Anatomical categorization of isolated non-focal dystonia: novel and existing patterns using a data-driven approach.

According to expert consensus, dystonia can be classified as focal, segmental, multifocal, and generalized, based on the affected body distribution. To provide an empirical and data-driven approach to categorizing these distributions, we used a data-driven clustering approach to compare frequency and co-occurrence rates of non-focal dystonia in pre-defined body regions using the Dystonia Coalition (DC) dataset. We analyzed 1,618 participants with isolated non-focal dystonia from the DC database. The analytic approach included construction of frequency tables, variable-wise analysis using hierarchical clustering and independent component analysis (ICA), and case-wise consensus hierarchical clustering to describe associations and clusters for dystonia affecting any combination of eighteen pre-defined body regions. Variable-wise hierarchical clustering demonstrated closest relationships between bilateral upper legs (distance = 0.40), upper and lower face (distance = 0.45), bilateral hands (distance = 0.53), and bilateral feet (distance = 0.53). ICA demonstrated clear grouping for the a) bilateral hands, b) neck, and c) upper and lower face. Case-wise consensus hierarchical clustering at k = 9 identified 3 major clusters. Major clusters consisted primarily of a) cervical dystonia with nearby regions, b) bilateral hand dystonia, and c) cranial dystonia. Our data-driven approach in a large dataset of isolated non-focal dystonia reinforces common segmental patterns in cranial and cervical regions. We observed unexpectedly strong associations between bilateral upper or lower limbs, which suggests that symmetric multifocal patterns may represent a previously underrecognized dystonia subtype.

A cross-sectional study of walking, balance and upper limb assessment scales in people with cervical dystonia.

Cervical dystonia (CD) is a neurological movement disorder causing the neck to move involuntarily away from the neutral position. CD is a network disorder, involving multiple brain areas and, therefore, may impair movement in parts of the body other than the neck. This study used clinical assessments to investigate walking, balance and upper limb function (UL) in people with CD; the reliability of scoring these assessments and examined for relationship between CD severity, usual exercise and clinical assessments. We conducted a prospective observational cohort study of participants with isolated, focal, idiopathic CD. Participants were assessed by experienced physiotherapists and completed three questionnaires and eight clinical assessments of fear of falling, balance confidence, walking, balance, UL function and usual exercise. Results were compared to published data from healthy adults and other neurological populations. Twenty-two people with mild to moderate CD participated. Fear of falling, gross UL function and usual exercise were worse in people with CD compared with healthy adults, while walking, balance and distal UL function were similar to healthy populations. All assessments were reliably performed by physiotherapists, and we found no correlations between the severity of dystonia or usual exercise and performance on the physical assessments. Routine performance of clinical assessment of walking and balance are likely not required in people with mild to moderate CD; however, fear of falling and gross upper limb function should be assessed to determine any problems which may be amenable to therapy.

MRI findings for diagnosis of postoperative foreign body granulomas versus recurrent tumours in patients of brain tumour surgery.

AIM: To evaluate the postoperative magnetic resonance imaging (MRI) findings of intracranial foreign body granulomas (FBGs) and true recurrent tumours (RTs) and thus lead to a basis for management decision-making. MATERIALS AND METHODS: Twenty-two patients with previous brain tumour surgery were diagnosed clinically with RT and underwent surgery. Re-operative pathology revealed FBG in eight patients and RT in 14 patients. MRI findings before the initial operation were compared to those before the re-operation. RESULTS: Features of FBGs versus RTs on MRI were as follows: (1) mean lesion size: 1.3 ± 0.7 (0.5-2.6) versus 3.2 ± 1.7 (1.1-6.3) cm (p=0.001, odds ratio [OR] = 4.18); (2) hypointensity on T2-weighted imaging (WI): 6/8 (75%) versus 0/14 (0%; p<0.001, OR=75.4); (3) non-restricted diffusion on diffusion-WI (DWI): 6/8 (75%) versus 2/14 (14.3%; p=0.008, OR=18); and (4) "ring and bubble" appearance on contrast-enhanced T1WI: 7/8 (87.5%) versus 2/14 (14.3%; p=0.001, OR=42). In comparison with their original tumours, the FBGs in the FBG group showed significantly lower T2 signal intensity, lower signal on DWI, and more cases of non-restricted diffusion on DWI (p=0.04, 0.04, 0.04, respectively). CONCLUSION: On brain MRI, FBGs can be differentiated from RTs by their relatively smaller size, hypointensity on T2WI, lack of restricted diffusion on DWI, and "ring and bubble" appearance on contrast-enhanced T1WI. Comparing the MRI findings of the focal lesion in the tumour bed with those of the original tumour is suggested to enhance diagnostic confidence.

Long-term comparison study of philtral ridge morphology with two different techniques of philtral reconstruction.

Cleft lip and/or cleft palate are the most common congenital craniofacial anomalies. Philtral ridge morphology is an important aesthetic component of unilateral cleft lip (UCL) repair. To this end, we have developed two techniques of philtral ridge reconstruction: (1) asymmetric mattress muscle sutures, and (2) overlapping mattress muscle sutures. The objective of this retrospective cohort study was to compare their outcomes in UCL repairs. Group I patients (n=30) underwent UCL repair before August 2003, including philtral ridge reconstruction by asymmetric mattress muscle sutures. Group II patients (n=30) underwent UCL repair after August 2003, including philtral ridge reconstruction by overlapping mattress muscle sutures. Philtral morphology was evaluated by ultrasonographic and three-dimensional photographic measurements, examining cleft side philtral projection and philtral ridge symmetry. These demonstrated that group II patients had better philtral column symmetry and projection on the cleft side when compared to group I. Overlapping mattress muscle sutures produced better philtral morphology in UCL repairs than asymmetric mattress muscle sutures.

Validating the Automatic Independent Component Analysis of DSA.

Time-density curve analysis of DSA provides useful blood flow information. However, manually selecting the ROI is time-consuming. We developed an automatic technique to provide arterial, capillary, and venous vasculatures with corresponding time-density curves. This study retrospectively analyzed the data of 36 patients with unilateral carotid stenosis. We found that the full width at half maximum of the time-density curve for the automatically segmented capillary vasculature is a suitable representation of the cerebral circulation time.

Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.

Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.

Peritherapeutic Hemodynamic Changes of Carotid Stenting Evaluated with Quantitative DSA in Patients with Carotid Stenosis.

BACKGROUND AND PURPOSE: Quantitative data from DSA have become important tools for understanding hemodynamic changes of intracranial lesions. In this study, we evaluated 8 hemodynamic parameters in patients before and after carotid artery angioplasty. MATERIALS AND METHODS: DSA images of 34 patients with carotid stenosis who underwent angioplasty and stent placement were retrospectively analyzed. Eleven ROIs (M1, M2, A1, A2, the parietal vein, superior sagittal sinus, internal jugular vein, and 4 in the ICA) were selected on color-coded DSA. Eight hemodynamic parameters (bolus arrival time, TTP, relative TTP, full width at half maximum, wash-in slope, washout slope, maximum enhancement, and area under the curve) were measured from the time-concentration curves of these ROIs. The dependent t test for paired samples was applied to these parameters before and after stent placement. RESULTS: We found that the treatment significantly reduced TTP, relative TTP, bolus arrival time, and washout slope at all arterial ROIs and full width at half maximum and area under the curve at some arterial ROIs. Bolus arrival time was significantly reduced after treatment for all arterial ROIs, the parietal vein, and the superior sagittal sinus. The maximum enhancement and wash-in slope did not show significant changes after treatment. After treatment, the relative TTP from the ICA to M1, M2, and the parietal vein returned to normal values. CONCLUSIONS: In addition to TTP and relative TTP, other parameters can be used to evaluate peritherapeutic cerebral hemodynamic changes. Bolus arrival time has the potential to evaluate brain circulation at arterial and venous sites, especially when TTP cannot be measured because of an incomplete time-concentration curve.

Impact of mTOR Inhibitors on Cancer Development in Kidney Transplantation Recipients: A Population-Based Study.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor is an immunosuppressive drug used in kidney transplantation. Whether the mTOR inhibitor is associated with reduced risk of cancer development and mortality after kidney transplantation is controversial. METHODS: We conducted a nationwide population-based study. Patients who did not have malignancy history and received kidney transplantation between 2010 and 2013 were enrolled. Recipients who had mTOR inhibitors (n = 430) for more than 30 days comprised the study group; 1720 recipients who did not have mTOR inhibitors comprised the control group. The primary outcome is the development of cancer after kidney transplantation. These patients were followed until the first-time admission with diagnosis of cancer, death, or the end of 2014. A Cox proportional-hazard model was used to determine the risk of cancer development and all-cause mortality. RESULTS: During the 35-month median duration of observation, there were 16 and 61 patients with cancer development in the study group and the control group, respectively. The cancer incidence was 12.8 and 12.4 per 1000 person-years. There were 10 and 135 mortality cases, with the incidence rate of 7.8 and 26.9 per 1000 person-years. After multivariable adjustment, the mTOR inhibitors users were not associated with reduced risk of new cancer development as compared with control (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.46-1.60; P = .63), nor risk of all-cause mortality (HR, 0.70; 95% CI, 0.33-1.46; P = .34). CONCLUSIONS: The use of mTOR inhibitors was not associated with a reduction in the risk of cancer development and all-cause mortality in kidney transplantation recipients.

Intervention versus Aggressive Medical Therapy for Cognition in Severe Asymptomatic Carotid Stenosis.

BACKGROUND AND PURPOSE: Asymptomatic carotid stenosis of ≥70% increases the incidence of microembolism and/or chronic hypoperfusion, which may consequently impair neurocognition and brain connections. We sought controlled evidence for any cognitive benefit of aggressive medical therapy and combined carotid revascularization. MATERIALS AND METHODS: Patients with asymptomatic, unilateral, ≧70% stenosis of the extracranial ICA chose either aggressive medical therapy alone or in combination with carotid artery stent placement in this nonrandomized controlled study. They were examined with a battery of neuropsychological tests, structural MR imaging, DTI, and resting-state fMRI before and 3 months after treatment. RESULTS: Forty patients were included with 15 in the medical group and 25 in the stent-placement group. Among them, 13 and 21 in the respective groups completed neuroimaging follow-up. The baseline characteristics and the changes in cognitive performance during 3 months showed no differences between treatment groups. Nevertheless, compared with the medical group, the stent-placement group showed subjective dizziness alleviation (P = .045) and a small increase in fractional anisotropy at the splenium of the corpus callosum and the posterior periventricular white matter ipsilateral to carotid artery stent placement. Moreover, only the stent-placement group showed interval improvement in immediate memory and visuospatial performance, which was accompanied by an increase of functional connectivity at the insular cortex of the dorsal attention network and the medial prefrontal cortex of the default mode network. CONCLUSIONS: Both aggressive medical therapy alone and combined carotid revascularization in ≧70% asymptomatic carotid stenosis similarly preserved cognition during 3-month follow-up, though the latter had the potential for dizziness alleviation and cognitive and connectivity enhancement.

Four cases of orthostatic myoclonus.

Orthostatic unsteadiness (unsteadiness on standing) is a relatively common symptom and can have neurological or non-neurological causes. Glass et al. have recently described a syndrome presenting with unsteadiness or leg jerking during standing or gait initiation difficulty which they have termed orthostatic myoclonus (OM). OM is a disabling syndrome but potentially treatable. It may develop on the background of neurodegenerative disease; other causes include pro-myoclonic drugs such as tricyclic antidepressants. In order to increase awareness of this syndrome, we report four patients with electrophysiologically confirmed OM who were referred to the movement disorder unit for lower limb tremor studies. All four patients presented with unsteadiness on standing. There were no signs suggestive of neurodegenerative disease and three of the patients had a provisional diagnosis of orthostatic tremor. The diagnosis of OM was supported by a surface electromyography showing 9-16Hz, non-rhythmic muscle bursts with burst duration of 50-100ms during standing. OM is unrecognised by many physicians as a cause of orthostatic intolerance. The most common syndrome with which OM may be confused is orthostatic tremor. A correct diagnosis is important as it may respond to treatment with clonazepam, gabapentin or piracetam.

Changes of time-attenuation curve blood flow parameters in patients with and without carotid stenosis.

BACKGROUND AND PURPOSE: From the time-attenuation curves of DSA flow parameters, maximal intensity, maximal slope, and full width at half maximum of selected vascular points are defined. The study explores the reliability of defining the flow parameters by the time-attenuation curves of DSA. MATERIALS AND METHODS: Seventy patients with unilateral carotid artery stenosis (group A) and 56 healthy controls (group B) were retrospectively enrolled. Fixed contrast injection protocols and DSA acquisition parameters were used with all patients. The M1, sigmoid sinus, and internal jugular vein on anteroposterior view DSA and the M2, parietal vein, and superior sagittal sinus on lateral view DSA were chosen as ROI targets for measuring flow parameters. The difference of time of maximal intensity between 2 target points was defined as the circulation time between the target points. RESULTS: The maximal intensity difference of 2 selected points from the ICA to the M1, sigmoid sinus, internal jugular vein, M2, parietal vein, and superior sagittal sinus was significantly longer in group A than in group B. The maximum slope of M1, M2, and the superior sagittal sinus was significantly lower in group A than in group B. The full width at half maximum of M1 and M2 was significantly larger in group A than in group B. The maximal slope of M1 demonstrated the best diagnostic performance. CONCLUSIONS: The maximal intensity difference of 2 selected points derived from DSA can be used as a definitive alternative flow parameter for intracranial circulation time measurement. Maximal slope and full width at half maximum complement the maximal intensity difference of 2 selected points in defining flow characteristics of healthy subjects and patients with carotid stenosis.

Photocatalytic reduction of CO2with SiC recovered from silicon sludge wastes.

In the present study, silicon carbide (SiC) recovered from silicon sludge wastes is used as catalysts for photocatalytic reduction of CO2. By X-ray diffraction, it is clear that the main components in the silicon sludge wastes are silicon and SiC. The grain size of the SiC separated from the sludge waste is in the range of 10-20 µm in diameter (observed by scanning electron microscopy). By solid state nuclear magnetic resonance, it is found that α-SiC is the main crystallite in the purified SiC. The α-SiC has the band-gap of 3.0 eV. To yield C1-C2chemicals from photocatalytic reduction of CO2, hydrogen is provided by simultaneous photocatalytic splitting of H2O. Under the light (253-2000 nm) illumination, 12.03 and 1.22 µmol/h g cat of formic and acetic acids, respectively, can be yielded.

Pretreatment diagnosis of suprasellar papillary craniopharyngioma and germ cell tumors of adult patients.

BACKGROUND AND PURPOSE: Suprasellar papillary craniopharyngiomas and germ cell tumors in adults share some clinical and imaging similarities but have different therapeutic strategies and outcomes. This study aimed to evaluate the pretreatment diagnosis of these 2 tumors to improve the therapeutic outcome. MATERIALS AND METHODS: We retrospectively enrolled 18 adults with papillary craniopharyngiomas and 17 with germ cell tumors. The MR imaging findings were evaluated, including signal change and anatomic extension. The medical records were reviewed to collect clinical findings, management, and outcomes. RESULTS: The clinical findings of papillary craniopharyngiomas versus germ cell tumors were as follows: age: 46 ± 13.9 years versus 23 ± 7.1 years (P < .0001); diabetes insipidus: 2/18 (11%) versus 11/17 (65%) (P = .001); recurrence 13/16 (81%) versus 4/17 (24%) (P = .0031). The MR imaging findings of papillary craniopharyngiomas versus germ cell tumors were as follows­pituitary stalk thickening: 1.6 ± 0.4 mm versus 5.4 ± 4.2 mm (P < .0001); vertical infundibular extension: 1/18 (6%) versus 16/17 (94%) (P < .0001); sagittal spheric shape: 17/18 (94%) versus 1/17 (6%) (P < .0001); diffusion restriction: 1/17 (6%) versus 8/12 (67%) (P = .0009). CONCLUSIONS: Younger age, diabetes insipidus, MR imaging characteristics of restricted diffusion, and vertical infundibular extension favor the diagnosis of germ cell tumors. Spheric shape without infundibular infiltration provides clues to papillary craniopharyngiomas, which originate from the pars tuberalis and are located outside the third ventricle. We suggest that suprasellar germ cell tumor is possibly an intraventricular lesion. Appropriate treatment planning can be initiated according to the diagnosis and anatomic location.

Conducting glasses recovered from thin film transistor liquid crystal display wastes for dye-sensitized solar cell cathodes.

Transparent conductive glasses such as thin film transistor (TFT) array and colour filter glasses were recovered from the TFT-liquid crystal display panel wastes by dismantling and sonic cleaning. Noble metals (i.e. platinum (Pt)) and indium tin oxide (ITO) are generally used in the cathode of a dye-sensitized solar cell (DSSC). To reduce the DSSC cost, Pt was replaced with nano nickel-encapsulated carbon-shell (Ni@C) nanoparticles, which were prepared by carbonization of Ni²âº-ß-cyclodextrin at 673 K for 2 h. The recovered conductive glasses were used in the DSSC electrodes in the substitution of relatively expensive ITO. Interestingly, the efficiency of the DSSC having the Ni@C-coated cathode is as high as 2.54%. Moreover, the cost of the DSSC using the recovered materials can be reduced by at least 24%.

Capacitive deionization of seawater effected by nano Ag and Ag@C on graphene.

Drinking water shortage has become worse in recent decades. A new capacitive deionization (CDI) method for increasing water supplies through the effective desalination of seawater has been developed. Silver as nano Ag and Ag@C which was prepared by carbonization of the Ag(+)-ß-cyclodextrin complex at 573 K for 30 min can add the antimicrobial function into the CDI process. The Ag@C and Ag nanoparticles dispersed on reduced graphene oxide (Ag@C/rGO and nano Ag/rGO) were used as the CDI electrodes. The nano Ag/rGO and Ag@C/rGO electrodes can reduce the charging resistant, and enhance the electrosorption capability. Better CDI efficiencies with the nano Ag/rGO and Ag@C/rGO electrodes can therefore be obtained. When reversed the voltage, the electrodes can be recovered up to 90% within 5 min. This work presents the feasibility for the nano Ag and Ag@C on rGO electrodes applied in CDI process to produce drinking water from seawater or saline water.

Photocatalytic splitting of seawater effected by (Ni-ZnO)@C nanoreactors.

Novel photocatalysts i.e., metallic nickel and zinc oxide nanoparticles embedded in the carbon-shell ((Ni-ZnO)@C) have been used for photocatalytic splitting of seawater to generate H2. The (Ni-ZnO)@C core-shell nanoparticles having the Zn/Ni ratios of 0-3 were prepared by carbonization of Ni(2+)- and Zn(2+)-ß-cyclodextrin at 673 K for 2 h. To increase the collision frequency of water and photoactive sites within the carbon-shell, Ni and ZnO are partially etched from the (Ni-ZnO)@C core-shell to form yolk-shell nanoparticles with a H2SO4 solution (2N). By X-ray diffraction spectroscopy, mainly Ni and ZnO crystallites are observed in the core- and yolk-shell nanoparticles. The sizes of the Ni and ZnO in the (Ni-ZnO)@C nanoreactors are between 7 and 23 nm in diameters determined by TEM and small angel scattering spectroscopy. Under a 5-h UV-Vis light irradiation, 5.01 µmol/hgcat of H2 are yielded from photocatalytic splitting of seawater effected by (Ni-ZnO)@C nanoreactors.

Artifact reduction of different metallic implants in flat detector C-arm CT.

BACKGROUND AND PURPOSE: Flat detector CT has been increasingly used as a follow-up examination after endovascular intervention. Metal artifact reduction has been successfully demonstrated in coil mass cases, but only in a small series. We attempted to objectively and subjectively evaluate the feasibility of metal artifact reduction with various metallic objects and coil lengths. MATERIALS AND METHODS: We retrospectively reprocessed the flat detector CT data of 28 patients (15 men, 13 women; mean age, 55.6 years) after they underwent endovascular treatment (20 coiling ± stent placement, 6 liquid embolizers) or shunt drainage (n = 2) between January 2009 and November 2011 by using a metal artifact reduction correction algorithm. We measured CT value ranges and noise by using region-of-interest methods, and 2 experienced neuroradiologists rated the degrees of improved imaging quality and artifact reduction by comparing uncorrected and corrected images. RESULTS: After we applied the metal artifact reduction algorithm, the CT value ranges and the noise were substantially reduced (1815.3 ± 793.7 versus 231.7 ± 95.9 and 319.9 ± 136.6 versus 45.9 ± 14.0; both P < .001) regardless of the types of metallic objects and various sizes of coil masses. The rater study achieved an overall improvement of imaging quality and artifact reduction (85.7% and 78.6% of cases by 2 raters, respectively), with the greatest improvement in the coiling group, moderate improvement in the liquid embolizers, and the smallest improvement in ventricular shunting (overall agreement, 0.857). CONCLUSIONS: The metal artifact reduction algorithm substantially reduced artifacts and improved the objective image quality in every studied case. It also allowed improved diagnostic confidence in most cases.

Stenotic transverse sinus predisposes to poststenting hyperperfusion syndrome as evidenced by quantitative analysis of peritherapeutic cerebral circulation time.

BACKGROUND AND PURPOSE: Hyperperfusion syndrome is a devastating complication of carotid stent placement. The shortening of cerebral circulation time after stent placement is seen as a good indicator of the development of hyperperfusion syndrome. The purpose of our study was to evaluate whether patients with ipsilateral transverse sinus stenosis are prone to having shortened cerebral circulation time after stent placement, subsequently leading to the possible development of hyperperfusion syndrome. MATERIALS AND METHODS: Forty-nine patients with >70% unilateral carotid stenosis undergoing stent placement were recruited for analysis. Group A consisted of patients with a stenotic ipsilateral transverse sinus >50% greater than the diameter of the contralateral transverse sinus; the remaining patients were in group B. Quantitative DSA was used to calculate cerebral circulation time. Cerebral circulation time was defined as the time difference between the relative time to maximal intensity of ROIs in the proximal internal carotid artery and the internal jugular vein. ΔCCT was defined as cerebral circulation time before stent placement minus cerebral circulation time after stent placement. ΔCCT, white matter hyperintensity signals, and sulcal effacement in MR imaging were compared between the 2 groups. RESULTS: ΔCCT was significantly shorter in group A (0.65 ± 1.3) than in group B (-0.12 ± 1.4). Three patients had white matter hyperintensity signals in group A, and 1 developed hyperperfusion syndrome. Group B showed no MR imaging signs of hyperperfusion syndrome. CONCLUSIONS: Ipsilateral hypoplastic transverse sinus was associated with prolonged cerebral circulation time before stent placement and greatly shortened cerebral circulation time after stent placement. Inadequate venous drainage might play a role in impaired cerebral autoregulation and might influence the development of poststenting hyperperfusion syndrome.

Dynamic MR imaging patterns of cerebral fat embolism: a systematic review with illustrative cases.

Different MR imaging patterns of cerebral fat embolism have been reported in the literature without a systematic review. Our goal was to describe the patterns, explore the relationship between disease course and the imaging patterns, and discuss the underlying mechanism. We reveal 5 distinctive MR imaging patterns: 1) scattered embolic ischemia occurring dominantly at the acute stage; 2) confluent symmetric cytotoxic edema located at the cerebral white matter, which mainly occurs at the subacute stage; 3) vasogenic edematous lesions also occurring at the subacute stage; 4) petechial hemorrhage, which persists from the acute to the chronic stage; and 5) chronic sequelae, occurring at late stage, including cerebral atrophy, demyelinating change, and sequelae of infarction or necrosis. Underlying mechanisms of these imaging patterns are further discussed. Recognition of the 5 evolving MR imaging patterns of cerebral fat embolism may result in adjustment of the appropriate management and improve the outcome.