Publications by authors named "David Lin"

449 Publications

A comprehensive assessment of Ga-PSMA-11 PET in biochemically recurrent prostate cancer: Results from a prospective multi-center study in 2005 patients.

J Nucl Med 2021 Jul 29. Epub 2021 Jul 29.

Radiology Department, University of Michigan, United States.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated prostate-specific-antigen (PSA) after initial therapy. Ga-PSMA-11 hybrid positron emission tomography (PET) was performed in 2005 patients at the time of biochemical recurrent prostate cancer (BCR) following either radical prostatectomy (RP) (50.8 %), definitive radiation therapy (RT) (19.7 %), or RP with post-operative RT (PORT) (29.6 %). Presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis creating a disease burden estimate from presence or absence of local (prostate/prostate bed), nodal (N1: pelvis) and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of Ga-PSMA-11 PET/CT confirmed by histopathology. Following prostatectomy, the scan detection rate increased significantly with rising PSA levels (44.8 % at PSA < 0.25 to 96.2 % at PSA > 10 ng/mL; < 0.001). The detection rate significantly increased with rising PSA levels in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from prostatectomy specimen ( < 0.001). Following RT, the detection rate for in-gland prostate recurrence was 64.0 % compared to 20.6 % prostate bed recurrences after RP and 13.3 % following PORT. PSMA-positive pelvic nodal disease was detected in 42.7 % following RP, in 40.8 % after PORT and 38.8 % after RT. In patients with histopathologic validation the PPV per-patient was 0.82 (146/179). The SUV of histologically proven true positive lesions was significantly higher than false positive lesions (median 11.0 (IQR 6.3 - 22.2) vs 5.1 (IQR 2.2 - 7.4) < 0.001). We confirmed a high PPV of Ga-PSMA-11 PET in BCR and the PSA level as the main predictor of scan positivity.
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http://dx.doi.org/10.2967/jnumed.121.262412DOI Listing
July 2021

A Smartwatch Heart Rate Monitor Prompts an Unusual Diagnosis.

JACC Case Rep 2020 Mar 18;2(3):431-433. Epub 2020 Mar 18.

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

We report the case of a 54-year-old woman who presented for cardiological evaluation having noted a decline in her heart rate on her wearable heart rate monitor. She was found to be in 2:1 atrioventricular block. Subsequent evaluation revealed cardiac and pulmonary sarcoidosis, treated with steroids and implantable cardioverter-defibrillator placement. ().
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http://dx.doi.org/10.1016/j.jaccas.2019.11.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311695PMC
March 2020

Diagnostic overlap: Complex post-traumatic stress disorder and borderline personality disorder.

Aust N Z J Psychiatry 2021 Jul 27:48674211034730. Epub 2021 Jul 27.

Monash Alfred Psychiatry Research Centre (MAPrc), Melbourne, VIC, Australia.

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http://dx.doi.org/10.1177/00048674211034730DOI Listing
July 2021

Maternal psychosocial risk factors and child gestational epigenetic age in a South African birth cohort study.

Transl Psychiatry 2021 07 2;11(1):358. Epub 2021 Jul 2.

Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.

Accelerated epigenetic aging relative to chronological age has been found to be associated with higher risk of mortality in adults. However, little is known about whether and how in utero exposures might shape child gestational epigenetic age (EA) at birth. We aimed to explore associations between maternal psychosocial risk factors and deviation in child gestational EA at birth (i.e., greater or lower EA relative to chronological age) in a South African birth cohort study-the Drakenstein Child Health Study. Maternal psychosocial risk factors included trauma/stressor exposure; posttraumatic stress disorder (PTSD); depression; psychological distress; and alcohol/tobacco use. Child gestational EA at birth was calculated using an epigenetic clock previously devised for neonates; and gestational EA deviation was calculated as the residuals of the linear model between EA and chronological gestational age. Bivariate linear regression was then used to explore unadjusted associations between maternal/child risk factors and child gestational EA residuals at birth. Thereafter, a multivariable regression method was used to determine adjusted associations. Data from 271 maternal-child dyads were included in the current analysis. In the multivariable regression model, maternal PTSD was significantly and negatively associated with child gestational EA residuals at birth (β = -1.95; p = 0.018), controlling for study site, sex of the child, head circumference at birth, birthweight, mode of delivery, maternal estimated household income, body mass index (BMI) at enrolment, HIV status, anaemia, psychological distress, and prenatal tobacco or alcohol use. Given the novelty of this preliminary finding, and its potential translational relevance, further studies to delineate underlying biological pathways and to explore clinical implications of EA deviation are warranted.
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http://dx.doi.org/10.1038/s41398-021-01434-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253754PMC
July 2021

Reducing the Impact of External Vibrations on Fiducial Point Detection in Seismocardiogram Signals.

IEEE Trans Biomed Eng 2021 Jun 23;PP. Epub 2021 Jun 23.

Objective: Wearable systems that enable continuous non-invasive monitoring of hemodynamic parameters can aid in cardiac health evaluation in non-hospital settings. The seismocardiogram (SCG) is a non-invasively acquired cardiovascular biosignal for which timings of fiducial points, like aortic valve opening (AO) and aortic valve closing (AC), can enable estimation of key hemodynamic parameters. However, SCG is susceptible to motion artifacts, making accurate estimation of these points difficult when corrupted by high-g or in-band vibration artifacts. In this paper, a novel denoising pipeline is proposed that removes vehicle-vibration artifacts from corrupted SCG beats for accurate fiducial point detection.

Methods: The noisy SCG signal is decomposed with ensemble empirical mode decomposition (EEMD). Corrupted segments of the decomposed signal are then identified and removed using the quasi-periodicity of the SCG. Signal quality assessment of the reconstructed SCG beats then removes unreliable beats before feature extraction. The overall approach is validated on simulated vehicle-corrupted SCG generated by adding real subway collected vibration signals onto clean SCG.

Results: SNR increased by 8.1dB in the AO complex and 11.5dB in the AC complex of the SCG signal. Hemodynamic timing estimation errors reduced by 16.5\% for pre-ejection period (PEP), 67.2\% for left ventricular ejection time (LVET), and 57.7\% for PEP/LVET---a feature previously determined in prior work to be of great importance for assessing blood volume status during hemorrhage.

Conclusion: These findings suggest that usable SCG signals can be recovered from vehicle-corrupted SCG signals using the presented denoising framework, allowing for accurate hemodynamic timing estimation.

Significance: Reliable hemodynamic estimates from vehicle-corrupted SCG signals will enable the adoption of the SCG in outside-of-hospital settings.
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http://dx.doi.org/10.1109/TBME.2021.3090376DOI Listing
June 2021

False positive pharmacologic myocardial perfusion SPECT study in the setting of a left bundle branch block.

Nucl Med Commun 2021 Jun 7. Epub 2021 Jun 7.

Department of Medicine (Cardiovascular Division) Department of Radiology and Biomedical Imaging, University of California, San Francisco Medical Center, San Francisco, California, USA.

We herein report a case of a false positive vasodilatory pharmacologic SPECT stress test in the setting of a left bundle branch block (LBBB). While this is more commonly seen with exercise stress testing, it can also occur with pharmacologic stress testing. In our SPECT exam, we illustrate the commonly mistaken septal/anteroseptal perfusion defects in those patients with a LBBB. PET stress testing may be more reliable for patients with LBBB.
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http://dx.doi.org/10.1097/MNM.0000000000001451DOI Listing
June 2021

Risky family climates presage increased cellular aging in young adulthood.

Psychoneuroendocrinology 2021 Aug 14;130:105256. Epub 2021 May 14.

Department of Psychology, Northwestern University, Evanston, IL, USA; Institute for Policy Research, Northwestern University, Evanston, IL, USA.

A scientific consensus is emerging that children reared in risky family climates are prone to chronic diseases and premature death later in life. Few prospective data, however, are available to inform the mechanisms of these relationships. In a prospective study involving 323 Black families, we sought to determine whether, and how, childhood risky family climates are linked to a potential risk factor for later-life disease: increases in cellular aging (indexed by epigenetic aging). As hypothesized, risky family climates were associated with greater outflows of the stress hormones epinephrine and norepinephrine at ages 19 and 20 years; this, in turn, led to increases in cellular aging across ages 20-27 years. If sustained, these tendencies may place children from risky family climates on a trajectory toward the chronic diseases of aging.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217285PMC
August 2021

Interatrial septal tachycardias following atrial fibrillation ablation or cardiac surgery: Electrophysiological features and ablation outcomes.

Heart Rhythm 2021 May 11. Epub 2021 May 11.

Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Interatrial septal tachycardias (IAS-ATs) following atrial fibrillation (AF) ablation or cardiac surgery are rare, and their management is challenging.

Objective: The purpose of this study was to investigate the electrophysiological features and outcomes associated with catheter ablation of IAS-AT.

Methods: We screened 338 patients undergoing catheter ablation of ATs following AF ablation or cardiac surgery. Diagnosis of IAS-AT was based on activation mapping and analysis of response to atrial overdrive pacing.

Results: Twenty-nine patients (9%) had IAS-AT (cycle length [CL] 311 ± 104 ms); 16 (55%) had prior AF ablation procedures (median 3; range 1-5), 3 (10%) had prior surgical maze, and 12 (41%) had prior cardiac surgery (including atrial septal defect surgical repair in 5 and left atrial myxoma resection in 1). IAS substrate abnormalities were documented in all patients. Activation mapping always demonstrated a diffuse early IAS breakout with centrifugal biatrial activation, and atrial overdrive pacing showed a good postpacing interval (equal or within 25 ms of the AT CL) only at 1 or 2 anatomically opposite IAS sites in all cases. Ablation was acutely successful in 27 patients (93%) (from only the right IAS in 2, only the left IAS in 9, both IAS sides with sequential ablation in 13, and both IAS sides with bipolar ablation in 3). After median follow-up of 15 (6-52) months, 17 patients (59%) remained free from recurrent arrhythmias.

Conclusion: IAS-ATs are rare and typically occur in patients with evidence of IAS substrate abnormalities and prior cardiac surgery. Catheter ablation can be challenging and may require sequential unipolar ablation or bipolar ablation.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.036DOI Listing
May 2021

Myosin cross-bridge kinetics slow at longer muscle lengths during isometric contractions in intact soleus from mice.

Proc Biol Sci 2021 05 12;288(1950):20202895. Epub 2021 May 12.

Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, USA.

Muscle contraction results from force-generating cross-bridge interactions between myosin and actin. Cross-bridge cycling kinetics underlie fundamental contractile properties, such as active force production and energy utilization. Factors that influence cross-bridge kinetics at the molecular level propagate through the sarcomeres, cells and tissue to modulate whole-muscle function. Conversely, movement and changes in the muscle length can influence cross-bridge kinetics on the molecular level. Reduced, single-molecule and single-fibre experiments have shown that increasing the strain on cross-bridges may slow their cycling rate and prolong their attachment duration. However, whether these strain-dependent cycling mechanisms persist in the intact muscle tissue, which encompasses more complex organization and passive elements, remains unclear. To investigate this multi-scale relationship, we adapted traditional step-stretch protocols for use with mouse soleus muscle during isometric tetanic contractions, enabling novel estimates of length-dependent cross-bridge kinetics in the intact skeletal muscle. Compared to rates at the optimal muscle length (), we found that cross-bridge detachment rates increased by approximately 20% at 90% of (shorter) and decreased by approximately 20% at 110% of (longer). These data indicate that cross-bridge kinetics vary with whole-muscle length during intact, isometric contraction, which could intrinsically modulate force generation and energetics, and suggests a multi-scale feedback pathway between whole-muscle function and cross-bridge activity.
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http://dx.doi.org/10.1098/rspb.2020.2895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190544PMC
May 2021

IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage.

Sci Immunol 2021 May;6(59)

Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1 mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from infection, IL-1R1-dependent RSPO3 production by GREM1 mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.
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http://dx.doi.org/10.1126/sciimmunol.abe8856DOI Listing
May 2021

A novel approach to mapping and ablation of septal outflow tract ventricular arrhythmias: Insights from multipolar intraseptal recordings.

Heart Rhythm 2021 Apr 20. Epub 2021 Apr 20.

Section of Cardiac Electrophysiology, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2021.04.016DOI Listing
April 2021

Health-related quality of life in patients with recurrent pericarditis: results from a phase 2 study of rilonacept.

BMC Cardiovasc Disord 2021 Apr 21;21(1):201. Epub 2021 Apr 21.

Kiniksa Pharmaceuticals Corp., 100 Hayden Avenue, Lexington, MA, 02421, USA.

Background: Impact of recurrent pericarditis (RP) on patient health-related quality of life (HRQoL) was evaluated through qualitative patient interviews and as an exploratory endpoint in a Phase 2 trial evaluating the efficacy and safety of rilonacept (IL-1α/IL-1β cytokine trap) to treat RP.

Methods: Qualitative interviews were conducted with ten adults with RP to understand symptoms and HRQoL impacts, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS GH) v1.2 was evaluated to determine questionnaire coverage of patient experience. The Phase 2 trial enrolled participants with active symptomatic RP (A-RP, n = 16) and corticosteroid-dependent participants with no active recurrence at baseline (CSD-RP, n = 9). All participants received rilonacept weekly during a 6-week base treatment period (TP) plus an optional 18-week extension period (EP). Tapering of concomitant medications, including corticosteroids (CS), was permitted during EP. HRQoL was assessed using the PROMIS GH, and patient-reported pain and blood levels of c-reactive protein (CRP) were collected at Baseline and follow-up periods. A secondary, descriptive analysis of the Phase 2 trial efficacy results was completed using HRQoL measures to characterize both the impact of RP and the treatment effect of rilonacept.

Results: Information from qualitative interviews demonstrated that PROMIS GH concepts are relevant to adults with RP. From the Phase 2 trial, both participant groups showed impacted HRQoL at Baseline (mean PROMIS Global Physical Health [GPH] and Global Mental Health [GMH], were lower than population norm average). In A-RP, GPH/MPH improved by end of base TP and were sustained through EP (similar trends were observed for pain and CRP). Similarly, in CSD-RP, GPH/MPH improved by end of TP and further improved during EP, during CS tapering or discontinuation, without disease recurrence (low pain scores and CRP levels continued during the TP and EP).

Conclusion: This is the first study demonstrating impaired HRQoL in RP. Rilonacept treatment was associated with HRQoL improvements using PROMIS GH scores. Maintained/improved HRQoL during tapering/withdrawal of CS without recurrence suggests that rilonacept may provide an alternative to CS.

Trial Registration: ClinicalTrials.Gov; NCT03980522; 5 June 2019, retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT03980522 .
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http://dx.doi.org/10.1186/s12872-021-02008-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061027PMC
April 2021

Cognitive Demands Influence Upper Extremity Motor Performance During Recovery From Acute Stroke.

Neurology 2021 05 15;96(21):e2576-e2586. Epub 2021 Apr 15.

From the Center for Neurotechnology and Neurorecovery (D.J.L., J.A.D., N.L., J.R., K.P., A.C., J.F., L.R.H.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston; Division of Neurocritical Care (D.J.L., L.R.H.), Department of Neurology, Stroke Service (D.J.L., S.P.F., L.H.S., L.R.H.), Department of Neurology, J. Philip Kistler Stroke Research Center (A.K.B.), Department of Neurology, Department of Occupational Therapy (J.R.), Department of Physical Therapy (K.P.), and Department of Speech, Language, and Swallowing Disorders (A.C., J.F.), Massachusetts General Hospital, Boston; VA RR&D Center for Neurorestoration and Neurotechnology (D.J.L., L.R.H.), Rehabilitation R&D Service, Department of VA Medical Center, Providence, RI; Department of Occupational Therapy (K.S.E., N.L.), MGH Institute of Health Professions, Boston, MA; Division of Neurocritical Care (S.B.S.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; School of Engineering (L.R.H.), Brown University, Providence, RI; Department of Neurology (S.C.C.), University of California, Los Angeles; and California Rehabilitation Hospital (S.C.C.), Los Angeles.

Objective: To test the hypothesis that cognitive demands influence motor performance during recovery from acute stroke, we tested patients with acute stroke on 2 motor tasks with different cognitive demands and related task performance to cognitive impairment and neuroanatomic injury.

Methods: We assessed the contralesional and ipsilesional upper extremities of a cohort of 50 patients with weakness after unilateral acute ischemic stroke at 3 time points with 2 tasks: the Box & Blocks Test, a task with greater cognitive demand, and Grip Strength, a simple and ballistic motor task. We compared performance on the 2 tasks, related motor performance to cognitive dysfunction, and used voxel-based lesion symptom mapping to determine neuroanatomic sites associated with motor performance.

Results: Consistent across contralesional and ipsilesional upper extremities and most pronounced immediately after stroke, Box & Blocks scores were significantly more impaired than Grip Strength scores. The presence of cognitive dysfunction significantly explained up to 33% of variance in Box & Blocks performance but was not associated with Grip Strength performance. While Grip Strength performance was associated with injury largely restricted to sensorimotor regions, Box & Blocks performance was associated with broad injury outside sensorimotor structures, particularly the dorsal anterior insula, a region known to be important for complex cognitive function.

Conclusions: Together, these results suggest that cognitive demands influence upper extremity motor performance during recovery from acute stroke. Our findings emphasize the integrated nature of motor and cognitive systems and suggest that it is critical to consider cognitive demands during motor testing and neurorehabilitation after stroke.
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http://dx.doi.org/10.1212/WNL.0000000000011992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205451PMC
May 2021

p300 Serine 89: A Critical Signaling Integrator and Its Effects on Intestinal Homeostasis and Repair.

Cancers (Basel) 2021 Mar 14;13(6). Epub 2021 Mar 14.

Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution.
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http://dx.doi.org/10.3390/cancers13061288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999107PMC
March 2021

Brain-Computer Interfaces in Neurorecovery and Neurorehabilitation.

Semin Neurol 2021 Apr 19;41(2):206-216. Epub 2021 Mar 19.

Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Recent advances in brain-computer interface technology to restore and rehabilitate neurologic function aim to enable persons with disabling neurologic conditions to communicate, interact with the environment, and achieve other key activities of daily living and personal goals. Here we evaluate the principles, benefits, challenges, and future directions of brain-computer interfaces in the context of neurorehabilitation. We then explore the clinical translation of these technologies and propose an approach to facilitate implementation of brain-computer interfaces for persons with neurologic disease.
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http://dx.doi.org/10.1055/s-0041-1725137DOI Listing
April 2021

Arm Motor Recovery After Ischemic Stroke: A Focus on Clinically Distinct Trajectory Groups.

J Neurol Phys Ther 2021 04;45(2):70-78

Department of Physical Therapy (D.K.K., M.P.-F., T.J.K.) and Center for Interprofessional Studies and Innovation (A.B.F.), MGH Institute of Health Professions, Boston, Massachusetts; Center for Neurotechnology and Neurorecovery, Department of Neurology (D.J.L., A.C., K.S., L.R.H.), Divisions of Neurocritical Care and Stroke, Department of Neurology (D.J.L., L.R.H.), Department of Physical Therapy (K.P.), and Department of Occupational Therapy (J.R.), Massachusetts General Hospital, Boston; VA RR&D Center for Neurotechnology and Neurorecovery, Providence, Rhode Island (L.R.H.); and School of Engineering, Brown University, Providence, Rhode Island (L.R.H.).

Background And Purpose: Recovery of arm function poststroke is highly variable with some people experiencing rapid recovery but many experiencing slower or limited functional improvement. Current stroke prediction models provide some guidance for clinicians regarding expected motor outcomes poststroke but do not address recovery rates, complicating discharge planning. This study developed a novel approach to defining recovery groups based on arm motor recovery trajectories poststroke. In addition, between-group differences in baseline characteristics and therapy hours were explored.

Methods: A retrospective cohort analysis was conducted where 40 participants with arm weakness were assessed 1 week, 6 weeks, 3 months, and 6 months after an ischemic stroke. Arm recovery trajectory groups were defined on the basis of timing of changes in the Fugl-Meyer Assessment Upper Extremity (FMA-UE), at least the minimal clinically important difference (MCID), 1 week to 6 weeks or 6 weeks to 6 months. Three recovery trajectory groups were defined: Fast (n = 19), Extended (n = 12), and Limited (n = 9). Between-group differences in baseline characteristics and therapy hours were assessed. Associations between baseline characteristics and group membership were also determined.

Results: Three baseline characteristics were associated with trajectory group membership: FMA-UE, NIH Stroke Scale, and Barthel Index. The Fast Recovery group received the least therapy hours 6 weeks to 6 months. No differences in therapy hours were observed between Extended and Limited Recovery groups at any time points.

Discussion And Conclusions: Three clinically relevant recovery trajectory groups were defined using the FMA-UE MCID. Baseline impairment, overall stroke severity, and dependence in activities of daily living were associated with group membership and therapy hours differed between groups. Stratifying individuals by recovery trajectory early poststroke could offer additional guidance to clinicians in discharge planning.

(See Supplemental Digital Content 1 for Video Abstract, available at: http://links.lww.com/JNPT/A337.).
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http://dx.doi.org/10.1097/NPT.0000000000000350DOI Listing
April 2021

Principles of Neural Repair and Their Application to Stroke Recovery Trials.

Semin Neurol 2021 Apr 4;41(2):157-166. Epub 2021 Mar 4.

Department of Neurology, University of California, Los Angeles, California.

Neural repair is the underlying therapeutic strategy for many treatments currently under investigation to improve recovery after stroke. Repair-based therapies are distinct from acute stroke strategies: instead of salvaging threatened brain tissue, the goal is to improve behavioral outcomes on the basis of experience-dependent brain plasticity. Furthermore, timing, concomitant behavioral experiences, modality specific outcome measures, and careful patient selection are fundamental concepts for stroke recovery trials that can be deduced from principles of neural repair. Here we discuss core principles of neural repair and their implications for stroke recovery trials, highlighting related issues from key studies in humans. Research suggests a future in which neural repair therapies are personalized based on measures of brain structure and function, genetics, and lifestyle factors.
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http://dx.doi.org/10.1055/s-0041-1725140DOI Listing
April 2021

The need to investigate hyperuricemia as a factor in the onset of age-related macular degeneration.

Eye (Lond) 2021 07 24;35(7):1804-1807. Epub 2021 Feb 24.

Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.

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http://dx.doi.org/10.1038/s41433-021-01456-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225777PMC
July 2021

Active esophageal cooling for the prevention of thermal injury during atrial fibrillation ablation: a randomized controlled pilot study.

J Interv Card Electrophysiol 2021 Feb 23. Epub 2021 Feb 23.

Cardiac Electrophysiology Section, Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Founders Pavilion, Philadelphia, PA, 19104, USA.

Background: Severe endoscopically detected esophageal thermal lesions (EDELs) have been associated with higher risk of progression to atrio-esophageal fistula (AEF) following radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). We sought to evaluate safety and feasibility of active esophageal cooling using the Attune Medical Esophageal Heat Transfer Device (EnsoETM) to limit frequency or severity of EDELs.

Objective: We sought To evaluate safety and feasibility of active esophageal cooling using the Attune Medical Esophageal Heat Transfer Device (EnsoETM) to limit frequency or severity of EDELs METHODS: Consecutive patients undergoing first-time RFCA were randomized in a 1:1 fashion to esophageal cooling (device group) or standard temperature monitoring (control group). Ablation on the posterior wall was performed with a maximum power of 30W for up to 20s. All patients underwent EGD within 48 h. Endoscopy findings were classified as 1, erythema-mild injury; 2, superficial ulceration-moderate injury; 3, deep ulceration-significant injury; and 4, fistula/perforation. Severe EDELs were defined as grade 3 or 4 lesions.

Results: Forty-four patients completed the study (22 device group, 22 control group). Adjunctive posterior wall isolation was performed more frequently in the device group (11/22, 50% vs. 4/22, 18%). EDELs were detected in 5/22 (23%) control group patients, with mild or moderate injury in 2/5 patients (40%) and severe thermal injury in 3/5 patients (60%). In the device group, EDELs were detected in 8/22 (36%) patients, with mild or moderate injury in 7/8 (87%) patients and severe thermal injury in 1/8 (12%) patients. There was no acute perforation or AEF during follow-up.

Conclusions: Active esophageal cooling may reduce the occurrence of severe EDELs. A larger randomized study is warranted to further evaluate the benefit of this strategy.
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http://dx.doi.org/10.1007/s10840-021-00960-wDOI Listing
February 2021

Periprocedural Acute Kidney Injury in Patients With Structural Heart Disease Undergoing Catheter Ablation of VT.

JACC Clin Electrophysiol 2021 02 28;7(2):174-186. Epub 2020 Oct 28.

Electrophysiology Section, Cardiovascular Medicine Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Objectives: This study sought to examine the impact of periprocedural acute kidney injury (AKI) in scar-related ventricular tachycardia (VT) patients undergoing radiofrequency catheter ablation (RFCA) on short- and long-term outcomes.

Background: The clinical significance of periprocedural AKI in patients with scar-related VT undergoing RFCA has not been previously investigated.

Methods: This study included 317 consecutive patients with scar-related VT undergoing RFCA (age: 64 ± 13 years, mean left ventricular ejection fraction: 33 ± 13%, 55% ischemic cardiomyopathy). Periprocedural AKI was defined as an absolute increase in creatinine of ≥0.3 mg/dl over 48 h or an increase of >1.5× the baseline values within 1 week post-procedure.

Results: Periprocedural AKI occurred in 31 patients (10%). Independent predictors of AKI included chronic kidney disease (odds ratio [OR]: 3.43; 95% confidence interval [CI]: 1.48 to 7.96; p = 0.004), atrial fibrillation (OR: 2.42; 95% CI: 1.01 to 5.78; p = 0.047), and peri-procedural acute hemodynamic decompensation (OR: 3.98; 95% CI: 1.17 to 13.52; p = 0.003). After a median follow-up of 39 months (interquartile range: 6 to 65 months), 95 patients (30%) died. Periprocedural AKI was associated with increased risk of early mortality (within 30 days; hazard ratio [HR]: 9.91; 95% CI: 2.87 to 34.22; p < 0.001) and late mortality (within 1 year) (HR: 4.57; 95% CI: 2.08 to 10.05; p < 0.001). After multivariable adjustment, AKI remained independently associated with increased risk of early and late mortality (HR: 4.49; 95% CI: 1.1 to 18.36; p = 0.04, and HR: 3.28; 95% CI: 1.43 to 7.49; p = 0.005, respectively).

Conclusions: Periprocedural AKI occurs in 10% of patients undergoing RFCA of scar-related VT and is strongly associated with increased risk of early and late post-procedural mortality.
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http://dx.doi.org/10.1016/j.jacep.2020.08.018DOI Listing
February 2021

Recognition of acute myocardial infarction caused by spontaneous coronary artery dissection of first septal perforator.

Eur Heart J Acute Cardiovasc Care 2021 Jan 4. Epub 2021 Jan 4.

Division of Cardiology, Vancouver General Hospital, Vancouver, BC, Canada.

Aims : Spontaneous coronary artery dissection (SCAD) diagnosis is challenging as angiographic findings are often subtle and differ from coronary atherosclerosis. Herein, we describe characteristics of patients with acute myocardial infarction (MI) caused by first septal perforator (S1) SCAD.

Methods And Results : Patients were gathered from SCAD registries at Minneapolis Heart Institute and Vancouver General Hospital. First septal perforator SCAD prevalence was 11 of 1490 (0.7%). Among 11 patients, age range was 38-64 years, 9 (82%) were female. Each presented with acute chest pain, troponin elevation, and non-ST-elevation MI diagnosis. Initial electrocardiogram demonstrated ischaemia in 5 (45%); septal wall motion abnormality was present in 4 (36%). Angiographic type 2 SCAD was present in 7 (64%) patients with S1 TIMI 3 flow in 7 (64%) and TIMI 0 flow in 2 (18%). Initial angiographic interpretation failed to recognize S1-SCAD in 6 (55%) patients (no culprit, n = 5, septal embolism, n = 1). First septal perforator SCAD diagnosis was established by review of initial coronary angiogram consequent to cardiovascular magnetic resonance (CMR) demonstrating focal septal late gadolinium enhancement with corresponding oedema (n = 3), occurrence of subsequent SCAD event (n = 2), or second angiogram showing healed S1-SCAD (n = 1). Patients were treated conservatively, each with ejection fraction >50%.

Conclusion : First septal perforator SCAD events may be overlooked at initial angiography and mis-diagnosed as 'no culprit' MI. First septal perforator SCAD prevalence is likely greater than reported herein and dependent on local expertise and availability of CMR imaging. Spontaneous coronary artery dissection events may occur in intra-myocardial coronary arteries, approaching the resolution limits of invasive coronary angiography.
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http://dx.doi.org/10.1093/ehjacc/zuaa036DOI Listing
January 2021

Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.

Commun Biol 2021 02 9;4(1):174. Epub 2021 Feb 9.

Neuroscience Discovery, Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA.

Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.
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http://dx.doi.org/10.1038/s42003-021-01678-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873226PMC
February 2021

Reimagining Stroke Rehabilitation and Recovery Across the Care Continuum: Results From a Design-Thinking Workshop to Identify Challenges and Propose Solutions.

Arch Phys Med Rehabil 2021 Feb 5. Epub 2021 Feb 5.

Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA; Stroke Service, Department of Neurology, Massachusetts General Hospital, Boston, MA. Electronic address:

Systems for stroke rehabilitation and recovery are variable and fragmented; stroke survivors often experience gaps in care with detrimental effects on their recovery. We designed and hosted a multidisciplinary and interactive workshop to discuss challenges facing patients recovering from stroke and to brainstorm solutions. Forty-one participants including clinicians, researchers, and stroke survivors attended the workshop. Participants were surveyed beforehand about challenges facing stroke recovery and results were tabulated as a word cloud. An interactive, design-thinking exercise was conducted that involved completing workbooks, hands-on prototype designing, and presentations, which were then analyzed through qualitative content analysis using an inductive approach. High frequency words in the word cloud of survey responses included access, fragmented, and uncertainty. Qualitative analysis revealed 6 major challenge themes including poor (1) transitions in and (2) access to care; (3) barriers to health insurance; (4) lack of patient support; (5) knowledge gaps; and (6) lack of standardized outcomes. Eleven unique solutions were proposed that centered around new technologies, health care system changes, and the creation of new support roles. Analysis of the alignment between the challenges and solutions revealed that the single proposed solution that solved the most identified challenges was a "comprehensive stroke clinic with follow-up programs, cutting edge treatments, patient advocation and research." Through our interactive design-thinking workshop process and inductive thematic analysis, we identified major challenges facing patients recovering from stroke, collaboratively proposed solutions, and analyzed their alignment. This process offers an innovative approach to reaching consensus among interdisciplinary stakeholders.
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http://dx.doi.org/10.1016/j.apmr.2021.01.074DOI Listing
February 2021

Stroke, Timing of Atrial Fibrillation Diagnosis, and Risk of Death.

Neurology 2021 03 3;96(12):e1655-e1662. Epub 2021 Feb 3.

From the Division of Cardiovascular Medicine, Department of Medicine (A.B., Y.B., M.C.H., J.A., D.J.C., N.C., S.D., A.E.E., D.S.F., F.C.G., R.K., J.J.L., D.L., S.N., M.P.R., P.S., R.D.S., G.E.S., F.M., R.D.), and Department of Neurology (S.R.M., S.E.K.), Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia; Department of Biostatistics (R.K.), University of Washington, Seattle; and Division of Cardiology (P.J.P.), St. Vincent Medical Group, Indianapolis, IN.

Objective: To evaluate the prognosis of patients with ischemic stroke according to the timing of an atrial fibrillation (AF) diagnosis, we created an inception cohort of incident stroke events and compared the risk of death between patients with stroke with (1) sinus rhythm, (2) known AF (KAF), and (3) AF diagnosed after stroke (AFDAS).

Methods: We used the Penn AF Free study to create an inception cohort of patients with incident stroke. Mortality events were identified after linkage with the National Death Index through June 30, 2017. We also evaluated initiation of anticoagulants and antiplatelets across the study duration. Cox proportional hazards models evaluated associations between stroke subtypes and death.

Results: We identified 1,489 individuals who developed an incident ischemic stroke event: 985 did not develop AF at any point during the study period, 215 had KAF before stroke, 160 had AF detected ≤6 months after stroke, and 129 had AF detected >6 months after stroke. After a median follow-up of 4.9 years (interquartile range 1.9-6.8), 686 deaths occurred. The annualized mortality rate was 8.8% in the stroke, no AF group; 12.2% in the KAF group; 15.8% in the AFDAS ≤6 months group; and 12.7% in the AFDAS >6 months group. Patients in the AFDAS ≤6 months group had the highest independent risk of all-cause mortality even after multivariable adjustment for demographics, clinical risk factors, and the use of antithrombotic therapies (hazard ratio 1.62 [1.22-2.14]). Compared to the stroke, no AF group, those with KAF had a higher mortality risk that was rendered nonsignificant after adjustment.

Conclusions: The AFDAS group had the highest risk of death, which was not explained by comorbidities or use of antithrombotic therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011633DOI Listing
March 2021

Myocardial Substrate Characterization by CMR T Mapping in Patients With NICM and No LGE Undergoing Catheter Ablation of VT.

JACC Clin Electrophysiol 2021 Jul 27;7(7):831-840. Epub 2021 Jan 27.

Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Objectives: The goal of this study was to characterize the relationship between DF, the electroanatomic mapping (EAM) substrate, and outcomes of catheter ablation of VT in NICM.

Background: A substantial proportion of patients with nonischemic dilated cardiomyopathy (NICM) and ventricular tachycardia (VT) do not have scar detectable by cardiac magnetic resonance late gadolinium enhancement (LGE) imaging. In these patients, the significance of diffuse fibrosis (DF) detected with T mapping has not been previously investigated.

Methods: This study included 51 patients with NICM and VT undergoing catheter ablation (median age 55 years; 77% male subjects) who had no evidence of LGE on pre-procedural cardiac magnetic resonance. Post-contrast T relaxation time determined on the septum was assessed as a surrogate of DF burden. The extent of endocardial low-voltage areas (LVAs) at EAM was correlated with T mapping data.

Results: Bipolar LVAs were present in 22 (43%) patients (median extent 15 cm [8 to 29 cm]) and unipolar LVA in all patients (median extent 48 cm [26 to 120 cm]). A significant inverse correlation was found between T values and both unipolar-LVA (R = 0.64; β = -0.85; p < 0.01) and bipolar-LVA (R = 0.16; β = -1.63; p < 0.01). After a median follow-up of 45 months (22 to 57 months), 2 (4%) patients died, 3 (6%) underwent heart transplantation, and 8 (16%) experienced VT recurrence. Shorter post-contrast T time was associated with an increased risk of VT recurrence (hazard ratio: 1.16; 95% confidence interval: 1.03 to 1.33 per 10 ms decrease; p = 0.02).

Conclusions: In patients with NICM and no evidence of LGE undergoing catheter ablation of VT, DF estimated by using post-contrast T mapping correlates with the voltage abnormality at EAM and seems to affect post-ablation outcomes.
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http://dx.doi.org/10.1016/j.jacep.2020.10.002DOI Listing
July 2021

Internalizing symptoms associate with the pace of epigenetic aging in childhood.

Biol Psychol 2021 02 15;159:108021. Epub 2021 Jan 15.

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, the Netherlands.

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms at ages 6-10 years. Similar trends for externalizing symptoms did not reach statistical significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108021DOI Listing
February 2021

An early experience on the effect of solid organ transplant status on hospitalized COVID-19 patients.

Am J Transplant 2021 07 13;21(7):2522-2531. Epub 2021 Jan 13.

North Shore University Hospital, Northwell Health, Manhasset, New York.

We compared the outcome of COVID-19 in immunosuppressed solid organ transplant (SOT) patients to a transplant naïve population. In total, 10 356 adult hospital admissions for COVID-19 from March 1, 2020 to April 27, 2020 were analyzed. Data were collected on demographics, baseline clinical conditions, medications, immunosuppression, and COVID-19 course. Primary outcome was combined death or mechanical ventilation. We assessed the association between primary outcome and prognostic variables using bivariate and multivariate regression models. We also compared the primary endpoint in SOT patients to an age, gender, and comorbidity-matched control group. Bivariate analysis found transplant status, age, gender, race/ethnicity, body mass index, diabetes, hypertension, cardiovascular disease, COPD, and GFR <60 mL/min/1.73 m to be significant predictors of combined death or mechanical ventilation. After multivariate logistic regression analysis, SOT status had a trend toward significance (odds ratio [OR] 1.29; 95% CI 0.99-1.69, p = .06). Compared to an age, gender, and comorbidity-matched control group, SOT patients had a higher combined risk of death or mechanical ventilation (OR 1.34; 95% CI 1.03-1.74, p = .027).
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http://dx.doi.org/10.1111/ajt.16460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206217PMC
July 2021

DNA methylation is associated with airflow obstruction in patients living with HIV.

Thorax 2021 05 18;76(5):448-455. Epub 2020 Dec 18.

Centre for Heart Lung Innovation, The University of British Columbia, Vancouver, British Columbia, Canada

Introduction: People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.

Methods: Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV, FEV/FVC ratio and FEV decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.

Results: Airflow obstruction as defined by a FEV/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV/FVC
Conclusion: A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070606PMC
May 2021

Establishment of a Tear Ferning Test Protocol in the Mouse Model.

Transl Vis Sci Technol 2020 12 1;9(13). Epub 2020 Dec 1.

Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung, Taiwan.

Purpose: Analysis of ferning formation after tear drop desiccation on a glass slide has been applied as a simple method to examine tear normality and is referred to as the tear ferning (TF) test. Despite use of the TF test in clinical settings and in some animals, thus far no TF test protocol has been developed for the mouse model. This study aimed to establish a mouse TF test protocol that can be used for dry eye research using the mouse as the study model.

Methods: Tear samples were collected from 24 healthy mice after repeated flushes with 2, 5, 10, or 20 µL wash solutions, either 0.9% NaCl saline or sterile water, on the ocular surface. After sample collection, TF tests were performed at variable drop volumes (2-20 µL), at a relative humidity of either 46% ± 2% or 53% ± 2%, and with temperature fixed at 24°C ± 2°C for comparison. Moreover, the influence of osmolarity (between 280 and 360 mOsm/L) and pH values (6.5-8.0) and the effect of centrifugation (4000 rpm, 10 minutes) on ferning formation were examined. Reproducibility and ferning storage stability were also determined.

Results: An optimized protocol was established with relative humidity at 46% ± 2% and drop aliquot at 2 µL, using 0.9% NaCl saline as the wash solution. Using sterilized water as the wash solution did not result in any crystalloid formation. Centrifugation did not aid ferning formation in any of the samples. Higher osmolarity increased ferning formation from grades between 0 to 1 to grades between 2 to 3, but pH values that varied between 6.5 and 8.0 did not affect ferning formation. The established mouse TF test protocol also displayed reproducibility and storage stability.

Conclusions: A TF test protocol for the mouse model was established that could be used for comparative analyses under various ocular surface disease conditions.

Translational Relevance: This mouse TF test protocol will facilitate the application of basic research into the mouse model to clinical care.
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http://dx.doi.org/10.1167/tvst.9.13.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718818PMC
December 2020

Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults.

Front Immunol 2020 4;11:580373. Epub 2020 Nov 4.

Department of Radiology, BC Children's Hospital, Vancouver, BC, Canada.

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.
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http://dx.doi.org/10.3389/fimmu.2020.580373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672042PMC
June 2021
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