Genetically-guided algorithm development and sample size optimization for age-related macular degeneration cases and controls in electronic health records from the VA Million Veteran Program.

Electronic health records (EHRs) linked to extensive biorepositories and supplemented with lifestyle, behavioral, and environmental exposure data, have enormous potential to contribute to genomic discovery, a necessary step in the pathway towards translational or precision medicine. A major bottleneck in incorporating EHRs into genomic studies is the extraction of research-grade variables for analysis, particularly when gold-standard measurements are not available or accessible. Here we develop algorithms for age-related macular degeneration (AMD), a common cause of blindness among the elderly, and controls free of AMD. These computable phenotypes were developed using billing codes (ICD-9-CM and ICD-10-CM) and Current Procedural Terminology (CPT) codes and evaluated in two study sites of the Veterans Affairs Million Veteran Program: Louis Stokes Cleveland VA Medical Center and the Providence VA Medical Center. After establishing a high overall positive and negative predictive values (93% and 95%, respectively) through manual chart review, the candidate algorithm was deployed in the full VA MVP dataset of >500,000 participants. The algorithm was then optimized in a data cube using a variety of approaches including adjusting inclusion age thresholds by examining previously-reported genetic associations for CFH (rs10801555, a proxy for rs1061170) and ARMS2 (rs10490924). The algorithm with the smallest p-values for the known genetic associations was selected for downstream and on-going AMD genomic discovery efforts. This two-phase approach to developing research-grade case/control variables for AMD genomic studies capitalizes on established genetic associations resulting in high precision and optimized sample sizes, an approach that can be applied to other large-scale biobanks linked to EHRs for precision medicine research.

The Role and Function of the Liaison Officer: Lessons Learned and Applied after Superstorm Sandy.

In October 2012, Superstorm Sandy had a wide impact on the public across New York City (NYC). The NYC Department of Health and Mental Hygiene (DOHMH) activated its incident command system (ICS) and deployed a liaison officer (LNO) to the NYC Emergency Operations Center (EOC) at NYC Emergency Management (NYCEM) 24 hours a day for 6 weeks. This prolonged response period, coupled with environmental effects on NYC's coastal communities, increased public awareness of Sandy's health impacts, requiring a broad scope of interagency coordination and operational input from the liaison officer. Liaison officers involved in this response later conducted a content analysis of issues handled throughout Sandy, to better understand the skill set required to serve in this role, identify greater staff depth, integrate liaison officers into DOHMH exercises, and update just-in-time training provided before liaison officers deploy. This analysis revealed defined training topics for liaison officers to improve staff performance and effectiveness in leading interagency coordination during emergency responses. Topics include resources, staffing, data management, public messaging, and vulnerable populations, and these topics have since been used to revamp liaison officer training and guide policy changes in the liaison officer job charter. Targeted use of liaison officers to support development and implementation and to coordinate response objectives with local, state, and federal partners has only become more important. This analysis continues to influence how DOHMH defines its citywide agency response role, to inform how best to staff and train liaison officers to respond, and to pose lessons for other jurisdictions seeking to maximize the effectiveness of liaison officers deployed in emergencies.

Using Health Information Exchange to Improve Family Reunification After a Mass Casualty Incident.

From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. Typically, National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org.

Social Media Monitoring: 2016 Zika Response in NYC.

From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org .

Integrating Social Media Monitoring Into Public Health Emergency Response Operations.

Social media monitoring for public health emergency response and recovery is an essential response capability for any health department. The value of social media for emergency response lies not only in the capacity to rapidly communicate official and critical incident information, but as a rich source of incoming data that can be gathered to inform leadership decision-making. Social media monitoring is a function that can be formally integrated into the Incident Command System of any response agency. The approach to planning and required resources, such as staffing, logistics, and technology, is flexible and adaptable based on the needs of the agency and size and scope of the emergency. The New York City Department of Health and Mental Hygiene has successfully used its Social Media Monitoring Team during public health emergency responses and planned events including major Ebola and Legionnaires' disease responses. The concepts and implementations described can be applied by any agency, large or small, interested in building a social media monitoring capacity. (Disaster Med Public Health Preparedness. 2016;page 1 of 6).

A medieval fallacy: the crystalline lens in the center of the eye.

OBJECTIVE: To determine whether, as most modern historians have written, ancient Greco-Roman authors believed the crystalline lens is positioned in the center of the eye. BACKGROUND: Historians have written that statements about cataract couching by Celsus, or perhaps Galen of Pergamon, suggested a centrally located lens. Celsus specifically wrote that a couching needle placed intermediate between the corneal limbus and the lateral canthus enters an empty space, presumed to represent the posterior chamber. METHODS: Ancient ophthalmic literature was analyzed to understand where these authors believed the crystalline lens was positioned. In order to estimate where Celsus proposed entering the eye during couching, we prospectively measured the distance from the temporal corneal limbus to the lateral canthus in 30 healthy adults. RESULTS: Rufus of Ephesus and Galen wrote that the lens is anterior enough to contact the iris. Galen wrote that the lens equator joins other ocular structures at the corneoscleral junction. In 30 subjects, half the distance from the temporal corneal limbus to the lateral canthus was a mean of 4.5 mm (range: 3.3-5.3 mm). Descriptions of couching by Celsus and others are consistent with pars plana entry of the couching needle. Anterior angulation of the needle would permit contact of the needle with the lens. CONCLUSION: Ancient descriptions of anatomy and couching do not establish the microanatomic relationships of the ciliary region with any modern degree of accuracy. Nonetheless, ancient authors, such as Galen and Rufus, clearly understood that the lens is located anteriorly. There is little reason to believe that Celsus or other ancient authors held a variant understanding of the anatomy of a healthy eye. The notion of the central location of the lens seems to have arisen with Arabic authors in 9th century Mesopotamia, and lasted for over 7 centuries.

The early history of glaucoma: the glaucous eye (800 BC to 1050 AD).

To the ancient Greeks, glaukos occasionally described diseased eyes, but more typically described healthy irides, which were glaucous (light blue, gray, or green). During the Hippocratic period, a pathologic glaukos pupil indicated a media opacity that was not dark. Although not emphasized by present-day ophthalmologists, the pupil in acute angle closure may appear somewhat green, as the mid-dilated pupil exposes the cataractous lens. The ancient Greeks would probably have described a (normal) green iris or (diseased) green pupil as glaukos. During the early Common Era, eye pain, a glaucous hue, pupil irregularities, and absence of light perception indicated a poor prognosis with couching. Galen associated the glaucous hue with a large, anterior, or hard crystalline lens. Medieval Arabic authors translated glaukos as zarqaa, which also commonly described light irides. Ibn Sina (otherwise known as Avicenna) wrote that the zarqaa hue could occur due to anterior prominence of the lens and could occur in an acquired manner. The disease defined by the glaucous pupil in antiquity is ultimately indeterminate, as the complete syndrome of acute angle closure was not described. Nonetheless, it is intriguing that the glaucous pupil connoted a poor prognosis, and came to be associated with a large, anterior, or hard crystalline lens.

Enduring influence of elizabethan ophthalmic texts of the 1580s: bailey, grassus, and guillemeau.

Three English ophthalmic texts of the 1580s were frequently republished: 1) Walter Bailey's A Briefe Treatise Touching the Preseruation of the Eie Sight, 2) The Method of Phisicke, an adaptation of the medieval treatise of Benevenutus Grassus, and 3) A Worthy Treatise of the Eyes, a translation of Jacques Guillemeau's treatise. Their history is intertwined through composite publications, some of which lacked clear attribution. At least 21 editions incorporated these texts. Although not previously realized, major elements of all 3 works are found in Two Treatises Concerning the Preseruation of Eie-sight, first published in 1616. To preserve eyesight, Bailey recommended eyebright (Euphrasia officinalis), fennel (Fæniculum vulgare), and a moderate lifestyle incorporating wine. In the works of Grassus and Guillemeau, cataracts were believed to lie anterior to the 'crystalline humor,' and were treated by the 'art of the needle,' or couching. Links are found between Grassus, Guillemeau, and eighteenth century glaucoma concepts. Although one of his students has traditionally received credit, it was English oculist John Thomas Woolhouse who first combined the early concepts and used the term glaucoma to describe the palpably hard eye in the early eighteenth century. The three primary ophthalmic texts of 1580s England influenced ophthalmic thought for over a century.

ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo.

ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.

Anulus fibrosus tension inhibits degenerative structural changes in lamellar collagen.

Mechanical stress is one of the risk factors believed to influence intervertebral disc degeneration. Animal models have shown that certain regimes of compressive loading can induce a cascade of biological effects that ultimately results in cellular and structural changes in the disc. It has been proposed that both cell-mediated breakdown of collagen and the compromised stability of collagen with loss of anular tension could result in degradation of lamellae in the anulus fibrosus (AF). To determine whether this may be important in the AF, we subjected entire rings of de-cellularized AF tissue to MMP-1 digestion with or without tension. Biomechanical testing found trends of decreasing strength and stiffness when tissues were digested without tension compared with those with tension. To determine the physiologic significance of tissue level tension in the AF, we used an established in vivo murine model to apply a disc compression insult known to cause degeneration. Afterward, that motion segment was placed in fixed-angle bending to impose tissue level tension on part of the AF and compression on the contralateral side. We found that the AF on the convex side of bending retained a healthy lamellar appearance, while the AF on the concave side resembled tissues that had undergone degeneration by loading alone. Varying the time of onset and duration of bending revealed that even a brief duration applied immediately after cessation of compression was beneficial to AF structure on the convex side of bending. Our results suggest that both cell-mediated events and cell-independent mechanisms may contribute to the protective effect of tissue level tension in the AF.

Quantitative regional associations between remodeling, modeling, and osteocyte apoptosis and density in rabbit tibial midshafts.

Evidence suggests that osteocyte apoptosis is involved in the adaptive response of bone, although the specific role of osteocytes in the signaling mechanism is unknown. Here, we examined and correlated regional variability in indices of remodeling, modeling, osteocyte apoptosis, and osteocyte density in rabbit tibia midshafts. Histomorphometric analysis indicated that remodeling parameters (BMU activation frequency, osteon density, forming osteon density, and resorption cavity density) were lower in the cranial region compared to other quadrants. In addition, pericortical subregions displayed less remodeling relative to intracortical and endocortical ones. Modeling indices also demonstrated regional variability in that periosteal surfaces exhibited a greater extent of bone forming surface than endosteal ones across all anatomic quadrants. In contrast, endosteal surfaces demonstrated significantly greater surface mineral apposition rates compared to periosteal surfaces in caudal, medial, and lateral but not cranial quadrants. Using TUNEL analysis to detect osteocytes undergoing apoptosis, the density of apoptotic osteocytes was found to be lower in cranial quadrants relative to medial ones. In addition, the densities of osteocyte lacunae, empty lacunae, and total osteocytes were higher in lateral fields relative to caudal quadrants. There was a strong, statistically significant linear correlation between the remodeling indices and apoptotic osteocyte density, supporting the theory that osteocytes undergoing apoptosis produce signals that attract or direct bone remodeling. In contrast, the modeling parameters did not exhibit a correlation with apoptotic osteocytes, although there was a strong correlation between the modeling indices and the density of empty osteocyte lacunae, corroborating previous studies that have found that osteocytes inhibit bone formation. It was found that osteocyte density and osteocyte lacunar density did not significantly correlate with modeling or remodeling parameters, suggesting that cell viability should be examined in studies correlating bone turnover parameters with the functional role of osteocytes in bone adaptation.

The instant axis of rotation influences facet forces at L5/S1 during flexion/extension and lateral bending.

Because the disc and facets work together to constrain spinal kinematics, changes in the instant axis of rotation associated with disc degeneration or disc replacement may adversely influence risk for facet overloading and arthritis. The relationships between L5/S1 segmental kinematics and facet forces are not well defined, since previous studies have separated investigations of spinal motion and facet force. The goal of this cadaveric biomechanical study was to report and correlate a measure of intervertebral kinematics (the centrode, or the path of the instant axis of rotation) and the facet forces at the L5/S1 motion segment while under a physiologic combination of compression and anterior shear loading. Twelve fresh-frozen human cadaveric L5/S1 joints (age range 50-64 years) were tested biomechanically under semi-constrained conditions by applying compression plus shear forces in several postures: neutral, and 3 degrees and 6 degrees of flexion, extension and lateral bending. The experimental boundary conditions imposed compression and shear representative of in vivo conditions during upright stance. The 3-D instantaneous axis of rotation (IAR) was calculated between two consecutive postures. The facet joint force was simultaneously measured using thin-film sensors placed between both facet surfaces. Variations of IAR location and facet force during motion were analyzed. During flexion and extension, the IAR was oriented laterally. The IAR intersection with the mid-sagittal plane moved cephalad relative to S1 endplate during flexion (P=0.010), and posterior during extension (P=0.001). The facet force did not correlate with posture (P=0.844). However, changes in the facet force between postures did correlate with IAR position: higher IAR's during flexion correlated with lower facet forces and vice versa (P=0.04). During lateral bending, the IAR was oblique relative to the main plane of motion and translated parallel to S1 endplate, toward the side of the bending. Overall, the facet force was increased on the ipsilateral side of bending (P=0.002). The IAR positions demonstrate that the L5 vertebral body primarily rotates forward during flexion (IAR close to vertebral body center) and rotates/translates backward during extension (IAR at or below the L5/S1 intervertebral disc). In lateral bending, the IAR obliquity demonstrated coupling with axial torsion due to resistance of the ipsilateral facet.

Basic fibroblast growth factor improves trabecular bone connectivity and bone strength in the lumbar vertebral body of osteopenic rats.

Recently, basic fibroblast growth factor (bFGF) has been found to increase trabecular bone mass and connectivity in the proximal tibial metaphyses (PTM) in osteopenic rats. The purpose of this study was to determine the bone anabolic effects of bFGF in the lumbar vertebral body (LVB), a less loaded skeletal site with a lower rate of bone turnover than the PTM. Six-month old female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated and untreated for 8 weeks to induce osteopenia. Then group 1 (sham) and group 2 (OVX) were treated subcutaneously (s.c.) with vehicle, and OVXed groups 3 and 4 were treated s.c. with PTH [hPTH (1-34) at 40 microg/kg, 5x/week] and bFGF (1 mg/kg, 5x/week), respectively, for 8 weeks. At sacrifice, the fifth LVB was removed, subjected to micro-CT for determination of trabecular bone structure and then processed for histomorphometry to assess bone turnover. The sixth LVB was used for mechanical compression testing (MTS, Bionix 858). The data were analyzed with the Kruskal-Wallis test followed by post-hoc testing as needed. After 16 weeks of estrogen deficiency, there were significant reductions in vertebral trabecular bone volume and trabecular thickness. Treatment with either bFGF or hPTH (1-34) increased BV/TV in OVX animals. Human PTH (1-34)-treated animals had significant increases in trabecular (48%) and cortical thickness (30%) and bone strength [maximum load (53%) and work to failure (175%)] compared to OVX + Vehicle animals. Treatment of osteopenic rats with bFGF increased bone volume (15%), trabecular thickness (13%), maximum load (45%) and work to failure (140%) compared to OVX + Vehicle animals (all P <0.05). Basic FGF increased trabecular bone volume in the lumbar vertebral body of osteopenic rats by restoring trabecular number, thickness and connectivity density. Also, bFGF improved bone mechanical properties (maximum force and work to failure) compared to the OVX + Vehicle group. Therefore, increasing the number, thickness and connections of the trabeculae contributes to increased bone strength in this small animal model of osteoporosis.

Effects of controlled dynamic disc distraction on degenerated intervertebral discs: an in vivo study on the rabbit lumbar spine model.

STUDY DESIGN: An in vivo study on the rabbit lumbar spine model. OBJECTIVES: Effects of temporary dynamic distraction on intervertebral discs were studied on the lumbar spine rabbit model to characterize the changes associated with disc distraction and to evaluate feasibility of temporary disc distraction to previously compressed discs in order to stimulate disc regeneration. SUMMARY OF BACKGROUND DATA: Studies have shown that accelerated degeneration of the intervertebral disc results from altered mechanical loading conditions. The development of methods for the prevention of disc degeneration and the restoration of disc tissue that has already degenerated are needed. METHODS: New Zealand white rabbits (n = 32) were used for this study. The rabbits were randomly assigned to one of five groups. In 12 animals, the discs were first loaded for 28 days using a custom-made external loading device to stimulate disc degeneration. After 28 days loading time, the discs in six animals were distracted for 7 days and in six animals for 28 days using the same external device, however, modified as dynamic distraction device. In six animals, the discs were distracted for 28 days without previous loading; and in six animals, the discs were loaded for 28 days and afterwards the loading device removed for 28 days for recovery without distraction. Six animals were sham operated. The external device was situated; however, the discs remained undistracted and they also served as controls. After 28 to 56 days loading and distraction time, the animals were killed and the lumbar spine was harvested for examination. Disc height, disc morphology, cell viability, relative neutral zone, and tangent modulus were measured. RESULTS: After 28 days of loading, the discs demonstrated a significant decrease in disc space. Histologically, disorganization of the architecture of the anulus occurred. The number of dead cells increased significantly in the anulus and cartilage endplate. These changes were reversible after 28 days of distraction. The disc thickness increased significantly as compared with the specimens from the 28 days loading group without distraction. Histologically, the discs showed signs of tissue regeneration after 28 days of distraction. The number of dead cells decreased significantly in comparison with the loaded discs without distraction. The flexibility of compressed discs was higher than of compressed/distracted discs. CONCLUSIONS: The results of this study suggest that disc regeneration can be induced by axial dynamic distraction in the rabbit intervertebral disc. The decompressed rabbit intervertebral discs showed signs of tissue recovery on a biologic, cellular, and a biomechanical level after 28 days of distraction.