Taiwan ocular inflammation society consensus recommendations for the management of juvenile idiopathic arthritis-associated uveitis.

We presented the development of a consensus guideline for managing juvenile idiopathic arthritis-associated uveitis (JIAU) in Taiwan, considering regional differences in manifestation and epidemiology. The Taiwan Ocular Inflammation Society (TOIS) committee formulated this guideline using a modified Delphi approach with two panel meetings. Recommendations were based on a comprehensive evidence-based literature review and expert clinical experiences, and were graded according to the Oxford Centre for Evidence-Based Medicine's "Levels of Evidence" guideline (March 2009). The TOIS consensus guideline consists of 10 recommendations in four categories: screening and diagnosis, treatment, complications, and monitoring, covering a total of 27 items. These recommendations received over 75% agreement from the panelists. Early diagnosis and a coordinated referral system between ophthalmologists and pediatric rheumatologists are crucial to prevent irreversible visual impairment in children with JIAU. However, achieving a balance between disease activity and medication use remains a key challenge in JIAU management, necessitating further clinical studies.

Characterization of autoimmune eye disease in association with Down's syndrome.

BACKGROUND: Autoimmunity and deficiency of the transcription factor autoimmune regulator protein (AIRE) are known associations with Down syndrome (DS). Lack of AIRE abrogates thymic tolerance. The autoimmune eye disease associated with DS has not been characterized. We identified a series of subjects with DS (n = 8) and uveitis. In three consecutive subjects, we tested the hypothesis that autoimmunity to retinal antigens might be a contributing factor. SUBJECTS/METHODS: This was a multicentred, retrospective case series. Deidentified clinical data of subjects with both DS and uveitis were collected via questionnaire by uveitis-trained ophthalmologists. Anti-retinal autoantibodies (AAbs) were detected using an Autoimmune Retinopathy Panel tested in the OHSU Ocular Immunology Laboratory. RESULTS: We characterized eight subjects (mean age 29 [range, 19-37] years). The mean age of detected uveitis onset was 23.5 [range, 11-33] years. All eight subjects had bilateral uveitis (p < 0.001 based on comparison to published university referral patterns), with anterior and intermediate uveitis found in six and five subjects respectively. Each of three subjects tested for anti-retinal AAbs was positive. Detected AAbs included anti-carbonic anhydrase II, anti-enolase, anti-arrestin, and anti-aldolase. DISCUSSION: A partial deficiency in the AIRE on chromosome 21 has been described in DS. The similarities in the uveitis presentations within this patient group, the known autoimmune disease predisposition in DS, the recognized association of DS and AIRE deficiency, the reported detection of anti-retinal antibodies in patients with DS in general, and the presence of anti-retinal AAbs in three subjects in our series supports a causal association between DS and autoimmune eye disease.

Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease - specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.

Intramedullary Screw Fixation of Metacarpal and Phalangeal Fractures.

Metacarpal and phalangeal fractures are the second and third most common hand and wrist fractures seen in the emergency department. There are a multitude of operative fixation methods for metacarpal and phalangeal fractures, including closed reduction percutaneous pinning, open reduction internal fixation, external fixation, and intramedullary screw fixation. Although intramedullary fixation is a relatively new surgical technique, it is gaining in popularity as it allows patients to resume range of motion early in the postoperative period with excellent clinical outcomes.

Staple Fixation in Ulnar-Shortening Osteotomies.

Ulnar-sided wrist pain is commonly caused by the ulnar impaction syndrome. Ulnar-shortening osteotomy is a surgical treatment that is used to address ulnar impaction syndrome that fails conservative management. Unfortunately, hardware irritation and nonunion are well-known complications of this procedure. This case report details the course of two patients with nonunion after ulnar-shortening osteotomy who were treated with a combination of a nitinol compression staple and neutralization plate. Further investigation is required to determine the long-term outcomes and indications for nitinol-staple fixation for nonunion after ulnar-shortening osteotomy.

Fixation Techniques for Scaphoid Nonunion.

Scaphoid fractures are common injuries with high risk of nonunion. Various fixation techniques exist for managing scaphoid nonunions, including Kirschner wires, single or dual headless compression screws, combination fixation techniques, volar plating, and compressive staple fixation. The indication for each fixation technique varies depending on the patient, type of nonunion, and clinical scenario.

Characterization of autoimmune eye disease in association with Down's Syndrome.

Background Autoimmunity and deficiency of the transcription factor autoimmune regulator protein (AIRE) are known associations with Down Syndrome (DS). Lack of AIRE abrogates thymic tolerance. The autoimmune eye disease associated with DS has not been characterized. We identified a series of subjects with DS (n = 8) and uveitis. In 3 consecutive subjects, we tested the hypothesis that autoimmunity to retinal antigens might be a contributing factor. Subjects/Methods: This was a multicentered, retrospective case series. De-identified clinical data of subjects with both DS and uveitis were collected via questionnaire by uveitis-trained ophthalmologists. Anti-retinal autoantibodies (AAbs) were detected using an Autoimmune Retinopathy Panel tested in the OHSU Ocular Immunology Laboratory. Results We characterized 8 subjects (mean age 29 [range, 19-37] years). The mean age of uveitis onset was 23.5 [range, 11-33] years. All 8 subjects had bilateral uveitis (p < 0.001 based on comparison to published university referral patterns), with anterior and intermediate uveitis found in 6 and 5 subjects respectively. Each of three subjects tested for anti-retinal AAbs was positive. Detected AAbs included anti-carbonic anhydrase II, anti-enolase, anti-arrestin, and anti-aldolase. Discussion A partial deficiency in the AIRE on chromosome 21 has been described in DS. The similarities in the uveitis presentations within this patient group, the known autoimmune disease predisposition in DS, the recognized association of DS and AIRE deficiency, the reported detection of anti-retinal antibodies in patients with DS in general, and the presence of anti-retinal AAbs in 3 subjects in our series supports a causal association between DS and autoimmune eye disease.

Ideal Length and Diameter for Intramedullary Screw Fixation of Metacarpal Fractures: A Biomechanical Study.

Purpose: This biomechanical study evaluated the effect of intramedullary screw diameter and length relative to 3-point bending force and torsional force when used to stabilize metacarpal shaft fractures. Methods: Transverse osteotomies were made in the proximal metacarpal shaft in 36 middle finger metacarpal fourth-generation composite Sawbones. To compare screw diameters, antegrade intramedullary screws of 30-mm length were placed in 6 metacarpals, which included 4.7-mm Acutrak 2, Standard Acutrak 2 (4.0 mm), and Mini-Acutrak 2 (3.5 mm) screws. To compare screw lengths, metacarpals were fixated with Standard Acutrak 2 screws of 26, 30, or 34 mm in length, with screw tips bypassing the osteotomy by 6, 10, or 14 mm, respectively. A 6 degrees of freedom robot was used for torsional and 3-point bending testing. Results: Increasing screw diameter demonstrated significant differences in both 3-point bending and torsional strengths. Maximum torsional loads were 69 Ncm (4.7-mm Acutrak 2), 45 Ncm (Standard Acutrak 2), and 27 Ncm (Mini-Acutrak 2) (P < .05). Loads to failure in the 3-point bending tests were 916 N (4.7-mm Acutrak 2), 713 N (Standard Acutrak 2), and 284 N (Mini-Acutrak 2) (P < .05). Differing screw lengths demonstrated significant differences with maximum torsional loads when comparing the 26-mm screws (22 Ncm) with 30- and 34-mm screws (45 and 55 Ncm, respectively) (P < .05). The 3-point dorsal bending strengths were significantly different between the 26-mm screws (320 N) and 30- and 34-mm screws (713 N and 702 N, respectively) (P < .05). Conclusions: The results demonstrated significantly higher torsional strength and resistance to 3-point bending with larger intramedullary screw diameters. Further, when selecting the intramedullary screw length, the screw tip should pass at least 10 mm beyond the fracture. Clinical Relevance: This study provided biomechanical evidence to guide surgeons in selecting intramedullary screw diameter and length for treating metacarpal fractures.

Biomechanics of Proximal Hamate Autograft in Scaphoid Nonunion.

Purpose Treatment of proximal scaphoid fractures remains a challenge with a risk of nonunions and avascular necrosis due to its retrograde blood supply. The ipsilateral proximal hamate has been described as a viable autograft option for osteochondral reconstruction of the proximal scaphoid. Our study evaluated the changes in the contact area and pressure of the radioscaphoid joint after proximal hamate autograft reconstruction. Methods Thin sensors (Tekscan Inc., Boston, MA) were placed in the radiocarpal joints of six fresh-frozen cadaveric forearms. Each specimen's tendons were loaded to 150 N in neutral, 45-degree flexion/extension positions through five cycles. Through a dorsal wrist approach, the proximal 10 mm of the scaphoid and hamate was excised. The proximal hamate autograft was affixed to the scaphoid with K-wires. Peak contact pressures and areas at the scaphoid facet were determined and averaged across loading cycles. Results At the radioscaphoid facet, peak contact pressures were equivalent, although an increasing trend in the neutral and extended wrist position was seen. At the radiolunate facet, contact pressure had an increasing trend in the hamate reconstructed wrists in all wrist positions. Contact areas had a decreasing trend and were nonequivalent at the radioscaphoid facet in the hamate reconstructed wrist. Conclusion After hamate autograft, the contact areas were not equivalent between the native and reconstructed wrists but contact pressures were equivalent in the facets. The proximal hamate has a more pointed morphology compared with the proximal scaphoid, which would explain the change in contact area in the hamate autografted wrist. Our study suggests hamate autograft may present a viable reconstruction for the proximal pole of the scaphoid without significantly altering peak contact pressures at the radioscaphoid facet.

Magnetic resonance imaging for elbow pathology: overused by both orthopedic surgeons and primary care providers.

Background: Magnetic resonance imaging (MRI) use by both orthopedic surgeons and primary care providers (PCP) for analysis of elbow pathology is expensive and growing in frequency. In light of this, scrutiny regarding the appropriate utilization of this technology is increasing. Currently, there is no literature investigating the appropriateness of MRI use for complex elbow pathology from either orthopedic surgeons or PCPs. Methods: A retrospective chart review was performed on consecutive elbow MRIs performed at a tertiary care center between January 1, 2012, and December 31, 2015. A total of 225 patients were included. Patients meeting the inclusion criteria were divided into two cohorts, determined by whether the ordering provider was an orthopedic surgeon or a PCP. MRI referrals were made by orthopedic surgeons in 94 patients and by nonorthopedic surgery providers in 131 patients. MRI diagnoses of no pathology, muscle/tendon tear, neuritis/nerve injury, tendinosis, ligament injury/instability, osteoarthritis/degenerative joint disease/decreased range of motion/contracture, or fracture/osteochondral injury were analyzed, as were the interventions of no intervention, nonprocedural treatment (therapy, orthosis, or nonoperative modality), nonsurgical procedure/referral for procedure, referral to surgeon, surgery, additional imaging/electrodiagnostic nerve testing, or other. Results: 1. Orthopedic surgeons are more accurate in their diagnoses after MRI, while PCPs order more MRI scans for 'routine' diagnoses typically made without MRI. 2. When the MRI did not validate an orthopedic surgeon's preimaging diagnosis, rates of surgery decreased. The same discrepancy in diagnosis leads to an increase in orthopedic surgeon referrals within the PCP cohort. 3. An MRI was ordered for "pain" by orthopedic surgeons and PCPs in approximately 30% of the patients in both groups with a similarly low rate of pathology discovery. Conclusions: The unexpected result of this study is that there is still a large quantity of MRI exams being conducted by orthopedic surgeons for the preMRI diagnosis of "pain." In both groups, there was a similar rate of negative imaging. We expected orthopedic surgeons who have advanced knowledge in musculoskeletal pathology would be less likely to order an MRI for pain and would also less likely order an MRI that resulted in no pathology. This places an increased and unnecessary burden on the financial aspect of the health care system.

Treatment responses for branch retinal vein occlusion predicted by semi-automated fluorescein angiography quantification.

BACKGROUNDS: Branch retinal vein occlusion (BRVO) is one of the most important causes of visual loss in retinal vascular diseases. The aim of this study is to predict the treatment response of anti-vascular endothelial growth factor (anti-VEGF) therapy in BRVO using semi-automated quantified fluorescein angiography (FA) features. METHODS: This retrospective case-control study enrolled patients with BRVO who are receiving anti-VEGF therapy and have been followed up for > 1 year. Those receiving < 5 anti-VEGF injections in the first year were classified as the responsive group, while those receiving ≥5 injections were the refractory group. The FA images were subjected to semi-automated pre-processing. Fluorescein leakages at the 5-min image were represented by mean gray value over parafoveal and perifoveal regions. FA leakages and central retinal thickness (CRT) on optical coherence tomography (OCT) were used for predicting the treatment response and compared using area under receiver operating characteristic curve (AUC). RESULTS: Eighty-nine patients (56 males, 33 females, mean age 62.5 ± 10.9 years) with BRVO were enrolled. Of the 89 eyes, 47 (53%) were in the responsive group and 42 (47%) were in the refractory group. The refractory group had a significantly higher number of anti-VEGF injections in the first year (5.9 ± 1.6 versus 2.4 ± 1.2, p < 0.001) when compared with that of the responsive group. It had thicker pre-treatment CRT (p = 0.011), post-treatment best CRT (p < 0.001) and CRT at 1-year (p < 0.001). It also had a higher mean gray value over the parafoveal (p < 0.001) and the perifoveal (p < 0.001) regions. The mean gray value over perifoveal (AUC 0.846) and parafovel (AUC 0.818) had significantly larger AUC than that of the pre-treatment OCT (AUC 0.653; p = 0.005 and p = 0.016, respectively) when predicting treatment response. CONCLUSION: The refractory group had a more severe fluorescein leakage over the parafoveal and the perifoveal regions than the responsive group had. Semi-automated quantified FA leakage can be used as a biomarker for the prediction of anti-VEGF treatment response in macular edema due to BRVO.

Foveal Microvascular Integrity Association With Anti-VEGF Treatment Response for Diabetic Macular Edema.

Purpose: To investigate the association between foveal microvascular integrity and anti-vascular endothelial growth factor (VEGF) treatment response for diabetic macular edema (DME). Methods: This retrospective study enrolled 58 eyes (from 45 patients) with DME. Treatment strategy was three to five monthly anti-VEGF injections followed by a PRN protocol. Treatment with an intravitreal corticosteroid would be considered for persistent DME after five consecutive anti-VEGF injections. Eyes achieving a treatment-free interval ≥ four months within two years were classified into the good clinical course group (group 1). Eyes with frequent recurrent edema (treatment-free interval < four months) or requiring an intravitreal corticosteroid within two years were classified into the suboptimal clinical course group (group 2). Foveal microvascular integrity was evaluated by two continuous variables, that is, vessel density (%) within a width of 300 µm around the foveal avascular zone (FD-300) on optical coherence tomography angiography (OCTA) and perifoveal leakage (area %) on fluorescein angiography (FA). Results: There were 37 eyes in group 1 and 21 eyes in group 2. FD-300 (odds ratio 0.733, 95% CI 0.620-0.867, P < 0.001) and perifoveal leakage (odds ratio 1.064, 95% CI 1.007-1.124, P = 0.027) were significantly associated with suboptimal clinical course. Area under curve (AUC) was 0.820 for FD-300 and 0.723 for perifoveal leakage in predicting clinical course. FD-300 was negatively correlated with perifoveal leakage (coefficient = -0.325, P = 0.014). Conclusions: Compromised foveal microvascular integrity, represented by lower FD-300 and more severe perifoveal fluorescein leakage, was associated with suboptimal clinical course in anti-VEGF treatment for DME. A negative correlation between FD-300 and perifoveal leakage existed.

A Morphometric Analysis of Hamate Autograft for Proximal Scaphoid Reconstruction.

Objective Recently, authors have investigated using the proximal hamate as osteochondral autograft for proximal pole scaphoid reconstruction in the case of nonunion with avascular necrosis. The aim of our study was to analyze the morphology and anatomic fit of the proximal hamate compared with the proximal pole of the scaphoid using cadaveric specimens. Materials and Methods Ten cadaver specimens (five males and five females) were dissected. Scaphoid and proximal hamate bones were measured by two independent investigators using electronic calipers and radius of curvature gauges. After measurements were determined to have good correlation, the average value of the two observers' measurements were used for further analysis. Sagittal radius of curvature (ROC), coronal ROC, depth, width, and maximum graft length were compared. Results The average depth of the scaphoid proximal pole was 12.3 mm (standard deviation [SD] = 1.12) compared with 11.3 mm (SD = 1.24) for the proximal hamate ( p = 0.36). The average width was 7.8 mm (SD = 1.00) in the scaphoids compared with 8.6 (SD = 1.05) in the hamates ( p = 0.09). There was also no significant difference in the sagittal ROC between hamates (9.1 mm, SD = 1.13) and scaphoids (9.5 mm, SD = 0.84; p = 0.36). All of these average measurements were within 1 mm. There was a significant difference between the coronal ROC of the hamate (23.4 mm) and scaphoid (21.1 mm) bones in our samples ( p = 0.03). Females were on average smaller than their males, but there was no significant difference in fit based on sex alone. Conclusion The proximal pole of the hamate has similar morphology and size as the scaphoid, with similar depth, width, and sagittal ROC. It has potential as an osteochondral autograft for proximal pole scaphoid reconstruction.

Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis.

Purpose:Anterior uveitis is the most common anatomic subset of uveitis. We developed a novel multi-parametric flow cytometry panel to identify immune dysregulation signatures in HLA B27-associated acute anterior uveitis (AAU) and axial spondyloarthritis (AxSpA).Methods: We used fluorescence activated cell sorting to characterize T cell cytokine expression in stimulated T cell subsets from patients with AAU (n = 4) compared to healthy controls (n = 14) or subjects with AxSpA (n = 6).Results: Positive findings among subjects with AAU included a statistically significant increase in stimulated granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, and IL-22 synthesized by CD8 cells, a trend for stimulated ILC (innate lymphoid cells)-3 cells to synthesize more IL-22 (p = .07), and stimulated MAIT (mucosa associated innate lymphoid cells)-like cells that express the T cell receptor V alpha 7.2 to express IL-17A, IL-17F, and IL-22 in a greater percentage of cells relative to controls. IL-17F, GM- CSF, and IL-22 represent potentially novel targets in AAU.Conclusion: Our report is arguably the first to implicate IL-17F or ILC-3 and MAIT cells in the pathogenesis of AAU.Abbreviations AAU: acute anterior uveitis; AxSpA: axial spondyloarthritis; BASDAI: Bath ankylosing spondylitis disease activity index; CCR: chemokine receptor; DMSO: dimethylsulfoxide; EULAR:European League Against Rheumatism; FACS: fluorescence activated cell sorter; FBS: fetal bovine serum; FSC: orward light scatter; GM-CSF: granulocyte-macrophage colony stimulating factor; HC: healthy control; ILC: innate lymphoid cell; KIR: killer immunoglobulin receptor; MAIT: mucosal associated immune T cell; ND: not detected; NK: natural killer cell; OHSU-Oregon Health & Science University; PBMC: peripheral blood mononuclear cell; SSC: side light scatter; TCR: T cell receptor.

An Anatomical Study of Metacarpal Morphology Utilizing CT Scans: Evaluating Parameters for Antegrade Intramedullary Compression Screw Fixation of Metacarpal Fractures.

PURPOSE: This study evaluated metacarpal morphology for antegrade placement of intramedullary headless compression screws (IMHCS) for metacarpal fracture fixation. METHODS: We analyzed 100 hand computed tomography scans to quantify cortical thickness, intramedullary diameter, and metacarpal lengths. In addition, dorsal or ulnar overhang of the metacarpals over their respective carpal bones was measured. We also predicted optimal entry points for guidewire placement at the metacarpal head. RESULTS: The ring finger metacarpal had the narrowest medullary canal width (coronal, 2.8 mm; sagittal, 3.5 mm). Not counting the thumb, the little finger metacarpal had the widest midshaft medullary width of 4.1 mm in the coronal plane and the middle metacarpal was widest in the sagittal plane with canal width of 3.9 mm. On average, there was maximal dorsal overhang at the base of the middle metacarpal (4.2 mm) and maximal ulnar overhang at the base of the small metacarpal (3.9 mm). The optimal entry point for guidewire placement over each metacarpal head was approximately 3.5 to 3.8 mm volar to the dorsal cortex. CONCLUSIONS: Minimum IMHCS diameters of 3.5 mm for the ring and 4.0 mm for the index, middle and little fingers are necessary to achieve interference fit within the medullary canal. Minimum screw lengths of 38 mm would be needed to ensure 6 mm fixation past the midshaft of the metacarpals. Antegrade IMHCS for fixation of proximal metacarpal fractures may be most feasible with thumb, middle, and little finger metacarpals because there was larger dorsal or ulnar overhang to allow screw placement without violating the carpometacarpal joints. CLINICAL RELEVANCE: Our analysis provides a reference guide for intramedullary screw sizes for each metacarpal of the hand to achieve interference fit with fracture fixation. Furthermore, the dorsal and ulnar overhangs of the metacarpal bases suggest the practicality of antegrade IMHCS fixation.

Evaluation of Antegrade Intramedullary Compression Screw Fixation of Metacarpal Shaft Fractures in a Cadaver Model.

PURPOSE: Surgical options for displaced metacarpal shaft fractures include the use of Kirschner wires, plates and screws, and most recently, intramedullary headless compression screws (IMHCS), which have been reported using only retrograde insertion through the metacarpal head. We evaluated IMHCS fixation of metacarpal shaft fractures through an antegrade approach in a cadaver model. METHODS: We performed antegrade placement of IMHCS in 10 cadaver hands including all 5 digits (total of 50). Displaced transverse proximal metacarpal shaft fractures were created and reduced with a retrograde guidewire from the metacarpal head across the shaft fracture and exiting the metacarpal base. This was retrieved through a 6-mm dorsal wrist incision and overdrilled before the placement of a 4.1-mm-diameter IMHCS in the ring finger and a 4.7-mm screw in all other metacarpals. After IMHCS placement, carpometacarpal (CMC) joint violation was measured along with the optimal starting point for the guidewire on the metacarpal head relative to the dorsal cortex. RESULTS: In all 50 metacarpals, we achieved successful fracture reduction and fixation without violating the extensor mechanism at the wrist. Our retrograde guidewire entry point through the metacarpal head ranged from 4.2 to 4.7 mm volar to the dorsal cortex. The actual area of CMC joint violated by IMHCS placement was largest in the index CMC joint (4.9%), followed by the middle (3.7%), little (2.9%), ring (0.5%), and thumb joints (0.2%). CONCLUSIONS: Placement of IMHCS through an antegrade approach from the CMC joint can be performed effectively for all transverse metacarpal fractures, including the thumb, using a limited incision. There is minimal violation of the articular surfaces of the trapezium, capitate, and hamate for the thumb, middle, ring, and little metacarpals. CLINICAL RELEVANCE: Antegrade IMHCS fixation successfully avoids the potential morbidity of creating a metacarpal head articular surface or extensor mechanism defect at the metacarpophalangeal joint seen with the retrograde approaches.

Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.

To understand how neural-immune-associated genes and pathways contribute to neurodegenerative disease pathophysiology, we performed a systematic functional genomic analysis in purified microglia and bulk tissue from mouse and human AD, FTD, and PSP. We uncover a complex temporal trajectory of microglial-immune pathways involving the type 1 interferon response associated with tau pathology in the early stages, followed by later signatures of partial immune suppression and, subsequently, the type 2 interferon response. We find that genetic risk for dementias shows disease-specific patterns of pathway enrichment. We identify drivers of two gene co-expression modules conserved from mouse to human, representing competing arms of microglial-immune activation (NAct) and suppression (NSupp) in neurodegeneration. We validate our findings by using chemogenetics, experimental perturbation data, and single-cell sequencing in post-mortem brains. Our results refine the understanding of stage- and disease-specific microglial responses, implicate microglial viral defense pathways in dementia pathophysiology, and highlight therapeutic windows.

Baseline clinical features predict visual outcome in young patients with central retinal vein occlusion.

PURPOSE: To evaluate prognostic factors in young patients with central retinal vein occlusion (CRVO). METHODS: Retrospective case series. CRVO patients aged ≤ 50 and follow-up ≥ 6 months were enrolled. The best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, 3 months, 6 months, and last visit were documented. Severity of retinopathy was graded by comparing to standard photos. Prognostic factors associated with visual outcome at 6 months were evaluated by multiple linear regression models. RESULTS: A total of 73 eyes from 69 patients with mean age 37.6 ± 8.5 were enrolled. Forty-seven (68%) patients were male. The mean follow-up duration was 25.9 ± 23.0 months. LogMAR BCVA improved from 0.979 ± 0.785 at baseline to 0.594 ± 0.748 at the 6 months (p < 0.001) and CRT improved from 475 ± 222 µm to 299 ± 104 µm (p < 0.001). Forty-eight (66%) eyes required anti-vascular endothelial growth factor (anti-VEGF) treatment. The mean number of injections was 2.25 ± 1.41 in the first 6 months and 75% of eyes received ≦ 3 injections during the clinical course. The baseline BCVA (coefficient 0.518, p < 0.001), grade of retinal hemorrhage (coefficient 0.230, p = 0.006), grade of retinal venous engorgement (coefficient 0.238, p = 0.011), grade of optic disc edema (coefficient - 0.226, p = 0.005), and diabetes mellitus (coefficient 0.264, p = 0.047) were the independent factors associated with visual outcome at 6 months. CONCLUSIONS: Baseline clinical features are useful for the prediction of visual outcome at 6 months in young CRVO patients.

Retinal neurovascular changes in chronic kidney disease.

PURPOSE: To examine retinal neurovascular changes in patients with chronic kidney disease (CKD). METHODS: Case-control study. A total of 171 CKD cases and 40 controls were recruited (mean age 62.9 ± 10.3 versus 60.8 ± 9.2, p = 0.257). Retinal neural parameters, including parafoveal retinal thickness (PfRT), macular ganglion cell complex thickness (GCCt), global loss volume (GLV), focal loss volume (FLV) and peripapillary retinal nerve fibre layer thickness (RNFLt), were measured using optical coherence tomography (OCT). Microvascular parameters, including foveal avascular zone size, vessel density over the parafoveal superficial vascular plexus (SVP-VD), parafoveal deep vascular plexus (DVP-VD) and radial peripapillary capillary (RPC-VD), were measured using OCT angiography. RESULTS: Chronic kidney disease (CKD) patients showed reduced PfRT, GCCt and RNFLt and increased GLV and FLV compared with the controls (all p < 0.005). Among patients with CKD, estimated glomerular filtration rate was an independent factor associated with PfRT (coefficient 0.19, p = 0.015), GCCt (coefficient 0.10, p = 0.006), GLV (coefficient - 0.08, p = 0.001), FLV (coefficient - 0.02, p = 0.006) and RNFLt (coefficient 0.15, p = 0.002). Parafoveal retinal thickness (PfRT), GCCt, GLV, FLV and RNFLt were correlated with SVP-VD (all p < 0.001) but not with DVP-VD (all p > 0.1). CONCLUSIONS: Chronic kidney disease (CKD) patients demonstrated a significant reduction in macular thickness and changes in retinal neural parameters. These changes were associated with the severity of CKD and correlated with the microvascular rarefaction in the parafoveal SVP.

Nanodisc technology facilitates identification of monoclonal antibodies targeting multi-pass membrane proteins.

Multi-pass membrane proteins are important targets of biologic medicines. Given the inherent difficulties in working with membrane proteins, we sought to investigate the utility of membrane scaffold protein nanodiscs as a means of solubilizing membrane proteins to aid antibody discovery. Using a model multi-pass membrane protein, we demonstrate how incorporation of a multi-pass membrane protein into nanodiscs can be used in flow cytometry to identify antigen-specific hybridoma. The use of target protein-loaded nanodiscs to sort individual hybridoma early in the screening process can reduce the time required to identify antibodies against multi-pass membrane proteins.