Neuroanatomical Substrates of Circuit-Specific Cholinergic Modulation across the Primate Anterior Cingulate Cortex.

Acetylcholine is a robust neuromodulator of the limbic system and a critical regulator of arousal and emotions. The anterior cingulate cortex (ACC) and the amygdala (AMY) are key limbic structures that are both densely innervated by cholinergic afferents and interact with each other for emotional regulation. The ACC is composed of functionally distinct dorsal (A24), rostral (A32), and ventral (A25) areas that differ in their connections with the AMY. The structural substrates of cholinergic modulation of distinct ACC microcircuits and outputs to AMY are thought to depend on the laminar and subcellular localization of cholinergic receptors. The present study examines the distribution of muscarinic acetylcholine receptors, m1 and m2, on distinct excitatory and inhibitory neurons and on AMY-targeting projection neurons within ACC areas, via immunohistochemistry and injections of neural tracers into the basolateral AMY in adult rhesus monkeys of both sexes. We found that laminar densities of m1+ and m2+ expressing excitatory and inhibitory neurons depended on area and cell type. Among the ACC areas, ventral subgenual ACC A25 exhibited greater m2+ localization on presynaptic inhibitory axon terminals and greater density of m1+ and m2+ expressing AMY-targeting (tracer+) pyramidal neurons. These patterns suggest robust cholinergic disinhibition and potentiation of amygdalar outputs from the limbic ventral ACC, which may be linked to the hyperexcitability of this subgenual ACC area in depression. These findings reveal the anatomical substrate of diverse cholinergic modulation of specific ACC microcircuits and amygdalar outputs that mediate cognitive-emotional integration and dysfunctions underlying stress and affective disorders.

Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys.

Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia-spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury.

On-tissue chemical derivatization in mass spectrometry imaging.

Mass spectrometry imaging (MSI) combines molecular and spatial information in a valuable tool for a wide range of applications. Matrix-assisted laser desorption/ionization (MALDI) is at the forefront of MSI ionization due to its wide availability and increasing improvement in spatial resolution and analysis speed. However, ionization suppression, low concentrations, and endogenous and methodological interferences cause visualization problems for certain molecules. Chemical derivatization (CD) has proven a viable solution to these issues when applied in mass spectrometry platforms. Chemical tagging of target analytes with larger, precharged moieties aids ionization efficiency and removes analytes from areas of potential isobaric interferences. Here, we address the application of CD on tissue samples for MSI analysis, termed on-tissue chemical derivatization (OTCD). MALDI MSI will remain the focus platform due to its popularity, however, alternative ionization techniques such as liquid extraction surface analysis and desorption electrospray ionization will also be recognized. OTCD reagent selection, application, and optimization methods will be discussed in detail. MSI with OTCD is a powerful tool to study the spatial distribution of poorly ionizable molecules within tissues. Most importantly, the use of OTCD-MSI facilitates the analysis of previously inaccessible biologically relevant molecules through the adaptation of existing CD methods. Though further experimental optimization steps are necessary, the benefits of this technique are extensive.

Assessment of hemodynamic indices of conjunctival microvascular function in patients with coronary microvascular dysfunction.

OBJECTIVE: Coronary microvascular dysfunction (CMD) is a cause of ischaemia with non-obstructive coronary arteries (INOCA). It is notoriously underdiagnosed due to the need for invasive microvascular function testing. We hypothesized that systemic microvascular dysfunction could be demonstrated non-invasively in the microcirculation of the bulbar conjunctiva in patients with CMD. METHODS: Patients undergoing coronary angiography for the investigation of chest pain or dyspnoea, with physiologically insignificant epicardial disease (fractional flow reserve ≥0.80) were recruited. All patients underwent invasive coronary microvascular function testing. We compared a cohort of patients with evidence of CMD (IMR ≥25 or CFR <2.0); to a group of controls (IMR <25 and CFR ≥2.0). Conjunctival imaging was performed using a previously validated combination of a smartphone and slit-lamp biomicroscope. This technique allows measurement of vessel diameter and other indices of microvascular function by tracking erythrocyte motion. RESULTS: A total of 111 patients were included (43 CMD and 68 controls). There were no differences in baseline demographics, co-morbidities or epicardial coronary disease severity. The mean number of vessel segments analysed per patient was 21.0 ± 12.8 (3.2 ± 3.5 arterioles and 14.8 ± 10.8 venules). In the CMD cohort, significant reductions were observed in axial/cross-sectional velocity, blood flow, wall shear rate and stress. CONCLUSION: The changes in microvascular function linked to CMD can be observed non-invasively in the bulbar conjunctiva. Conjunctival vascular imaging may have utility as a non-invasive tool to both diagnose CMD and augment conventional cardiovascular risk assessment.

Layer-specific pyramidal neuron properties underlie diverse anterior cingulate cortical motor and limbic networks.

The laminar cellular and circuit mechanisms by which the anterior cingulate cortex (ACC) exerts flexible control of motor and affective information for goal-directed behavior have not been elucidated. Using multimodal tract-tracing, in vitro patch-clamp recording and computational approaches in rhesus monkeys (M. mulatta), we provide evidence that specialized motor and affective network dynamics can be conferred by layer-specific biophysical and structural properties of ACC pyramidal neurons targeting two key downstream structures -the dorsal premotor cortex (PMd) and the amygdala (AMY). AMY-targeting neurons exhibited significant laminar differences, with L5 more excitable (higher input resistance and action potential firing rates) than L3 neurons. Between-pathway differences were found within L5, with AMY-targeting neurons exhibiting greater excitability, apical dendritic complexity, spine densities, and diversity of inhibitory inputs than PMd-targeting neurons. Simulations using a pyramidal-interneuron network model predict that these layer- and pathway-specific single-cell differences contribute to distinct network oscillatory dynamics. L5 AMY-targeting networks are more tuned to slow oscillations well-suited for affective and contextual processing timescales, while PMd-targeting networks showed strong beta/gamma synchrony implicated in rapid sensorimotor processing. These findings are fundamental to our broad understanding of how layer-specific cellular and circuit properties can drive diverse laminar activity found in flexible behavior.

Extracellular Vesicle Treatment Alleviates Neurodevelopmental and Neurodegenerative Pathology in Cortical Spheroid Model of Down Syndrome.

Down syndrome (DS), or trisomy 21, is manifested in a variety of anatomical and cellular abnormalities resulting in intellectual deficits and early onset of Alzheimer's disease (AD) with no effective treatments available to alleviate the pathologies associated with the disorder. The therapeutic potential of extracellular vesicles (EVs) has emerged recently in relation to various neurological conditions. We have previously demonstrated the therapeutic efficacy of mesenchymal stromal cell-derived EVs (MSC-EVs) in cellular and functional recovery in a rhesus monkey model of cortical injury. In the current study, we evaluated the therapeutic effect of MSC-EVs in a cortical spheroid (CS) model of DS generated from patient-derived induced pluripotent stem cells (iPSCs). Compared to euploid controls, trisomic CS display smaller size, deficient neurogenesis, and AD-related pathological features, such as enhanced cell death and depositions of amyloid beta (Aß) and hyperphosphorylated tau (p-tau). EV-treated trisomic CS demonstrated preserved size, partial rescue in the production of neurons, significantly decreased levels of Aß and p-tau, and a reduction in the extent of cell death as compared to the untreated trisomic CS. Together, these results show the efficacy of EVs in mitigating DS and AD-related cellular phenotypes and pathological depositions in human CS.

Spatial localization of ß-unsaturated aldehyde markers in murine diabetic kidney tissue by mass spectrometry imaging.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Limitations in current diagnosis and screening methods have sparked a search for more specific and conclusive biomarkers. Hyperglycemic conditions generate a plethora of harmful molecules in circulation and within tissues. Oxidative stress generates reactive α-dicarbonyls and ß-unsaturated hydroxyhexenals, which react with proteins to form advanced glycation end products. Mass spectrometry imaging (MSI) enables the detection and spatial localization of molecules in biological tissue sections. Here, for the first time, the localization and semiquantitative analysis of "reactive aldehydes" (RAs) 4-hydroxyhexenal (4-HHE), 4-hydroxynonenal (4-HNE), and 4-oxo-2-nonenal (4-ONE) in the kidney tissues of a diabetic mouse model is presented. Ionization efficiency was enhanced through on-tissue chemical derivatization (OTCD) using Girard's reagent T (GT), forming positively charged hydrazone derivatives. MSI analysis was performed using matrix-assisted laser desorption ionization (MALDI) coupled with Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR). RA levels were elevated in diabetic kidney tissues compared to lean controls and localized throughout the kidney sections at a spatial resolution of 100 µm. This was confirmed by liquid extraction surface analysis-MSI (LESA-MSI) and liquid chromatography-mass spectrometry (LC-MS). This method identified ß-unsaturated aldehydes as "potential" biomarkers of DN and demonstrated the capability of OTCD-MSI for detection and localization of poorly ionizable molecules by adapting existing chemical derivatization methods. Untargeted exploratory distribution analysis of some precursor lipids was also assessed using MALDI-FT-ICR-MSI.

Treatment with Mesenchymal-Derived Extracellular Vesicles Reduces Injury-Related Pathology in Pyramidal Neurons of Monkey Perilesional Ventral Premotor Cortex.

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.

Assessment of the conjunctival microcirculation in adult patients with cyanotic congenital heart disease compared to healthy controls.

PURPOSE: Congenital heart disease (CHD) is the most common live birth defect and a proportion of these patients have chronic hypoxia. Chronic hypoxia leads to secondary erythrocytosis resulting in microvascular dysfunction and increased thrombosis risk. The conjunctival microcirculation is easily accessible for imaging and quantitative assessment. It has not previously been studied in adult CHD patients with cyanosis (CCHD). METHODS: We assessed the conjunctival microcirculation and compared CCHD patients and matched healthy controls to determine if there were differences in measured microcirculatory parameters. We acquired images using an iPhone 6s and slit-lamp biomicroscope. Parameters measured included diameter, axial velocity, wall shear rate and blood volume flow. The axial velocity was estimated by applying the 1D + T continuous wavelet transform (CWT). Results are for all vessels as they were not sub-classified into arterioles or venules. RESULTS: 11 CCHD patients and 14 healthy controls were recruited to the study. CCHD patients were markedly more hypoxic compared to the healthy controls (84% vs 98%, p = 0.001). A total of 736 vessels (292 vs 444) were suitable for analysis. Mean microvessel diameter (D) did not significantly differ between the CCHD patients and controls (20.4 ± 2.7 µm vs 20.2 ± 2.6 µm, p = 0.86). Axial velocity (Va) was lower in the CCHD patients (0.47 ± 0.06 mm/s vs 0.53 ± 0.05 mm/s, p = 0.03). Blood volume flow (Q) was lower for CCHD patients (121 ± 30pl/s vs 145 ± 50pl/s, p = 0.65) with the greatest differences observed in vessels >22 µm diameter (216 ± 121pl/s vs 258 ± 154pl/s, p = 0.001). Wall shear rate (WSR) was significantly lower for the CCHD group (153 ± 27 s-1 vs 174 ± 22 s-1, p = 0.04). CONCLUSIONS: This iPhone and slit-lamp combination assessment of conjunctival vessels found lower axial velocity, wall shear rate and in the largest vessel group, lower blood volume flow in chronically hypoxic patients with congenital heart disease. With further study this assessment method may have utility in the evaluation of patients with chronic hypoxia.

Does Femoral Component Cementation Affect Costs or Clinical Outcomes After Hip Arthroplasty in Medicare Patients?

BACKGROUND: Bundled payment initiatives were introduced to reduce costs and improve quality of care. Cemented vs cementless femoral fixation is a modifiable variable that may influence the cost and quality of care. New bundled payment data from the Centers for Medicare and Medicaid Services allowed us to study the influence of femoral fixation strategy on (1) 90-day costs; (2) readmission rates; (3) reoperation rates; (4) length of stay (LOS); and (5) discharge disposition for Medicare patients undergoing total hip arthroplasty. METHODS: We retrospectively studied 1671 primary total hip arthroplasty Medicare cases, comparing 359 patients who received cemented femoral fixation to 1312 patients who received cementless fixation. Centers for Medicare and Medicaid Services cost data as well as clinical data were reviewed. Demographic differences were present between the 2 cohorts. Statistical analyses were performed, including multiple regression models to adjust for baseline differences. RESULTS: Controlling for cohort differences, cemented patients were significantly more likely to be discharged home compared to cementless patients. Cemented patients also demonstrated trends toward lower costs, lower readmission rates, and shorter LOS compared to cementless patients. All reoperations within the early postoperative period occurred in patients managed with cementless femoral fixation. CONCLUSION: Among Medicare patients, cemented femoral fixation outperformed cementless fixation with respect to discharge disposition and also trended toward superiority with regards to LOS, readmission, cost of care, and reoperation. Cemented femoral fixation remains relevant and useful despite the rising popularity of cementless fixation.

Quantitative assessment of the conjunctival microcirculation using a smartphone and slit-lamp biomicroscope.

PURPOSE: The conjunctival microcirculation is a readily-accessible vascular bed for quantitative haemodynamic assessment and has been studied previously using a digital charge-coupled device (CCD). Smartphone video imaging of the conjunctiva, and haemodynamic parameter quantification, represents a novel approach. We report the feasibility of smartphone video acquisition and subsequent haemodynamic measure quantification via semi-automated means. METHODS: Using an Apple iPhone 6 s and a Topcon SL-D4 slit-lamp biomicroscope, we obtained videos of the conjunctival microcirculation in 4 fields of view per patient, for 17 low cardiovascular risk patients. After image registration and processing, we quantified the diameter, mean axial velocity, mean blood volume flow, and wall shear rate for each vessel studied. Vessels were grouped into quartiles based on their diameter i.e. group 1 (<11 µm), 2 (11-16 µm), 3 (16-22 µm) and 4 (>22 µm). RESULTS: From the 17 healthy controls (mean QRISK3 6.6%), we obtained quantifiable haemodynamics from 626 vessel segments. The mean diameter of microvessels, across all sites, was 21.1µm (range 5.8-58 µm). Mean axial velocity was 0.50mm/s (range 0.11-1mm/s) and there was a modestly positive correlation (r 0.322) seen with increasing diameter, best appreciated when comparing group 4 to the remaining groups (p < .0001). Blood volume flow (mean 145.61pl/s, range 7.05-1178.81pl/s) was strongly correlated with increasing diameter (r 0.943, p < .0001) and wall shear rate (mean 157.31 s-1, range 37.37-841.66 s-1) negatively correlated with increasing diameter (r - 0.703, p < .0001). CONCLUSIONS: We, for the first time, report the successful assessment and quantification of the conjunctival microcirculatory haemodynamics using a smartphone-based system.

Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein-dependent, salt-sensitive hypertension.

NEW FINDINGS: • What is the central question of this study? We hypothesized that central inflammatory processes that involve activation of microglia and astrocytes contribute to the development of Gαi2 protein-dependent, salt-sensitive hypertension. • What is the main finding and its importance? The main finding is that PVN-specific inflammatory processes, driven by microglial activation, appear to be linked to the development of Gαi2 protein-dependent, salt-sensitive hypertension in Sprague-Dawley rats. This finding might reveal new mechanistic targets in the treatment of hypertension. ABSTRACT: The central mechanisms underlying salt-sensitive hypertension, a significant public health issue, remain to be established. Researchers in our laboratory have reported that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the sympathoinhibitory and normotensive responses to high sodium intake in salt-resistant rats. Given the recent evidence of central inflammation in animal models of hypertension, we hypothesized that PVN inflammation contributes to Gαi2 protein-dependent, salt-sensitive hypertension. Male Sprague-Dawley rats received chronic intracerebroventricular infusions of a targeted Gαi2 or control scrambled oligodeoxynucleotide (ODN) and were maintained for 7 days on a normal-salt (NS; 0.6% NaCl) or high-salt (HS; 4% NaCl) diet; in subgroups on HS, intracerebroventricular minocycline (microglial inhibitor) was co-infused with ODNs. Radiotelemetry was used in subgroups of rats to measure mean arterial pressure (MAP) chronically. In a separate group of rats, plasma noradrenaline, plasma renin activity, urinary angiotensinogen and mRNA levels of the PVN pro-inflammatory cytokines TNFα, IL-1ß and IL-6 and the anti-inflammatory cytokine IL-10 were assessed. In additional groups, immunohistochemistry was performed for markers of PVN and subfornical organ microglial activation and cytokine levels and PVN astrocyte activation. High salt intake evoked salt-sensitive hypertension, increased plasma noradrenaline, PVN pro-inflammatory cytokine mRNA upregulation, anti-inflammatory cytokine mRNA downregulation and PVN-specific microglial activation in rats receiving a targeted Gαi2 but not scrambled ODN. Minocycline co-infusion significantly attenuated the increase in MAP and abolished the increase in plasma noradrenaline and inflammation in Gαi2 ODN-infused animals on HS. Our data suggest that central Gαi2 protein prevents microglial-mediated PVN inflammation and the development of salt-sensitive hypertension.

A method for assessing recovery of fine motor function of the hand in a rhesus monkey model of cortical injury: an adaptation of the Fugl-Meyer Scale and Eshkol-Wachman Movement Notation.

Motor dysfunction of the upper extremity can result from stroke, cortical injury and neurological diseases and causes significant disruption of activities of daily living. While some spontaneous recovery in terms of compensatory movements does occur after injury to cortical motor areas, full recovery is rare. The distinction between complete recovery and compensatory recovery is important as the development of compensatory movements in the upper extremity may not translate into full functional use in human patients. However, current animal models of stroke do not distinguish full recovery from compensatory recovery. We have developed a Non-Human Primate Grasp Assessment Scale (GRAS) to quantify the precise recovery of composite movement, individual digit action, and finger-thumb pinch in our rhesus monkey model of cortical injury. To date, we have applied this GRAS scale to assess the recovery of fine motor function of the hand in young control and cell-therapy treated monkeys with cortical injury confined to the hand representation in the dominant primary motor cortex. We have demonstrated that with this scale we can detect and quantify significant impairments in fine motor function of the hand, the development of compensatory function during recovery and finally a return to full fine motor function of the hand in monkeys treated with a cell therapy.

Fibromyalgia Increases the Risk of Surgical Complications Following Total Knee Arthroplasty: A Nationwide Database Study.

BACKGROUND: Although fibromyalgia is a common comorbidity with knee osteoarthritis, the orthopedic literature on this population is limited. Therefore, the purpose of this study is to assess if fibromyalgia patients have a higher likelihood of developing surgical complications after total knee arthroplasty (TKA) than a matched control cohort. METHODS: The Medicare Standard Analytical Files of the PearlDiver supercomputer was utilized to identify patients who underwent a TKA between 2005 and 2014. Patients were 1:1 propensity score matched based on the diagnosis of fibromyalgia, age, gender, and the Charlson Comorbidity Index, yielding a total of 305,510 patients. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-values (<.05) were calculated to examine the likelihood of developing any surgical complication, as well as specific surgical complications. RESULTS: Compared to a matched cohort, fibromyalgia patients had increased odds of developing any surgical complication (OR 1.55, 95% CI 1.51-1.60, P < .001), such as bearing wear (OR 2.11, 95% CI 1.48-3.01, P < .0001) and periprosthetic osteolysis (OR 1.71, 95% CI 1.10-2.66, P = .018). Furthermore, these patients had significantly greater odds of developing revision of tibial insert (OR 1.5, 95% CI 1.14-2.05, P = .046), mechanical loosening (OR 1.34, 95% CI 1.26-1.53, P < .0001), infection/inflammation (OR 1.33, 95% CI 1.26-1.14, P < .0001), dislocations (OR 1.33, 95% CI 1.21-1.47, P < .0001), as well as other complications (OR 1.74, 95% CI 1.68-1.80, P < .0001). CONCLUSION: This analysis of over 300,000 patients identified that fibromyalgia patients can have a greater risk of developing certain surgical complications after TKA. Therefore, fibromyalgia patients must be made aware of the increased postoperative risks and surgeons should consider enhanced preoperative medical and surgical optimization.

Oral curcumin supplementation improves fine motor function in the middle-aged rhesus monkey.

Aged individuals experience decreased fine motor function of the hand and digits, which could result, in part, from the chronic, systemic state of inflammation that occurs with aging. Recent research for treating age-related inflammation has focused on the effects of nutraceuticals that have anti-inflammatory properties. One particular dietary polyphenol, curcumin, the principal curcuminoid of the spice turmeric, has been shown to have significant anti-inflammatory effects and there is mounting evidence that curcumin may serve to reduce systemic inflammation. Therefore, it could be useful for alleviating age-related impairments in fine motor function. To test this hypothesis we assessed the efficacy of a dietary intervention with a commercially available optimized curcumin to ameliorate or delay the effects of aging on fine motor function of the hand of rhesus monkeys. We administered oral daily doses of curcumin or a control vehicle to 11 monkeys over a 14- to 18-month period in which they completed two rounds of fine motor function testing. The monkeys receiving curcumin were significantly faster at retrieving a food reward by round 2 of testing than monkeys receiving a control vehicle. Further, the monkeys receiving curcumin demonstrated a greater degree of improvement in performance on our fine motor task by round 2 of testing than monkeys receiving a control vehicle. These findings reveal that fine motor function of the hand and digits is improved in middle-aged monkeys receiving chronic daily administration of curcumin.

Rotationally asymmetric multifocal intraocular lenses: preoperative considerations and postoperative outcomes.

PURPOSE OF REVIEW: The manuscript presents a review of recently published studies reporting objective and subjective outcomes and preoperative considerations of asymmetrical multifocal intraocular lenses (IOLs). RECENT FINDINGS: Current publications suggest that asymmetrical multifocal IOLs provide good, distance, intermediate and near vision for cataract and clear lens extraction patients. The contrast sensitivity achieved is similar to monofocal IOLs. Photopic phenomenon such as glare and halos has been reduced through the use of these IOLs leading to better patient satisfaction. Centration plays a critical role and the lack of a gold standard assessment tool has led to a minority of patients experiencing lower quality of vision and side-effects such as glare and hazy vision. The frequency of dissatisfied patients can be minimized by appropriate patient selection. This is achieved by assessing pupil parameters which guides the surgeon to align the IOL accordingly. SUMMARY: Asymmetric multifocal IOLs provide the surgeon with an IOL that achieves excellent visual and refractive outcomes enabling patients to see clearly at a range of distances. Subjectively patients report low levels of photopic phenomena and high levels of spectacle independence resulting in high overall patient satisfaction.

Implementation of a health information exchange into community pharmacy workflow.

OBJECTIVES: To explore the feasibility and report preliminary outcomes of the integration of a health information exchange (HIE) into community pharmacy workflow clinical service delivery. SETTING: Independent pharmacy in eastern Tennessee. PRACTICE DESCRIPTION: The pharmacy offers medication reconciliation services via HIE access, as well as other clinical pharmacy services. The average number of prescriptions filled weekly is 1900, and staffing included 3.5 full-time-equivalent (FTE) pharmacists, and 7 FTE technicians. PRACTICE INNOVATION: HIE integration within the workflow of the pharmacy was used to enhance existing patient care services, such as medication distribution, drug use review, medication therapy management, and immunizations, as well as to implement a novel transitional care service. EVALUATION: A mixed-methods design was used to explore HIE workflow. Data collection included a pharmacist and pharmacy technician perceptions survey, mapping steps involved in HIE use in workflow via a think-aloud protocol, and quantitatively reporting the number and type of discordant medications found on medication reconciliation. RESULTS: In total, 25 patients qualified for the medication reconciliation intervention and data collection. All 25 patients (100%) had at least 1 discordant medication. HIE access was used for 60% of patients. Community pharmacists were confident in their abilities to perform medication reconciliation and were able to perform the medication reconciliation with the use of the HIE within their workflow, albeit with some reported barriers. The average time spent per patient for HIE-facilitated transitional care was 21 minutes. CONCLUSION: Integration and utilization of an HIE within the workflow for the purposes of patient care service delivery in the community pharmacy is feasible, but not without limitations. Such HIE utilization and extended access to the patient's clinical picture may represent a scalable method to enhance currently delivered pharmacist services.

Career Development Institute with Enhanced Mentoring: A Revisit.

OBJECTIVE: The need for innovative methods to promote training, advancement, and retention of clinical and translational investigators in order to build a pipeline of trainees to focus on mental health-relevant research careers is pressing. The specific aim of the Career Development Institute for Psychiatry is to provide the necessary skill set and support to a nationally selected broad-based group of young psychiatrists and PhD researchers to launch and maintain successful research careers in academic psychiatry. The program targets such career skills as writing, negotiating, time management, juggling multiple demanding responsibilities, networking, project management, responsible conduct of research, and career goal setting. The current program builds on the previous program by adding a longitudinal, long-distance, virtual mentoring, and training program, seen as integral components to sustaining these career skills. METHODS: Career development activities occur in four phases over a 24-month period for each annual class of up to 18 participants: online baseline career and skills self-assessment and goal setting, preparations for 4-day in-person workshop, long-distance structured mentoring and online continued learning, peer-mentoring activities, and post-program career progress and process evaluation. Program instructors and mentors consist of faculty from the University of Pittsburgh and Stanford University as well as successful past program graduates from other universities as peer mentors. A comprehensive website facilitates long-distance activities to occur online. Continued training occurs via webinars every other month by experts discussing topics selected for the needs of each particular class. Personally assigned mentors meet individually bimonthly with participants via a secure web-based "mentor center" that allows mentor dyads to collaborate, share, review, and discuss career goals and research activities. RESULTS: Preliminary results after the first 24 months are favorable. Almost uniformly, participants felt the program was very helpful. They had regular contact with their long-distance mentor at least every 2 months over the 2-year period. At the end of the 2-year period, the majority of participants had full-time faculty appointments with K-award support and very few were doing primarily clinical work. CONCLUSIONS: The longitudinal program of education, training, mentoring, peer support, and communications for individuals making the transition to academic research should increase the number of scientists committed to research careers in mental health.

Determinants of patient satisfaction and function related to vision following cataract surgery in eyes with no visually consequential ocular co-morbidity.

PURPOSE: To investigate subjectively reported outcomes following cataract surgery and the relationships between such outcomes in the context of falling thresholds for cataract surgery. SETTING: Large, private, non-refractive cataract practice, Institute of Eye Surgery, Whitfield Clinic, Waterford, Ireland METHODS: Pre-operative, intra-operative and post-operative data of 2552 eyes undergoing phacoemulsification and implantation of the Tecnis(R) ZCB00 1-piece intraocular lens (IOL) by a single surgeon between July 2009 and October 2013 was analysed. Patients without visually consequential ocular co-morbidity completed two validated questionnaires, designed to assess subjectively perceived visual functioning and identify symptoms of dysphotopsia following cataract surgery. RESULTS: 54.8 % of questionnaire respondents were entirely satisfied (satisfaction 10/10) post-operatively, with 83.7 % reporting satisfaction of ≥7/10. Satisfaction was positively associated with patient age and negatively associated with spectacle dependence, dysphotopsia, and function related to vision (NEI VF-11) score. The mean (±standard deviation[SD]) dysphotopsia score was 1.36 (±1.9; scale 0-10), with 40 % of respondents reporting no dysphotopsia symptoms and 9.8 % reporting clinically meaningful dysphotopsia. The mean (±SD) National Eye Institute visual function-11 (NEI VF-11) score was 0.33 (±0.53; scale 0-4) and reduced function related to vision was associated with increasing severity of dysphotopsia symptoms. When linear regression was applied, 17.5 % of the variation in functionality was attributable to symptoms of dysphotopsia. CONCLUSION: Dysphotopsia is an important determinant of a patient having difficulty with vision-related tasks following cataract surgery, and patient satisfaction is positively associated with patient age and negatively associated with spectacle in dependence, dysphotopsia and function related to the vision (NEI VF-11) score.

Incidence of dislocated and subluxed iris-fixated phakic intraocular lens and outcomes following re-enclavation.

BACKGROUND: The purpose of this study was to establish the incidence of re-enclavation of iris-fixated phakic intraocular lenses in our centre and evaluate outcomes following re-enclavation. DESIGN: Retrospective observational case series. Single surgeon, hospital setting. PARTICIPANTS: Six hundred and nine patients (1218 eyes) implanted with iris-fixated phakic intraocular lenses between 2000 and 2011. METHODS: Eyes requiring re-enclavation were identified, and outcome measures were evaluated 12 months following re-enclavation. MAIN OUTCOME MEASURES: Rate of re-enclavation, uncorrected distance visual acuity and manifest refractive spherical equivalent were measured 12 months following re-enclavation. RESULTS: Twenty-five eyes (2% of eyes overall) of 20 patients required re-enclavation of a dislocated or subluxed phakic intraocular lens. Eight cases (32%) dislocated secondary to trauma and 17 (68%) subluxed spontaneously. No significant difference was detected (P = 0.59) in uncorrected distance visual acuity (logMAR equivalent) 12 months post-re-enclavation (0.18 ± 0.04) compared with that recorded 6 months post-initial uneventful phakic intraocular lens implantation (0.10 ± 0.06). No significant difference was detected (P = 0.95) in mean manifest refractive spherical equivalent 12 months post-re-enclavation (-0.59D ± 0.29D) compared with that recorded 6 months post-initial phakic intraocular lens implantation (-0.57D ± 0.17D). Following re-enclavation, mean endothelial cell count was 2627 ± 101 cells/mm(2) 12 months postoperatively in 16 eyes. This did not differ significantly from that recorded 6 months post-initial phakic intraocular lens implantation in these eyes (P = 1). CONCLUSION: Dislocation and subluxation of iris-fixated phakic intraocular lenses may occur secondary to trauma or spontaneously because of inadequate iris enclavation. Re-enclavation can be carried out successfully with no significant adverse effect on clinical outcomes.