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Brommer B, He M, Zhang Z, Yang Z, Page JC, Su J, Zhang Y, Zhu J, Gouy E, Tang J, Williams P, Dai W, Wang Q, Solinsky R, Chen B, He Z. Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury. Nat Commun 2021;12(1):781.Abstract
After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.
Baker TL, Greiner JV, Vesonder M. SARS-CoV-2 safety: Guidelines for shielding frontline nurses. Nursing 2021;51(3):32-42.Abstract
ABSTRACT: Protecting nurses in healthcare facilities from SARS-CoV-2 infection is essential for maintaining an adequate nursing force. Foundational guidelines, consistently utilized, protect the nursing staff from infection. This article describes guidelines designed to reduce acute infection and associated morbidity and mortality among nursing staff and improve compliance with infection prevention protocols.
Chan YK, Wang SK, Chu CJ, Copland DA, Letizia AJ, Costa Verdera H, Chiang JJ, Sethi M, Wang MK, Neidermyer WJ, Chan Y, Lim ET, Graveline AR, Sanchez M, Boyd RF, Vihtelic TS, Inciong RGCO, Slain JM, Alphonse PJ, Xue Y, Robinson-McCarthy LR, Tam JM, Jabbar MH, Sahu B, Adeniran JF, Muhuri M, Tai PWL, Xie J, Krause TB, Vernet A, Pezone M, Xiao R, Liu T, Wang W, Kaplan HJ, Gao G, Dick AD, Mingozzi F, McCall MA, Cepko CL, Church GM. Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses. Sci Transl Med 2021;13(580)Abstract
Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.
Waksmunski AR, Song YE, Kinzy TG, Laux RA, Sewell J, Fuzzell D, Fuzzell S, Miller S, Wiggs JL, Pasquale LR, Skarie JM, Haines JL, Cooke Bailey JN. The GGLEAM Study: Understanding Glaucoma in the Ohio Amish. Int J Environ Res Public Health 2021;18(4)Abstract
Glaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.
Hellström A, Nilsson AK, Wackernagel D, Pivodic A, Vanpee M, Sjöbom U, Hellgren G, Hallberg B, Domellöf M, Klevebro S, Hellström W, Andersson M, Lund A-M, Löfqvist C, Elfvin A, Sävman K, Hansen-Pupp I, Hård A-L, Smith LEH, Ley D. Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr 2021;175(4):359-367.Abstract
Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.
Wolfe JM. Guided Search 6.0: An updated model of visual search. Psychon Bull Rev 2021;28(4):1060-1092.Abstract
This paper describes Guided Search 6.0 (GS6), a revised model of visual search. When we encounter a scene, we can see something everywhere. However, we cannot recognize more than a few items at a time. Attention is used to select items so that their features can be "bound" into recognizable objects. Attention is "guided" so that items can be processed in an intelligent order. In GS6, this guidance comes from five sources of preattentive information: (1) top-down and (2) bottom-up feature guidance, (3) prior history (e.g., priming), (4) reward, and (5) scene syntax and semantics. These sources are combined into a spatial "priority map," a dynamic attentional landscape that evolves over the course of search. Selective attention is guided to the most active location in the priority map approximately 20 times per second. Guidance will not be uniform across the visual field. It will favor items near the point of fixation. Three types of functional visual field (FVFs) describe the nature of these foveal biases. There is a resolution FVF, an FVF governing exploratory eye movements, and an FVF governing covert deployments of attention. To be identified as targets or rejected as distractors, items must be compared to target templates held in memory. The binding and recognition of an attended object is modeled as a diffusion process taking > 150 ms/item. Since selection occurs more frequently than that, it follows that multiple items are undergoing recognition at the same time, though asynchronously, making GS6 a hybrid of serial and parallel processes. In GS6, if a target is not found, search terminates when an accumulating quitting signal reaches a threshold. Setting of that threshold is adaptive, allowing feedback about performance to shape subsequent searches. Simulation shows that the combination of asynchronous diffusion and a quitting signal can produce the basic patterns of response time and error data from a range of search experiments.
Arroyo JG, Seto B, Yamada K, Zeng K, Minturn R, Lemire CA. Rapid reduction of macular edema due to retinal vein occlusion with low-dose normobaric hyperoxia. Graefes Arch Clin Exp Ophthalmol 2021;259(8):2113-2118.Abstract
PURPOSE: We investigated the effects of a relatively inexpensive, non-invasive, short-term treatment with low-dose normobaric hyperoxia (NBH) on macular edema in patients with retinal vein occlusion (RVO). METHODS: Participants with macular edema associated with RVO were treated with 5 LPM of NBH via facemask (40% fraction of inspired oxygen, FIO2) for 3 h. Patients with non-fovea involving edema who elected to be observed returned for a second treatment 1 month later to test reproducibility. RESULTS: A 3-h session of NBH (n = 45) resulted in decreased maximum macular thickness (MMT) (mean 7.10%, t34=9.63 P<.001) and central macular thickness (CMT) (mean 4.64%, t34=6.90, P<.001) when compared to untreated eyes with RVO measured over the same period of time (n = 12) or their healthy fellow eye (n = 34; MMT:t34=-9.60, P<.001;CMT: t34=-6.72, P<.001). Patients who had a second NBH treatment 1 month later experienced a recurrence of their edema, but demonstrated a similar significant reduction in MMT and CMT after the second NBH treatment. CONCLUSIONS: Three-hour treatment with 40% FIO2 NBH results in a significant reduction in MMT and CMT. This study supports an ischemic mechanism for macular edema associated with retinal vein occlusion. TRANSLATIONAL RELEVANCE: Short-term low-dose normobaric hyperoxia is a simple, inexpensive, and ubiquitous treatment that may provide an alternate or adjunctive approach to treating macular edema in patients who are resistant to or cannot afford anti-VEGF medications.
Zhang YJ, Jimenez L, Azova S, Kremen J, Chan Y-M, Elhusseiny AM, Saeed H, Goldsmith J, Al-Ibraheemi A, O'Connell AE, Kovbasnjuk O, Rodan L, Agrawal PB, Thiagarajah JR. Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis. Eur J Hum Genet 2021;29(6):998-1007.Abstract
WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.
Ma KK, Yuan A, Sharifi S, Pineda R. A Biomechanical Study of Flanged Intrascleral Haptic Fixation of Three-Piece Intraocular Lenses. Am J Ophthalmol 2021;227:45-52.Abstract
PURPOSE: Flanged intrascleral haptic fixation (FISHF) is a useful method for securing intraocular lenses (IOLs) in eyes without capsular support. Biomechanical studies were conducted to support the use of this technique. DESIGN: Laboratory investigation. METHODS: Haptics of 3-piece IOLs were passed through cadaveric human sclera using 30- and 27-gauge needles. Flanges were created by melting 1.0 mm from the haptic ends using cautery. The forces required to remove the flanged haptic from the sclera and disinsert the haptic from the optic were measured using a mechanical tester and a custom-fabricated mount. RESULTS: The mean FISHF dislocation force using 30-gauge needles was greatest with the CT Lucia 602 (2.04 ± 0.24 newtons [N]) compared to the LI61AO (0.93 ± 0.41 N; P = .001), ZA9003 (0.70 ± 0.34 N; P = <.001), and MA60AC (0.27 ± 0.19 N; P <.001). Using 27-gauge needles with the CT Lucia resulted in a lower dislocation force (0.56 ± 0.36 N; P <.001). The FISHF dislocation force was correlated with the flange-to-needle diameter ratio (r = 0.975). The FISHF dislocation forces of the CT Lucia and LI61AO using 30-gauge needles were not significantly different from their haptic-optic disinsertion forces (P = .79 and .27, respectively). There were no differences in flange diameters between 1.0 mm and 2.0 mm haptic melt lengths across the IOLs (P = .15-.85). CONCLUSIONS: These data strongly support the biomechanical stability of FISHF with the polyvinylidene fluoride haptics of the CT Lucia using small diameter instruments for the creation of an intrascleral tunnel. 1.0 mm of haptic may be the optimal melt length.
Gong D, Kras A, Miller JB. Application of Deep Learning for Diagnosing, Classifying, and Treating Age-Related Macular Degeneration. Semin Ophthalmol 2021;36(4):198-204.Abstract
Age-related macular degeneration (AMD) affects nearly 200 million people and is the third leading cause of irreversible vision loss worldwide. Deep learning, a branch of artificial intelligence that can learn image recognition based on pre-existing datasets, creates an opportunity for more accurate and efficient diagnosis, classification, and treatment of AMD on both individual and population levels. Current algorithms based on fundus photography and optical coherence tomography imaging have already achieved diagnostic accuracy levels comparable to human graders. This accuracy can be further increased when deep learning algorithms are simultaneously applied to multiple diagnostic imaging modalities. Combined with advances in telemedicine and imaging technology, deep learning can enable large populations of patients to be screened than would otherwise be possible and allow ophthalmologists to focus on seeing those patients who are in need of treatment, thus reducing the number of patients with significant visual impairment from AMD.
Pistilli M, Gangaputra SS, Pujari SS, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Foster SC, Begum H, Fitzgerald TD, Dreger KA, Kempen JH. Contemporaneous Risk Factors for Visual Acuity in Non-Infectious Uveitis. Ocul Immunol Inflamm 2021;:1-8.Abstract
INTRODUCTION: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population. METHODS: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled. RESULTS: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA. CONCLUSION: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.
Sharifi S, Islam MM, Sharifi H, Islam R, Huq TN, Nilsson PH, Mollnes TE, Tran KD, Patzer C, Dohlman CH, Patra HK, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Electron Beam Sterilization of Poly(Methyl Methacrylate)-Physicochemical and Biological Aspects. Macromol Biosci 2021;21(4):e2000379.Abstract
Electron beam (E-beam) irradiation is an attractive and efficient method for sterilizing clinically implantable medical devices made of natural and/or synthetic materials such as poly(methyl methacrylate) (PMMA). As ionizing irradiation can affect the physicochemical properties of PMMA, understanding the consequences of E-beam sterilization on the intrinsic properties of PMMA is vital for clinical implementation. A detailed assessment of the chemical, optical, mechanical, morphological, and biological properties of medical-grade PMMA after E-beam sterilization at 25 and 50 kiloGray (kGy) is reported. Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry studies indicate that E-beam irradiation has minimal effect on the chemical properties of the PMMA at these doses. While 25 kGy irradiation does not alter the mechanical and optical properties of the PMMA, 50 kGy reduces the flexural strength and transparency by 10% and 2%, respectively. Atomic force microscopy demonstrates that E-beam irradiation reduces the surface roughness of PMMA in a dose dependent manner. Live-Dead, AlamarBlue, immunocytochemistry, and complement activation studies show that E-beam irradiation up to 50 kGy has no adverse effect on the biocompatibility of the PMMA. These findings suggest that E-beam irradiation at 25 kGy may be a safe and efficient alternative for PMMA sterilization.
WuDunn D, Takusagawa HL, Sit AJ, Rosdahl JA, Radhakrishnan S, Hoguet A, Han Y, Chen TC. OCT Angiography for the Diagnosis of Glaucoma: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(8):1222-1235.Abstract
PURPOSE: To review the current published literature on the use of OCT angiography (OCTA) to help detect changes associated with the diagnosis of primary open-angle glaucoma. METHODS: Searches of the peer-reviewed literature were conducted in March 2018, June 2018, April 2019, December 2019, and June 2020 in the PubMed and Cochrane Library databases. Abstracts of 459 articles were examined to exclude reviews and non-English articles. After inclusion and exclusion criteria were applied, 75 articles were selected and the panel methodologist rated them for strength of evidence. Three articles were rated level I and 57 articles were rated level II. The 15 level III articles were excluded. RESULTS: OCT angiography can detect decreased capillary vessel density within the peripapillary nerve fiber layer (level II) and macula (level I and II) in patients with suspected glaucoma, preperimetric glaucoma, and perimetric glaucoma. The degree of vessel density loss correlates significantly with glaucoma severity both overall and topographically (level II) as well as longitudinally (level I). For differentiating glaucomatous from healthy eyes, some studies found that peripapillary and macular vessel density measurements by OCTA show a diagnostic ability (area under the receiver operating characteristic curve) that is comparable with structural OCT retinal nerve fiber and ganglion cell thickness measurements, whereas other studies found that structural OCT measurements perform better. Choroidal or deep-layer microvasculature dropout as measured by OCTA is also associated with glaucoma damage (level I and II). Lower peripapillary and macular vessel density and choroidal microvasculature dropout are associated with faster rates of disease progression (level I and II). CONCLUSIONS: Vessel density loss associated with glaucoma can be detected by OCTA. Peripapillary, macular, and choroidal vessel density parameters may complement visual field and structural OCT measurements in the diagnosis of glaucoma.
Leme RCP, Martins Bispo PJ, Salles MJ. Community-genotype methicillin-resistant Staphylococcus aureus skin and soft tissue infections in Latin America: a systematic review. Braz J Infect Dis 2021;:101539.Abstract
BACKGROUND: Community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) emerged in the 1990s as a global community pathogen primarily involved in skin and soft tissue infections (SSTIs) and pneumonia. To date, the CG-MRSA SSTI burden in Latin America (LA) has not been assessed. OBJECTIVE: The main objective of this study was to report the rate and genotypes of community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) causing community-onset skin and soft tissue infections (CO-SSTIs) in LA over the last two decades. In addition, this research determined relevant data related to SSTIs due to CG-MRSA, including risk factors, other invasive diseases, and mortality. DATA SOURCES: Relevant literature was searched and extracted from five major databases: Embase, PubMed, LILACS, SciELO, and Web of Science. METHODS: A systematic review was performed, and a narrative review was constructed. RESULTS: An analysis of 11 studies identified epidemiological data across LA, with Argentina presenting the highest percentage of SSTIs caused by CG-MRSA (88%). Other countries had rates of CG-MRSA infection ranging from 0 to 51%. Brazil had one of the lowest rates of CG-MRSA SSTI (4.5-25%). In Argentina, being younger than 50 years of age and having purulent lesions were predictive factors for CG-MRSA CO-SSTIs. In addition, the predominant genetic lineages in LA belonged to sequence types 8, 30, and 5 (ST8, ST30, and ST5). CONCLUSION: There are significant regional differences in the rates of CG-MRSA causing CO-SSTIs. It is not possible to conclude whether or not CG-MRSA CO-SSTIs resulted in more severe SSTI presentations or in a higher mortality rate.

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