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Use of magnetic resonance imaging (MRI) as a tool to aid in neuroprognostication after cardiac arrest (CA) has been described, yet details of specific indications, timing, and sequences are unknown. We aim to define the current practices in use of brain MRI in prognostication after pediatric CA.A survey was distributed to pediatric institutions participating in three international studies. Survey questions related to center demographics, clinical practice patterns of MRI after CA, neuroimaging resources, and details regarding MRI decision support.Response rate was 31% (44 of 143). Thirty-four percent (15 of 44) of centers have a clinical pathway informing the use of MRI after CA. Fifty percent (22 of 44) of respondents reported that an MRI is obtained in nearly all patients with CA, and 32% (14 of 44) obtain an MRI in those who do not return to baseline neurological status. Poor neurological examination was reported as the most common factor (91% [40 of 44]) determining the timing of the MRI. Conventional sequences (T1, T2, fluid-attenuated inversion recovery, and diffusion-weighted imaging/apparent diffusion coefficient) are routinely used at greater than 97% of centers. Use of advanced imaging techniques (magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI) were reported by less than half of centers.Conventional brain MRI is a common practice for prognostication after CA. Advanced imaging techniques are used infrequently. The lack of standardized clinical pathways and variability in reported practices support a need for higher-quality evidence regarding the indications, timing, and acquisition protocols of clinical MRI studies.

Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

This research investigates the use of a multiple-thickness sea-ice model for opera- tional Antarctic sea-ice forecasts. Deterministic predictions are generated with a finite difference sea-ice model for the Southern Ocean. The forecast model includes a new method for ridging sea ice on semi-diurnal timescales and includes a modified Coulombic rheology. This approach differs from formalistic techniques used in existing thickness distribution models, and is introduced to simulate oriented fractures with multiple thickness- categories. Behaviour of the dynamic component of the model is assessed on a test grid to illustrate its properties and numerical limitations. The dynamic component is then combined with a constant salinity, enthalpy-conserving thermodynamic model on a 50 km resolution polar stereographic grid using 11 thickness categories to simulate circum-Antarctic sea ice. Sea-ice assimilations are generated for observation intensive years (1992 and 1996) to compare model output with drafts from Upward Looking Sonar, ice velocities from drifting buoys and concentration from satellite measurements. The assimilations are forced with atmospheric fields from the European Centre for Medium Range Weather Forecasting (ECMWF) and National Oceanic and Atmospheric Administration Sea Surface Temperatures. Climatological-mean ocean currents are used as a background geostrophic field beneath the ice. The sea-ice analyses are then filtered with Special Sensor Microwave/Imager (SSM/I) derived sea-ice concentrations, adjusting the inno- vation sequence (sequence of observation minus forecast at each timestep) for the unique thermodynamic lag of each ice-thickness category. This method provides an estimate of oceanic heat flux and explicitly adjusts vertical ice temperature profiles. It improves approximations of sea-ice extent and mean thickness, suggesting a significant source of error in the unassimilated model results from incorrect heat flux specification between ice, ocean and atmosphere. However the scheme was less successful at assimilating individual thickness categories of the thickness distribution, and possible future im- provements to the scheme are discussed. A series of G-day forecast case studies designed to test short-term predictability of the model are provided in the final part of this thesis. Pack forecasts are generated with both ECMWF and National Centre for Environment Prediction (NCEP) atmospheric reanalyses. They are verified against assimilations and SSM/I-derived sea-ice concen- tration. The results demonstrate that as long as the initial sea-ice state used to initialise forecasts is physically consistent, the medium-range forecast will itself be quite skilled. Information obtained from two sets of forecasts, one forced with ECMWF and the other with NCEP, shows both sets of forcings generate regionally different but simi- larly skilled forecasts. This suggests that ensembles methods may improve operational forecast guidance. Overall, the work paves the way for regular operational Antarc- tic sea-ice forecasts and the potential of determining Antarctic sea-ice thickness from remotely-sensed observations.

Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P P P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical atrophy to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods: 513 participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter atrophy. Results: Although NPS were frequent across the five disease groups, participants with Frontotemporal Dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both Frontotemporal Dementia and Parkinson’s Disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that increased cortical atrophy and white matter hyperintensities burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

The ability of synapses to maintain physiological levels of evoked neurotransmission is essential for neuronal stability. A variety of perturbations can disrupt neurotransmission, but synapses often compensate for disruptions and work to stabilize activity levels, using forms of homeostatic synaptic plasticity. Presynaptic homeostatic potentiation (PHP) is one such mechanism. PHP is expressed at theDrosophila melanogasterlarval neuromuscular junction (NMJ) synapse, as well as other NMJs. In PHP, presynaptic neurotransmitter release increases to offset the effects of impairing muscle transmitter receptors. PriorDrosophilawork has studied PHP using different ways to perturb muscle receptor function – either acutely (using pharmacology) or chronically (using genetics). Some of our prior data suggested that cytoplasmic calcium signaling was important for expression of PHP after genetic impairment of glutamate receptors. Here we followed up on that observation. We used a combination of transgenicDrosophilaRNA interference and overexpression lines, along with NMJ electrophysiology, synapse imaging, and pharmacology to test if regulators of the calcium/calmodulin-dependent protein phosphatase calcineurin are necessary for the normal expression of PHP. We found that either pre- or postsynaptic dysregulation of aDrosophilagene regulating calcineurin,sarah(sra), blocks PHP. Tissue-specific manipulations showed that either increases or decreases insraexpression are detrimental to PHP. Additionally, pharmacologically and genetically induced forms of expression of PHP are functionally separable depending entirely upon whichsragenetic manipulation is used. Surprisingly, dual-tissue pre- and postsynapticsraknockdown or overexpression can ameliorate PHP blocks revealed in single-tissue experiments. Pharmacological and genetic inhibition of calcineurin corroborated this latter finding. Our results suggest tight calcineurin regulation is needed across multiple tissue types to stabilize peripheral synaptic outputs.

Oceanic tides are seldom represented in Earth System Models (ESMs) owing to the need for high horizontal resolution to accurately represent the associated barotropic waves close to coasts. This paper presents results of tides implemented in the Model for Prediction Across Scales–Ocean or MPAS-Ocean, which is the ocean component within the US Department of Energy developed Energy Exascale Earth System Model (E3SM). MPAS-Ocean circumvents the limitation of low resolution using unstructured global meshing. We are at this stage simulating the largest semidiurnal (M2, S2, N2) and diurnal (K1, O1) tidal constituents in a single layer version of MPAS-O. First, we show that the tidal constituents calculated using MPAS-Ocean closely agree with TPXO8 results when suitably tuned topographic wave drag and bottom drag coefficients are employed. Thereafter, we present the sensitivity of global tidal evolution due to the presence of Antarctic ice shelf cavities. The effect of ice shelves on the amplitude and phase of tidal constituents are presented. Lower values of complex errors (with respect to TPX08 results) for the M2 tidal constituents are observed when ice shelf is added in the simulations, with particularly strong improvement in the Southern Ocean. Our work points towards future research with varying Antarctic ice shelf geometries and sea ice coupling that might lead to better comparison and prediction of tides, and thus better prediction of sea-level rise and also the future climate variability.

Introduction Following burn injury, the ecology of the host microbiota is disrupted to varying degrees and may leave the patient susceptible to opportunistic pathogens or disrupt the endogenous flora needed to potentiate recovery and homeostasis. Studies examining the microbiome post-burn injury usually have a limited sample size which, coupled with experimental and analysis variation, impacts overall interpretation of data. Methods We performed a meta-analysis of publicly available sequencing data from burn patients and burn animals to determine if there were consistent alterations in the microbiome across various anatomical sites and species. A MEDLINE search was used to identify applicable publications. Corresponding authors of papers without available data were contacted, and data were used if a response occurred. Ten human and animal 16S rRNA sequencing studies spanning respiratory, urinary, cutaneous, and gastrointestinal microbiomes were included. Raw sequencing data were systematically analyzed with taxonomic classification and α and β diversity metrics generated. Results Alpha diversity was consistently lower post-burn, except for human skin (Figure 1) due to perianal skin sampling of burn patients resulting in higher species richness than controls. Weighted UniFrac distance analysis showed that rodent specimens clustered less closely to humans than pig samples (P < 0.0001) for both rectal and skin samples. Host species (R2 = 0.21, P = 0.001), and institute (R2 = 0.35, P = 0.001) had a significant impact on the β diversity. In rectal samples, bacterial composition in pig and human burn samples included Bacteroidetes, Firmicutes, and Proteobacteria, while rodent samples were dominated by over 90% Firmicutes. Burns induced an increase of Proteobacteria and a decrease in Bacteroidetes and Firmicutes in pig rectal samples. Proteobacteria and Firmicutes increased on burned skin in each host species. Longitudinal studies revealed a decrease in α diversity upon burn injury with β diversity and taxa shifts. Conclusions Overall, our results suggest that host species and the sequencing site strongly influence microbiome structure. Burn-induced alterations in microbiome diversity and taxa exist across hosts, with certain metrics more influenced by host. Applicability of Research to Practice Coordinated, multi-center studies, both clinical and pre-clinical, are needed to truly realize the diagnostic and therapeutic potential of the microbiome for improving outcomes post-burn.

Introduction Burn injury causes a complex pathophysiology resulting in morbidity and mortality often characterized by the development of infectious complications. In health, the microbiota is crucial in host homeostasis and provides numerous benefits. The oral cavity and intestines are important physiologic structures for energy intake where resident microbes participate in metabolic processing. Any potential commonalities in the alterations in oral and gut microbiota after burn have not been previously addressed. Therefore, our study aimed to determine whether severe burns affect the oral and gut microbiota in a consistent pattern during the early stages post-burn. Methods Yorkshire swine were placed under anesthesia, and 60% total body surface area burn (n =4) or sham (n =6) injuries were created. Animals were resuscitated with lactated ringer’s based on the Parkland formula. These two cohorts were used to investigate longitudinal microbiome alterations at hours 2, 4, 16, 24, 36, and 48. No antibiotics were given. Shallow shotgun sequencing was performed on DNA isolated from lingual and rectal swabs with downstream α-diversity, β-diversity, and taxonomic analyses performed. Results The lingual microbiome had a significantly higher Shannon α-diversity as compared to the gut microbiota in the control (Kruskal-Wallis (KW), P = 0.04) and burn (P = 0.01) cohorts. There were distinct community differences between the lingual and gut microbiomes based on the Jaccard β-diversity metrics (PERMANOVA, P = 0.02). In lingual samples, Shannon diversity significantly increased from baseline by hour 16 in both the control (KW, P = 0.009) and burn (P = 0.02) groups returning closer to baseline values at hour 48. Jaccard diversity for lingual samples in both groups followed the Shannon diversity trend with significant community shifts observed by hour 16 in controls (PERMANOVA, P = 0.011) and burn samples (P = 0.032). Bacteroidetes levels increased in lingual samples from baseline to hour 16 in both groups, significantly in the control cohort (Dunnett’s test, P = 0.016). In the rectal samples, Shannon diversity decreased from baseline in the control and burn groups to hour 16 although no significant differences were observed. No significant differences in Jaccard β-diversity were seen in rectal samples from the control or burn groups between baseline communities or time points. Similar trends in rectal bacterial composition at the phylum level in both groups were observed with longitudinal non-significant increases in Bacteroidetes and decreases in Firmicutes. Conclusions The results suggest that induction and anesthesia cause microbial alterations similar to burn injury during the acute 48-hour time period. Applicability of Research to Practice Multi-center whole genome sequencing studies are needed to explore microbial changes post-burn and should include clinical interventions to gain a more thorough understanding of the connection between the oral and gut microbiota.

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?. Methods/Design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. Results: We found three components in the ZBI. The first was “overall burden” and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = −0.566, basic ADLs r = −0.43), (2) moderately related to cognition (MoCA r = −0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

BACKGROUND Vaccine coverage for 18-month-old children in Canada is often below recommended levels, which may be partially due to parental forgetfulness. Text message reminders have been shown to potentially improve childhood immunization uptake, but were not widely utilized in Alberta, Canada. Additionally, it has been noted that language barriers may impede immunization service delivery but continue to be unaddressed in many existing reminder/recall systems. OBJECTIVE We aimed to assess the effectiveness and acceptability of using text messages, containing a link to online immunization information in different languages, to remind parents of their child’s 18-month immunization appointment. METHODS The Childhood Immunization Reminder Project (ChIRP) was a pilot intervention at two public health centres, one each in Lethbridge and Edmonton, Alberta, Canada. Two text message reminders were sent to parents: (1) a booking reminder 3 months before their child turned 18 months old, and (2) an appointment reminder three days before their scheduled appointment. Booking reminders included a link to the study website hosting immunization information in nine languages. To evaluate the intervention effectiveness, we compared absolute attendance no-show rates pre- and post-intervention. Acceptability of the intervention was evaluated through online surveys completed by parents and public health centre staff. Google Analytics was used to determine how often the online immunization information was accessed, from where, and in which languages. RESULTS Following the intervention, the Edmonton health centre had a reduction of 6.4% (95% CI: 3.0, 9.8) in appointment no-shows, with no change at the Lethbridge health centre (0.8%; 95% CI: -1.4, +3.0). Acceptability surveys were completed by 222 parents (response rate: 23.9%) and 22 staff. Almost all (>95%) respondents indicated that the reminders were helpful and had useful suggestions for improvements. All surveyed parents (100.0%) found it helpful to read the online immunization information in their language of choice. Google Analytics data showed that the immunization information was most often read in English (57.0%), Punjabi (25.1%), Arabic (6.3%), Spanish (5.8%), Italian (1.9%), Chinese (1.9%), French (1.0%), Tagalog (0.5%), and Vietnamese (0.5%). CONCLUSIONS The study findings support the use of text message reminders as a convenient and acceptable method to minimize parental forgetfulness and potentially reduce appointment no-shows. The diverse languages accessed in the online immunization information suggest the need to provide appropriate translated immunization information. Further research is needed to evaluate the impact of text message reminders on childhood immunization coverage in different settings.

Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Background: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults. Objective: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians’ awareness of hearing loss and improve access to timely hearing care. Methods: Patients referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology. Results: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology. Conclusion: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia.

To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function and plasticity by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (300 Drosophila lines screened). From our screen, knockdown of a Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. We localized this neurotransmission function to the muscle. Pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns or pharmacological inhibition led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinson’s disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

Introduction: Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases.Methods: 513 participants with Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia (FTD), Parkinson’s Disease, or Cerebrovascular Disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness.Results: A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex(female), global cognition, and right parietal and occipital WMH.Conclusions: Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.

New York State has one of the most richly funded Medicaid programs in the United States. In an effort to achieve the triple aim New York State is undergoing a significant redesign of its Medicaid program including transitioning nearly all Medicaid funded behavioral health services into Medicaid managed care. In preparation for this transition, a state funded technical assistance center assessed the behavioral health care system's readiness to undergo this reform across 11 domains. Between September and November, 2014, the TA center electronically distributed a readiness survey to 897 mental health and substance abuse agencies: 313 (n = 269, 33%) organizations completed the assessment. As a whole, the sample felt partially ready to transition; analysis by domain revealed agencies were most ready to interface with managed care providers, and least ready to collect and evaluate outcome data. Significant differences in readiness were found depending by organizational characteristics (number of programs, licensure, and region). In anticipation of large-scale reforms, states would benefit from an initial needs assessment to identify gaps in knowledge and skills, which in turn, can then guide preparatory efforts and provide needed supports to facilitate major changes in service delivery and billing.

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. TheDrosophila melanogasterneuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content during evoked neurotransmission – again, resulting in normal levels of postsynaptic excitation.We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapse’s ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we did find loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R –itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.

Objectives Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible PVS volumes, a putative marker of perivascular dysfunction, are associated with compensatory differences in real-world human sleep behavior. Methods We analyzed data from 152 cerebrovascular disease patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). PVS volumes were measured using 3T-MRI. Self-reported total sleep time, time in bed, and daytime dysfunction were extracted from the Pittsburgh Sleep Quality Index. Results Individuals with greater PVS volumes reported longer time in bed (+0.85 h per log10 proportion of intracranial volume (ICV) occupied by PVS, SE = 0.30, p = 0.006) and longer total sleep times (+0.70 h per log10 proportion of ICV occupied by PVS volume, SE = 0.33, p = 0.04), independent of vascular risk factors, sleep apnea, nocturnal sleep disturbance, depression, and global cognitive status. Further analyses suggested that the positive association between PVS volumes and total sleep time was mediated by greater time in bed. Moreover, despite having on average greater total sleep times, individuals with greater basal ganglia PVS volumes were more likely to report daytime dysfunction (OR 5.63 per log10 proportion of ICV occupied by PVS, 95% CI: 1.38–22.26, p = 0.018). Conclusions Individuals with greater PVS volumes spend more time in bed, resulting in greater total sleep time, which may represent a behavioral compensatory response to perivascular space dysfunction.

Whole-genome sequencing (WGS) has shown immense value in enabling identification and characterization of bacterial taxa. This is particularly true for mycobacteria, where culture-based characterization becomes delayed by the inherently slow growth rate of these organisms. This chapter reviews the general techniques behind WGS and their optimization, existing techniques for species-level identification and the advantages of WGS for this purpose, and a variety of useful tools for the genomic characterization of mycobacterial strains.

Mycobacterium tuberculosis (Mtb) infects one-quarter of the world’s population. Mtb and HIV coinfections enhance the comorbidity of tuberculosis (TB) and AIDS, accounting for one-third of all AIDS-associated mortalities. Humoral antibody to Mtb correlates with TB susceptibility, and engineering of Mtb antibodies may lead to new diagnostics and therapeutics. The characterization and validation of functional immunoglobulin (Ig) variable chain (IgV) sequences provide a necessary first step towards developing therapeutic antibodies against pathogens. The virulence-associated Mtb antigens SodA (Superoxide Dismutase), KatG (Catalase), PhoS1/PstS1 (regulatory factor), and GroES (heat shock protein) are potential therapeutic targets but lacked IgV sequence characterization. Putative IgV sequences were identified from the mRNA of hybridomas targeting these antigens and isotype-switched into a common immunoglobulin fragment crystallizable region (Fc region) backbone, subclass IgG2aκ. Antibodies were validated by demonstrating recombinant Ig assembly and secretion, followed by the determination of antigen-binding specificity using ELISA and immunoblot assay.