GP trainees' values and knowledge regarding global health competencies.

Globalisation is having a significant impact on health through the increasingly interconnected nature of our world, population movement and effects of political and environmental issues. In response, medical educators are urged to review postgraduate training programmes to ensure that doctors are up-to-date with training in contemporary global health issues. Positioned on the frontline of healthcare provision, GPs have an integral role to play in addressing local and global health inequities. However, GP trainees in the UK currently receive little formal education on global health. We sought to investigate GP trainees' understanding and perceived competence in relation to global health issues and cross-cultural practice and their views regarding whether it is indeed time for GP postgraduate training to 'go global'. We invited trainees across Health Education England: Wessex (N = 476) to complete an anonymous online questionnaire. The majority of respondents either 'agreed' or 'strongly agreed' that 'it is important for doctors training to be GPs in the UK to have education on global health' (89%). Similarly, the majority either 'agreed' or 'strongly agreed' that 'it is important for doctors training to be GPs in the UK to develop intercultural competence' (93%). In contrast to the high degree of importance that GP trainees placed on establishing proficiency in these domains, approximately half (45-54%) reported their current level of competence as only being 'average'. Our findings indicate a mismatch and unmet need for further training in the postgraduate setting, with strong GP trainee support for a shift in curriculum design and delivery, towards more globally competent general practice.

A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies.

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

Examination of orthodontic expenditures and trends in the United States from 1996 to 2016: disparities across demographics and insurance payers.

BACKGROUND: Orthodontics prevent and treat facial, dental, and occlusal anomalies. Untreated orthodontic problems can lead to significant dental public health issues, making it important to understand expenditures for orthodontic treatment. This study examined orthodontic expenditures and trends in the United States over 2 decades. METHODS: This study used data collected by the Medical Expenditure Panel Survey to examine orthodontic expenditures in the United States from 1996 to 2016. Descriptive statistics for orthodontic expenditures were computed and graphed across various groups. Trends in orthodontic expenditures were adjusted to the 2016 United States dollar to account for inflation and deflation over time. Sampling weights were applied in estimating per capita and total expenditures to account for non-responses in population groups. RESULTS: Total orthodontic expenditures in the United States almost doubled from $11.5 billion in 1996 to $19.9 billion in 2016 with the average orthodontic expenditure per person increasing from $42.69 in 1996 to $61.52 in 2016. Black individuals had the lowest per capita orthodontic visit expenditure at $30.35. Out-of-pocket expenses represented the highest total expenditure and although the amount of out-of-pocket expenses increased over the years, they decreased as a percentage of total expenditures. Public insurance increased the most over the study period but still accounted for the smallest percentage of expenditures. Over the course of the study, several annual decreases were interspersed with years of increased spending CONCLUSION: While government insurance expenditure increased over the study period, out of pocket expenditures remained the largest contributor. Annual decreases in expenditure associated with economic downturns and result from the reliance on out-of-pocket payments for orthodontic care. Differences in spending among groups suggest disparities in orthodontic care among the US population.

Renal scarring is the most significant predictor of breakthrough febrile urinary tract infection in patients with simplex and duplex primary vesico-ureteral reflux.

INTRODUCTION: The association of high-grade vesico-ureteral reflux (VUR) with renal dysplasia and/or scarring is well-established, and the combination of these factors has been shown to decrease the likelihood of VUR resolution. Other VUR parameters have similarly been shown to be associated with VUR non-resolution, including VUR grade and timing at cystography, associated urinary tract anatomical abnormalities, and bladder dysfunction. OBJECTIVE: To establish independent risk factors that can predict symptomatic persistence of VUR. DESIGN: This was a single-centre study (2011-2017) including consecutive prospectively collected patients with primary VUR on voiding cystourethrogram (VCUG). Patients with dilating VUR also underwent renography (dimercaptosuccinic acid [DMSA] or 99m-technetium mercaptoacetyltriglycine [99mTc-MAG3]). All patients were initially managed medically with antibiotic prophylaxis. Primary outcome was febrile culture-positive breakthrough urinary tract infection (BT-UTI). Demographic parameters, as well as VUR grade, VUR timing at cystography, presence of ureteral anomaly, VUR index (VURx), and differential renal function (DRF) or scarring were analysed to determine independent predictors. RESULTS: A total of 61 patients (41 male, of whom 7 circumcised at presentation) were studied. VUR was diagnosed following investigation of prenatal hydronephrosis in 37 patients (62%) and following a febrile UTI in 22 (37%). Median [range] follow-up period was 38 [12-84] months. Data from a total of 77 refluxing renal units (RUs) were used for analysis. Analysis of VCUG data demonstrated that high VURx might be a potential significant predictor of breakthrough UTI (RR: 1.7, 95% CI: 1.1-2.7, p < 0.05 vs low VURx) but this was not the case for individual VURx components. Renography data showed increased risk of breakthrough UTI in patients with renal scarring (relative risk (RR): 5.1, 95% confidence interval (CI: 2.0-10.7, p < 0.0001 vs no renal scarring), but not in patients with reduced DRF. Multivariate regression analysis revealed that renal scarring was the only significant risk factor for breakthrough UTI. VUR patients with renal scarring were three times more likely to develop breakthrough UTI (odds ratio (OR): 3.3, 95% CI: 1.4-7.4, p < 0.01). DISCUSSION: Multiple factors have been shown to be significant predictors of radiological VUR resolution. Univariate analysis of these factors suggests that only scarring on DMSA and VURx are significant predictors of symptomatic non-resolution. On multivariate analysis, scarring on DMSA was the only significant predictive variable. This information will be useful in targeting investigation and treatment in susceptible patients and when counselling families. CONCLUSION: Renal scarring is the most significant risk factor for breakthrough UTI in primary VUR patients and could be used to determine those at risk of symptomatic VUR persistence.

Predictors of in-laboratory polysomnography attendance in a cohort of patients with stroke or TIA.

STUDY OBJECTIVES: After cerebrovascular events, obstructive sleep apnea (OSA) is associated with poor functional outcomes, an increased risk of recurrent stroke, and mortality. Although the significant under-diagnosis of OSA is likely multifactorial in nature, factors associated with attendance at in-laboratory polysomnography (iPSG) are poorly understood. We evaluated demographic, lifestyle, and clinical variables that predicted attendance at iPSG in a cohort of patients with stroke and transient ischemic attack (TIA) enrolled in a clinical research study. METHODS: Demographic, lifestyle, and clinical variables were summarized for the patients who did and did not attend iPSG. Multivariable binary logistic regression analyses were performed to examine four models that thematically aggregated predictors expected to relate to attendance. Further, t-tests for continuous variables, and chi-squared tests for categorical variables, were performed to uncover differences between the two groups. RESULTS: In the 122 participants included in our analyses, mean age was 66.6 ± 15.7 (64.8% males) with only 59.0% of participants attending iPSG. Only Model 1, which investigated the impact of demographic, lifestyle, and cognitive status, was significant (χ2 = 35.31, p < 0.001). Among our variables, (1) younger age, (2) better cognition, (3) higher level of education, and (4) never-smoking status significantly predicted attendance at iPSG. CONCLUSION: By understanding the relationship between variables that significantly predict attendance, we hope our results will translate into practices that promote iPSG attendance, which may help improve outcomes in the stroke/TIA population. CLINICAL TRIALS: SLEep APnea Screening Using Mobile Ambulatory Recorders After TIA/Stroke (SLEAP SMART) (NCT02454023); https://clinicaltrials.gov/ct2/show/NCT02454023.

Functional diversity of brain networks supports consciousness and verbal intelligence.

How are the myriad stimuli arriving at our senses transformed into conscious thought? To address this question, in a series of studies, we asked whether a common mechanism underlies loss of information processing in unconscious states across different conditions, which could shed light on the brain mechanisms of conscious cognition. With a novel approach, we brought together for the first time, data from the same paradigm-a highly engaging auditory-only narrative-in three independent domains: anesthesia-induced unconsciousness, unconsciousness after brain injury, and individual differences in intellectual abilities during conscious cognition. During external stimulation in the unconscious state, the functional differentiation between the auditory and fronto-parietal systems decreased significantly relatively to the conscious state. Conversely, we found that stronger functional differentiation between these systems in response to external stimulation predicted higher intellectual abilities during conscious cognition, in particular higher verbal acuity scores in independent cognitive testing battery. These convergent findings suggest that the responsivity of sensory and higher-order brain systems to external stimulation, especially through the diversification of their functional responses is an essential feature of conscious cognition and verbal intelligence.

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease.

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy.

OBJECTIVE: Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents. In this study we investigated the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population. METHODS: The medical records of 202 adult patients with 22q11.2DS were retrospectively reviewed for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings. Epilepsy status was assigned in accordance with 2010 International League Against Epilepsy Classification. RESULTS: Of 202 patients, 32 (15.8%) had a documented history of seizure. Of these 32, 23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use. Nine patients (9/32, 28%; 9/202, 4%) met diagnostic criteria for epilepsy. Two patients had genetic generalized epilepsy; two patients had focal seizures of unknown etiology; two had epilepsy due to malformations of cortical development; in two the epilepsy was due to acquired structural changes; and in one patient the epilepsy could not be further classified. SIGNIFICANCE: Similarly to children, the prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population. Hypocalcemia continues to be a risk factor for adults, but differently from kids, the main cause of seizures in adults with 22q11.2DS is exposure to antipsychotics and antidepressants. Further prospective studies are warranted to investigate how 22q11.2 microdeletion leads to an overall decreased seizure threshold.

Anesthesia and neuroimaging: investigating the neural correlates of unconsciousness.

In the past 15 years, rapid technological development in the field of neuroimaging has led to a resurgence of interest in the study of consciousness. However, the neural bases of consciousness and the boundaries of unconscious processing remain poorly understood. Anesthesia combined with functional neuroimaging presents a unique approach for studying neural responses as a function of consciousness. In this review we summarize findings from functional neuroimaging studies that have used anesthetic drugs to study cognition at different levels of conscious awareness. We relate the results to those of psychophysical studies of cognition and explore their potential usefulness in interpreting clinical findings from studies of non-responsive patients.

Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI.

OBJECTIVE: Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions. METHODS: Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI. RESULTS: The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI. INTERPRETATION: These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.

Hypoconnectivity and hyperfrontality in retired American football players.

Recent research has raised concerns about the long-term neurological consequences of repetitive concussive and sub-concussive injuries in professional players of American Football. Despite this interest, the neural and psychological status of retired players remains unknown. Here, we evaluated the performances and brain activation patterns of retired National Football League players (NFL alumni) relative to controls using an fMRI-optimised neuropsychological test of executive function. Behaviourally, the NFL alumni showed only modest performance deficits on the executive task. By contrast, they showed pronounced hyperactivation and hypoconnectivity of the dorsolateral frontal and frontopolar cortices. Critically, abnormal frontal-lobe function was correlated with the number of times that NFL alumni reported having been removed from play after head injury and was evident in individual players. These results support the hypothesis that NFL alumni have a heightened probability of developing executive dysfunction and suggest that fMRI provides the most sensitive biomarker of the underlying neural abnormality.

Differential effects of Parkinson's disease and dopamine replacement on memory encoding and retrieval.

Increasingly memory deficits are recognized in Parkinson's disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients' cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms.

Parkinson's disease duration determines effect of dopaminergic therapy on ventral striatum function.

We investigated the hypothesis that variation in endogenous dopamine (DA) across brain regions explains dissimilar effects of dopaminergic therapy on aspects of cognition in early Parkinson's disease (PD). Extensive degeneration of DA-producing cells in the substantia nigra cause dorsal striatum (DS) DA deficiency and movement abnormalities. Particularly in early PD, this contrasts with relative sparing of the dopaminergic cells of the ventral tegmental area (VTA). The hypothesis predicts that DS-mediated cognitive functions are deficient at baseline and improved by DA replacement, whereas functions depending upon VTA-innervated brain regions are normal off medication and worsen with treatment. The latter pattern presumably owes to overdose of relatively DA-replete VTA-supplied brain regions with medication levels titrated to DS-mediated motor symptoms. As PD progresses, however, VTA degeneration increases. Impairment in cognitive operations performed by VTA-innervated brain regions, such as the ventral striatum (VS), is expected. We compared the performance of early and late PD patients, on and off dopaminergic medication, relative to age-matched controls, on reward learning, previously shown to implicate the VS. As expected, in early PD, stimulus-reward learning was normal off medication, but worsened with DA replacement. At more advanced disease stages, PD patients learned stimulus-reward contingencies more poorly than controls and early PD patients off medication. Furthermore, dopaminergic medication did not worsen reward learning in late PD patients, in line with the dopamine overdose hypothesis. Unlike its effect on DS-mediated functions, however, DA-replacement therapy did not improve reward learning in late PD patients.

Volume-of-interest cone-beam CT using a 2.35 MV beam generated with a carbon target.

PURPOSE: This is a proof-of-concept study addressing volume of interest (VOI) cone beam CT (CBCT) imaging using an x-ray beam produced by 2.35 MeV electrons incident on a carbon linear accelerator target. Methodology is presented relevant to VOI CBCT image acquisition and reconstruction. Sample image data are given to demonstrate and compare two approaches to minimizing artifacts arising from reconstruction with truncated projections. Dosimetric measurements quantify the potential dose reduction of VOI acquisition relative to full-field CBCT. The dependence of contrast-to-noise ratio (CNR) on VOI dimension is investigated. METHODS: A paradigm is presented linking the treatment planning process with the imaging technique, allowing definition of an imaging VOI to be tailored to the geometry of the patient. Missing data in truncated projection images are completed using a priori information in the form of digitally reconstructed radiographs (DRRs) generated from the planning CT set. This method is compared to a simpler technique of extrapolating truncated projection data prior to reconstruction. The utility of these approaches is shown through imaging of a geometric phantom and the head-and-neck section of a lamb. The total scatter factor of the 2.35 MV∕carbon beam on field size is measured and compared to a standard therapeutic beam to estimate the comparative dose reduction inside the VOI. Thermoluminescent dosimeters and Gafchromic film measurements are used to compare the imaging dose distributions for the 2.35 MV∕carbon beam between VOI and full-field techniques. The dependence of CNR on VOI dimension is measured for VOIs ranging from 4 to 15 cm diameter. RESULTS: Without compensating for missing data outside of truncated projections prior to reconstruction, pronounced boundary artifacts are present, in three dimensions, within 2-3 cm of the edges of the VOI. These artifacts, as well as cupping inside the VOI, can be reduced substantially using either the DRR filling or extrapolation techniques presented. Compared to 6 MV, the 2.35 MV∕carbon beam shows a substantially greater dependence of total scatter factor on field size, indicating a comparative advantage of the VOI approach when combined with the low-Z target beam. Dosimetric measurements in the anthropomorphic head phantom demonstrate a dose reduction by up to 15% and 75% inside and outside of the VOI, respectively, compared to full-field imaging. For the 2.35 MV∕carbon beam, CNR was shown to be approximately invariant with VOI dimension for bone and lung objects. CONCLUSIONS: The low-Z target, VOI CBCT technique appears to be feasible and combines the desirable characteristics of the low-Z target beam with regard to CNR, with the capacity to localize the imaging dose to the anatomy relevant to the image guidance task.

The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson's disease: support from functional MRI.

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson's disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson's disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson's disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson's disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities.

The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma.

UNLABELLED: GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics. METHODS: In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR. RESULTS: GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects. CONCLUSIONS: GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.