Faculty Bibliography

OBJECTIVE:Understanding barriers and facilitators to engaging with implementation science (IS) research can provide insight into how to improve efforts to encourage more researchers to participate in IS research. STUDY DESIGN/METHODS:The study design used is a grounded theory qualitative study. METHODS:We conducted semistructured telephone interviews with 20 health researchers familiar with IS that both report engaging in IS research and those that do not. We explored perceptions of barriers and facilitators to engaging in IS research. Themes surrounding difficulties defining IS, lack of training availability, and obstacles to forming research partnerships were discussed as barriers to engaging IS research. Interview topics were informed by the result of an online survey of health researchers in the US. RESULTS:Themes surrounding difficulties defining IS, lack of training availability, and obstacles to forming research partnerships were discussed as barriers to engaging IS research. While accessible mentorship, exposure to formative experiences that develop interest in IS research and an increasing IS visibility were described as motivators for engaging in IS research. CONCLUSIONS:These results highlight the importance of mentorship and exposure to IS ideas in motivating engagement in IS research and the presence of training and methodological barriers to engagement. Future research should expand this line of inquiry to include the perspectives of more junior researchers and students to better reflect the current IS environment.

The paranodal junctions flank mature nodes of Ranvier and provide a barrier between ion channels at the nodes and juxtaparanodes. These junctions also promote node assembly and maintenance by mechanisms that are poorly understood. Here, we examine their role in the accumulation of NF186, a key adhesion molecule of PNS and CNS nodes. We previously showed NF186 is initially targeted/accumulates via its ectodomain to forming PNS (hemi)nodes by diffusion trapping whereas it is later targeted to mature nodes by a transport-dependent mechanism mediated by its cytoplasmic segment. To address the role of the paranodes in this switch, we compared accumulation of NF186 ectodomain and cytoplasmic domain constructs in wild type vs. paranode defective, i.e. Caspr-null mice. Both pathways are affected in the paranodal mutants. In the PNS of Caspr-null mice, diffusion trapping mediated by the NF186 ectodomain aberrantly persists into adulthood whereas the cytoplasmic domain/transport-dependent targeting is impaired. In contrast, accumulation of NF186 at CNS nodes does not undergo a switch - it is predominantly targeted to both forming and mature CNS nodes via its cytoplasmic domain and requires intact paranodes. FRAP analysis indicates the paranodes provide a membrane diffusion barrier that normally precludes diffusion of NF186 to nodes. Linkage of paranodal proteins to the underlying cytoskeleton likely contributes to this diffusion barrier based on 4.1B and βII spectrin expression in Caspr-null mice. Together, these results implicate the paranodes as membrane diffusion barriers that regulate targeting to nodes and highlight differences in the assembly of PNS and CNS nodes.SIGNIFICANCE STATEMENTNodes of Ranvier are essential for effective saltatory conduction along myelinated axons. A major question is how the various axonal proteins that comprise the multimeric nodal complex accumulate at this site. Here we examine how targeting of NF186, a key nodal adhesion molecule, is regulated by the flanking paranodal junctions. We show the transition from diffusion-trapping to transport-dependent accumulation of NF186 requires the paranodal junctions. We also demonstrate that these junctions are a barrier to diffusion of axonal proteins into the node and highlight differences in PNS and CNS node assembly. These results provide new insights into the mechanism of node assembly and the pathophysiology of neurological disorders in which impaired paranodal function contributes to clinical disability.

OBJECTIVE:To identify similarities and differences in protocols on determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS:We collected and reviewed official national BD/DNC protocols from contacts around the world between January 2018 and April 2019. RESULTS:We communicated with contacts in 136 countries and found that 83 (61% of countries with contacts identified, 42% of the world) had BD/DNC protocols, 78 of which were unique. Protocols addressed the following prerequisites and provided differing instructions: drug clearance (64, 82%), temperature (61, 78%), laboratory values (56, 72%), observation period (37, 47%), and blood pressure (34, 44%). Protocols did not consistently identify the same components for the clinical examination of brain death; 70 (90%) included coma, 70 (90%) included the pupillary reflex, 68 (87%) included the corneal reflex, 67 (86%) included the oculovestibular reflex, 64 (82%) included the gag reflex, 62 (79%) included the cough reflex, 58 (74%) included the oculocephalic reflex, 37 (47%) included noxious stimulation to the face, and 22 (28%) included noxious stimulation to the limbs. Apnea testing was mentioned in 71 (91%) protocols; there was variability in the technique and target across protocols. Ancillary testing was included as a requirement for all determinations of BD/DNC in 22 (28%) protocols. CONCLUSIONS:There is considerable variability in BD/DNC determination protocols around the world. Medical standards for death should be the same everywhere. We recommend that a worldwide consensus be reached on the minimum standards for BD/DNC.

OBJECTIVE:To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS:A total of 100 individuals with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls were enrolled between July 2018 and June 2019. Blood was drawn from the antecubital vein and subsequently analyzed using a validated radioimmunoassay for human CGRP. Measurements were performed on coded samples by a board-certified laboratory technician who was blind to clinical information. RESULTS: = 0.85). CONCLUSIONS:CGRP plasma measurements are unlikely a feasible blood-based biomarker of persistent PTH. Future studies should assess whether CGRP plasma measurements can be used to predict development of persistent PTH.

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing-and, ultimately, treating-rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.

22q11.2 deletion syndrome (also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability to neuropsychiatric symptoms, with approximately 30% of individuals with the deletion going on to develop schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Using a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms, when compared to individuals with idiopathic schizophrenia and age-matched neurotypical controls. Twenty-eight participants diagnosed with 22q11.2DS (14-35 years old; 14 with at least one psychotic symptom), 15 individuals diagnosed with schizophrenia (18-63 years old) and two neurotypical control groups (one age-matched to the 22q11.2DS sample, the other age-matched to the schizophrenia sample) participated in this study. Analyses focused on the N2 and P3 no-go responses and error-related negativity (Ne) and positivity (Pe). Atypical inhibitory processing was shown behaviorally and by significantly reduced P3, Ne, and Pe responses in 22q11.2DS and schizophrenia. Interestingly, whereas P3 was only reduced in the presence of psychotic symptoms, Ne and Pe were equally reduced in schizophrenia and 22q11.2DS, regardless of the presence of symptoms. We argue that while P3 may be a marker of disease severity, Ne and Pe might be candidate markers of risk.

The second King's College London Symposium on Ageing and Long-term Care in China was convened from 4 to 5th July 2019 at King's College London in London. The aim of the Symposium was to have a better understanding of health and social challenges for aging and long-term care in China. This symposium draws research insights from a wide range of disciplines, including economics, public policy, demography, gerontology, public health and sociology. A total of 20 participants from eight countries, seek to identify the key issues and research priorities in the area of aging and long-term care in China. The results published here are a synthesis of the top four research areas that represent the perspectives from some of the leading researchers in the field.

OBJECTIVE/UNASSIGNED:There are more than 325,000 health-related smartphone applications (apps) on the market. To better understand the apps currently on the market for the five most disabling neuropsychiatric conditions, the authors conducted a study investigating their intended uses (target population and intervention), the data collected, and any privacy policies. METHODS/UNASSIGNED:This was a cross-sectional study of apps for the five most disabling neuropsychiatric conditions per the World Health Organization: stroke, migraine, depression, Alzheimer's disease and dementia, and anxiety. Up to 15 apps in the U.S. Google Play and Apple app stores were selected based on the following prespecified inclusion criteria: the app appeared in the top 50 search results, offered intervention or tracking capabilities, and listed the condition in the app title or description. Exclusion criteria were <$5.00 to purchase, solely motor versus cognitive-based intervention, or designed for use by caregivers or health care providers. Data abstracted included function, behavior change rewards, and information about intervention, privacy policy, and payment. RESULTS/UNASSIGNED:Eighty-three apps were reviewed (stroke, N=8; migraine, N=25; Alzheimer's disease and dementia, N=8; depression, N=7; anxiety, N=14; apps targeting depression and anxiety, N=21). Sixty-nine percent of apps had an intervention component, 18% were deemed evidence based, 77% had a privacy policy, 70% required payment for access to all features, and 19% rewarded user behavior changes. CONCLUSIONS/UNASSIGNED:Most apps on the market targeted migraine, depression, and anxiety and contained interventions, although most of the interventions did not appear to be evidence based. Additionally, although most apps had privacy policies, lay people may have difficulty understanding these policies due to their complexities.

OBJECTIVE:To account for factors affecting family approach and consent for organ donation after brain death (BD). MATERIAL AND METHODS/METHODS:A prospective cohort study in a large, tertiary, urban hospital, where we reviewed the database of all brain-dead patients between January 2006 and December 2017 cross-matched with local organ procurement organization (OPO) records. RESULTS:Two-hundred sixty-six brain-dead patients were included (55% African Americans (AAs)). Two-hundred twenty-two were approached for donation. The reason for not approaching families was medical exclusion due to cancer or multi-organ failure. Patient demographics or religion were not associated with approaching families. Lower creatinine level was the only independent factor associated with higher approach. Consent rate for organ donation was 72.5%. Consent was significantly higher in Caucasians (89% vs 62% for AAs), younger patients (46.7 vs 52.5 years old), in patients with lower creatinine at time of death (1.7 vs 2.4 mg/dL), patients for whom apnea testing was completed (92% vs 80%) and patients with diabetes insipidus (DI) (72% vs 54%). There was no significant relationship between consent and patient gender, admission diagnosis, number of examinations or completion of a confirmatory test. In a logistic regression model, only AA race independently predicted consent for donation (odds, 95% CI, 0.27, 0.12-0.57 p < .001). In a different model, apnea test completion was an additional independent predictor (3.66, 1.28-10.5 p = .015). CONCLUSIONS:Approaching families for organ donation consent was associated with medical suitability only and not with demographic or religious characteristics. AAs were 3.7 times less likely to consent for organ donation than non-AAs. Completion of apnea testing was associated with higher consent rates, an observation that needs to be explored in future studies documenting the effect on bedside family presence during this test.