Hz. Individual steps were defined from foot contact to foot contact, determined by the anterior-posterior displacement of the toe marker. For individuals with SCI, the stronger limb was defined as the limb with the higher LEMS, and the weaker limb was defined as the limb with the lower LEMS at pre-training. In SCI03, who had the same LEMS on the left and right, the weaker limb was defined as the limb with the shorter step-length , 36, 44.The percent change in pre- and post-training SCI-FAP and 10MWT measurements were used to quantify the change in skilled walking and walking speed, respectively. For the SCI-FAP, negative values indicate an improvement in skilled walking function. For the 10MWT, positive values indicate an improvement in walking speed.ROMH) and knee ROM (ROMK) were calculated by subtracting the average minimum angle during the gait cycle from the average maximum achieved during swing  was calculated by subtracting the average ankle angle at toe off from the average ankle angle at mid-swing , hip-ankle (HA) and knee-ankle (KA) coordination, was determined by comparing pre- and post-training angle-angle plots. Following the method described by Awai and Curt [SSDpre-post). Thus, if pre- and post-training cyclograms are identical, the SSDpre-post score will be 0. Larger values indicate a greater change in coordination patterns at post-training.Inter-joint coordination, examining hip-knee  and post-training (SSDnormpost). The reference cyclogram from the AB group was drawn from the appropriate combination of treadmill speed and BWS used by each SCI participant. Here, SSD scores of 0 would indicate no difference between the SCI and AB cyclograms.To evaluate differences in inter-joint coordination with respect to a ‘normative’ pattern, the SSD was also calculated between the reference cyclograms from the AB group and the cyclograms of SCI participants at pre-training  were presented descriptively to evaluate whether inter-limb coordination was reinstated to the AB pattern following training. To account for multiple correlations of the SCI-FAP and 10MWT with each set of kinematic variables, we used the Bonferroni adjusted alpha value of 0.016 (0.05/3) to evaluate statistical significance. All statistical analyses were conducted using SPSS v.20 statistics .Given the small sample size of this data set we employed non-parametric analyses. Descriptive statistics were used to describe the characteristics of each group. Spearman’s rho (ρ) was used to determine the relationship between changes in lower limb kinematic parameters and walking function. We calculated ρ between SSDHKAB and SCI participant characteristics and treadmill test parameters are reported in Table pre-post values indicated in Fig. In Fig. As mentioned below, the change in HA coordination of the weaker limb from pre- to post-training was most associated with improvements in the SCI-FAP score. In Fig. A comparison of pre- and post-training SSD scores normalized to the AB reference values show that SSDnorm scores in the weaker limb approached zero following training, indicating a reversion towards normative inter-joint coordination patterns in the weaker limb , such that improvements in skilled walking were associated with a reduction in knee range of motion  such that improvements in SCI-FAP were associated with larger changes in HA coordination , and it was evident that the cyclograms were not identical to the AB cyclograms. Moreover, there were participants like SCI04 who showed improvements in skilled walking but whose cyclogram did not revert towards the AB reference data. Our interpretation of this finding is that this participant may rely on compensatory strategies to improve their skilled walking. Thus, our findings suggest that improvements in skilled walking could potentially be from a combination of restoring normative motor control strategies and compensatory coordination strategies depending on the individual.Previous research in SCI  and stroWe found that the improvements in walking function seen after the locomotor intervention were associated with changes in inter-joint coordination and ROM only in the weaker limb. Results from the literature on whether the kinematics of the stronger or weaker limb is more affected by locomotor training in individuals with iSCI is limited and variable. Following locomotor training, individuals with iSCI have shown improvements in the kinematics of the stronger limb , 44, theIn this analysis of secondary data collected as part of a pilot clinical trial, we were limited by the small data set available to us, which limits the generalizability of our results. Nevertheless, our results provide some insight into possible links between functional walking ability and inter-joint coordination that warrant further investigation. Another limitation is that kinematic parameters were derived during treadmill walking with BWS while the clinical walking measures of skill and speed were conducted over-ground with no BWS. However, the kinematics of treadmill walking and over ground walking are very similar , 50, sugFollowing gait training in individuals with m-iSCI, we observed that larger changes in hip-ankle inter-joint coordination and a decrease in knee range of motion during treadmill walking were associated with improvements in skilled walking. The changes in inter-joint coordination reflected some re-establishment of normative patterns as well as compensatory strategies, that varied across participants. No relationships were observed between the changes in joint range of motion or inter-joint coordination and walking speed. This study highlights the distinction of inter-joint coordination and range of motion on skilled walking as opposed to uninterrupted overground walking. Future studies should incorporate measures of inter-joint coordination, along with standard kinematic measures, during different walking tasks to further delineate the regulation of lower limb motor control associated with functional recovery after spinal cord injury.


Investigators from Boston University and the University of San Francisco studied whether EEG could be reliably used as an early biomarker for diagnosis of autism spectrum disorder (ASD). Investigators from Boston University and the University of San Francisco studied whether EEG could be reliably used as an early biomarker for diagnosis of autism spectrum disorder (ASD). They enrolled 99 infant siblings of older children with a diagnosis of ASD ("high-risk" group), and 89 infants with no siblings or first-degree relatives with ASD ("low-risk" group) beginning at 3 months of age and continuing until 36 months. Ultimately, 3 children from the low-risk group and 32 from the high-risk group were diagnosed with ASD. Children were evaluated at several time points with EEG and the Autism Diagnostic Observation Schedule (ADOS), the current gold-standard clinical diagnostic tool which also quantifies severity of symptoms through the Calibrated Severity Score (CSS). The authors analyzed various features of the EEG data to create an algorithm to predict ASD diagnosis. They found that the EEG algorithm was highly predictive in distinguishing those children who were ultimately diagnosed with ASD from those who were not, at as early as 3 months of age. The EEG algorithm was able to differentiate the ASD and low-risk/no-autism group with 100% specificity and positive predictive value (PPV) at all ages of testing. Sensitivity in this group ranged from 82-100%. High-risk/no-autism infants were also distinguished from the ASD group at high rates but were generally more difficult to classify as their EEG data placed them near the diagnostic borderline. When EEG data from high and low risk non-autism groups were combined and compared to the ASD group, sensitivity ranged from 82-100%, specificity 88-99%, and PPV 65-97%. An overall dip in predictive accuracy was seen in both groups at 12 months of age, with improvement at and beyond 18 months. EEG findings were also used to predict severity of autism symptoms, with moderately strong correlation to actual CSS scores (r 0.45-0.55). [COMMENTARY. This study’s results offer a promising future diagnostic possibility for early, reliable diagnosis of ASD. The institution of early autism-specific therapies is critical in supporting optimal development and is associated with better outcomes in ASD . HoweverThe author(s) have declared that no competing interests exist.