Overcoming Challenges to Teamwork in Patient-Centered Medical Homes: A Qualitative Study

There is emerging consensus that enhanced inter-professional teamwork is necessary for the effective and efficient delivery of primary care, but there is less practical information specific to primary care available to guide practices on how to better work as teams. The purpose of this study was to describe how primary care practices have overcome challenges to providing team-based primary care and the implications for care delivery and policy

Adaptive alterations in brain structure and function in young people with Tourette Syndrome

Tourette Syndrome (TS) is a developmental neurological disorder characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit dysfunction and hyper-excitability within cortical motor areas. TS symptoms often become more controlled throughout adolescence until the individual is largely tic-free by early adulthood. It is likely that adaptive changes occur in the development of brain structure and function throughout the critical developmental period of adolescence in people with TS, which leads to tic remission in some individuals. To investigate this I used multiple brain-imaging approaches including diffusion tensor imaging to look at white matter microstructure, T1-weighted anatomical MR imaging to measure cortical grey matter thickness and MR-Spectroscopy (MRS) to measure neurotransmitters of interest (GABA and glutamate) in a group of young people with TS and a typically developing matched control group. Brain function (measures of excitation and inhibition in M1) was also considered by using transcranial magnetic stimulation. A significant positive relationship was found between white matter structural integrity (FA) measured from the body of the corpus callosum that contained projections to M1 or the SMA and motor tic severity. The TS group had increased levels of GABA in the SMA, as measured by MRS, compared to the control group. SMA- GABA levels had a significant positive relationship with FA from the SMA ROI but a negative relationship with TMS measures of cortical excitability during movement preparation. This suggests that those individuals with the least severe tic symptoms also have reduced callosal white matter from the SMA (an area implicated in the production and suppression of tics) in adolescents with TS, which relates to a reduction in task based cortical excitability and a reduction in SMA-GABA compared to those with more severe tics. The results from this thesis suggest that tic-suppression may occur through decreasing excitatory inputs to M1, either through increasing the inhibition (GABA levels) of the SMA, or by decreasing the number of excitatory interhemispheric inputs to sensorimotor regions

Adaptive alterations in brain structure and function in young people with Tourette Syndrome

Tourette Syndrome (TS) is a developmental neurological disorder characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit dysfunction and hyper-excitability within cortical motor areas. TS symptoms often become more controlled throughout adolescence until the individual is largely tic-free by early adulthood. It is likely that adaptive changes occur in the development of brain structure and function throughout the critical developmental period of adolescence in people with TS, which leads to tic remission in some individuals. To investigate this I used multiple brain-imaging approaches including diffusion tensor imaging to look at white matter microstructure, T1-weighted anatomical MR imaging to measure cortical grey matter thickness and MR-Spectroscopy (MRS) to measure neurotransmitters of interest (GABA and glutamate) in a group of young people with TS and a typically developing matched control group. Brain function (measures of excitation and inhibition in M1) was also considered by using transcranial magnetic stimulation. A significant positive relationship was found between white matter structural integrity (FA) measured from the body of the corpus callosum that contained projections to M1 or the SMA and motor tic severity. The TS group had increased levels of GABA in the SMA, as measured by MRS, compared to the control group. SMA- GABA levels had a significant positive relationship with FA from the SMA ROI but a negative relationship with TMS measures of cortical excitability during movement preparation. This suggests that those individuals with the least severe tic symptoms also have reduced callosal white matter from the SMA (an area implicated in the production and suppression of tics) in adolescents with TS, which relates to a reduction in task based cortical excitability and a reduction in SMA-GABA compared to those with more severe tics. The results from this thesis suggest that tic-suppression may occur through decreasing excitatory inputs to M1, either through increasing the inhibition (GABA levels) of the SMA, or by decreasing the number of excitatory interhemispheric inputs to sensorimotor regions

Premonitory urges are associated with decreased grey matter thickness within the insula and sensorimotor cortex in young people with Tourette syndrome

Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics and is associated with cortical–striatal–thalamic–cortical circuit (CSTC) dysfunction and hyperexcitability of cortical limbic and motor regions, which are thought to lead to the occurrence of tics. Importantly, individuals with TS often report that their tics are preceded by ‘premonitory sensory phenomena’ (PSP) that are described as uncomfortable cognitive or bodily sensations that precede the execution of a tic, and are experienced as a strong urge for motor discharge. While the precise role played by PSP in the occurrence of tics is controversial, PSP are nonetheless of considerable theoretical and clinical importance in TS, not least because they form the core component in many of the behavioural therapies that are currently used in the treatment of tic disorders. In this study, we investigated the brain structure correlates of PSP. Specifically, we conducted a whole-brain analysis of cortical (grey matter) thickness in 29 children and young adults with TS and investigated the association between grey matter thickness and PSP. We demonstrate for the first time that PSP are inversely associated with grey matter thickness measurements within the insula and sensori-motor cortex. We also demonstrate that grey matter thickness is significantly reduced in these areas in individuals with TS relative to a closely age- and gender-matched group of typically developing individuals and that PSP ratings are significantly correlated with tic severity

Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome

Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4, 5, 6, 7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8, 9, 10, 11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics

The dual action of human antibodies specific to Plasmodium falciparum PfRH5 and PfCyRPA: Blocking invasion and inactivating extracellular merozoites

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the current leading blood-stage malaria vaccine candidate. PfRH5 functions as part of the pentameric PCRCR complex containing PTRAMP, CSS, PfCyRPA and PfRIPR, all of which are essential for infection of human red blood cells (RBCs). To trigger RBC invasion, PfRH5 engages with RBC protein basigin in a step termed the RH5-basigin binding stage. Although we know increasingly more about how antibodies specific for PfRH5 can block invasion, much less is known about how antibodies recognizing other members of the PCRCR complex can inhibit invasion. To address this, we performed live cell imaging using monoclonal antibodies (mAbs) which bind PfRH5 and PfCyRPA. We measured the degree and timing of the invasion inhibition, the stage at which it occurred, as well as subsequent events. We show that parasite invasion is blocked by individual mAbs, and the degree of inhibition is enhanced when combining a mAb specific for PfRH5 with one binding PfCyRPA. In addition to directly establishing the invasion-blocking capacity of the mAbs, we identified a secondary action of certain mAbs on extracellular parasites that had not yet invaded where the mAbs appeared to inactivate the parasites by triggering a developmental pathway normally only seen after successful invasion. These findings suggest that epitopes within the PfCyRPA-PfRH5 sub-complex that elicit these dual responses may be more effective immunogens than neighboring epitopes by both blocking parasites from invading and rapidly inactivating extracellular parasites. These two protective mechanisms, prevention of invasion and inactivation of uninvaded parasites, resulting from antibody to a single epitope indicate a possible route to the development of more effective vaccines

Comparing GABA-­dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-­high-­field MRI

Imbalances in glutamatergic (excitatory) and GABA (inhibitory) signalling within key brain networks are thought to underlie many brain and mental health disorders, and for this reason there is considerable interest in investigating how individual variability in localised concentrations of these molecules relate to brain disorders. Magnetic resonance spectroscopy (MRS) provides a reliable means of measuring, in vivo, concentrations of neurometabolites such as GABA, glutamate and glutamine that can be correlated with brain function and dysfunction. However, an issue of much debate is whether the GABA observed and measured using MRS represents the entire pool of GABA available for measurement (i.e., metabolic, intracellular, and extracellular) or is instead limited to only some portion of it. GABA function can also be investigated indirectly in humans through the use of non-invasive transcranial magnetic stimulation (TMS) techniques that can be used to measure cortical excitability and GABA-mediated physiological inhibition. To investigate this issue further we collected in a single session both types of measurement, i.e., TMS measures of cortical excitability and physiological inhibition and ultra-high-field (7 Tesla) MRS measures of GABA, glutamate and glutamine, from the left sensorimotor cortex of the same group of right-handed individuals. We found that TMS and MRS measures were largely uncorrelated with one another, save for the plateau of the TMS IO curve that was negatively correlated with MRS-Glutamate (Glu) and intra-cortical facilitation (10ms ISI) that was positively associated with MRS-Glutamate concentration. These findings are consistent with the view that the GABA concentrations measured using MRS largely represent pools of GABA that are linked to tonic rather than phasic inhibition and thus contribute to the inhibitory tone of a brain area rather than GABAergic synaptic transmission

Heterotypic interactions drive antibody synergy against a malaria vaccine candidate

Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes. Here we present a panel of anti-CyRPA monoclonal antibodies that strongly inhibit parasite growth in in vitro assays. Structural studies show that growth-inhibitory antibodies bind epitopes on a single face of CyRPA. We also show that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. These antibodies bind to neighbouring epitopes on CyRPA and form lateral, heterotypic interactions which slow antibody dissociation. We predict that such heterotypic interactions will be a feature of many immune responses. Immunogens which elicit such synergistic antibody mixtures could increase the potency of vaccine-elicited responses to provide robust and long-lived immunity against challenging disease targets

Acute gabapentin administration in healthy adults. A double-blind placebo-controlled study using transcranial magnetic stimulation and 7T 1H-MRS

Gamma-aminobutyric acid (GABA) and glutamate are the primary neurotransmitters responsible for modulating excitatory and inhibitory signalling within the human brain. Dysfunctional GABAergic and glutamatergic signalling has been identified as a key factor in a range of neuropsychiatric conditions; hence measurement and modulation of these neurometabolites is important for improving our understanding of neuropsychiatric conditions and treatment options. Gabapentin (GBP) is one of several drugs developed to increase GABA levels and is routinely prescribed for conditions such as epilepsy and neuralgia. While animal and human studies indicate that GBP can elevate GABA levels, its exact mechanisms of action are not fully understood, although animal studies indicate that GBP does not have a direct effect upon GABAergic receptors.To investigate the impact of acute GBP administration in the human motor system we used two complimentary approaches – transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). MRS and TMS measures of GABA have repeatedly been found to be uncorrelated and are likely to reflect different pools of synaptic and extra synaptic GABA, hence, measuring both within the same participants allows for an in-depth assessment of GBP effects.Despite significantly increased ratings of fatigue and tiredness within the GBP group, we failed to find any statistically significant changes in our MRS or TMS measures of GABA. Measures of MRS Glutamate (glu) and glutamine (gln) were also not affected by the administration of GBP. These findings are important as they run counter to previous work, and suggest that the effect of an acute dose of GBP is likely to be subject to substantial individual variation, with timing of measures particularly likely to impact observed effects. These findings have implications for the use of acute GBP dosing as a means to explore GABAergic function in health and disease