Clinicomolecular Identification of Conserved and Individualized Features of Granulomatous Uveitis.

Objective: To identify molecular features that distinguish individuals with shared clinical features of granulomatous uveitis. Design: Cross-sectional, observational study. Participants: Four eyes from patients with active granulomatous uveitis. Methods: We performed single-cell RNA-sequencing with antigen-receptor sequence analysis to obtain an unbiased gene expression survey of ocular immune cells and identify clonally expanded lymphocytes. Main Outcomes Measures: For each inflamed eye, we measured the proportion of distinct immune cell types, the amount of B or T cell clonal expansion, and the transcriptional profile of T and B cells. Results: Each individual had robust clonal expansion arising from a single T or B cell lineage, suggesting distinct, antigen-driven pathogenic processes in each patient. This variability in clonal expansion was mirrored by individual variability in CD4 T cell populations, whereas ocular CD8 T cells and B cells were more transcriptionally similar between patients. Finally, ocular B cells displayed evidence of class-switching and plasmablast differentiation within the ocular microenvironment, providing additional support for antigen-driven immune responses in granulomatous uveitis. Conclusions: Collectively, our study identified both conserved and individualized features of granulomatous uveitis, illuminating parallel pathophysiologic mechanisms, and suggesting that future personalized therapeutic approaches may be warranted.

Safety and efficacy outcomes of the Xen45 Gel Stent use for refractory glaucoma: a surgery series from surgeon trainees at a tertiary teaching hospital.

BACKGROUND: To study the effect of an ab interno gelatin stent (XEN45 Gel Stent, Allergan Inc., Irvine, California, USA) on intraocular pressure (IOP) as placed by glaucoma fellowship trainees in eyes with refractory glaucoma. METHODS: A prospective noncomparative study at a tertiary training center on 28 unique eyes undergoing ab interno gelatin stent implantation by glaucoma fellowship trainees. Data was collected at baseline and postoperatively at day 1, week 1, and months 1, 3, 5, and 12. Primary outcome was mean IOP change. Secondary outcomes included change in number of glaucoma medication classes and visual acuity. Safety outcomes included needling rates. Surgical success was defined by achieving ≥20% reduction in IOP with the same or fewer classes of antiglaucoma medications from baseline without the need for secondary surgical intervention and/or stent removal. RESULTS: At baseline, 28.6% (8/28) of the subjects had prior failed incisional glaucoma surgery in a study population that was 54% African-American, with 78% with severe glaucoma (average mean deviation of - 14.58 dB). Thirteen subjects terminated their clinic visits before their 12-month postoperative visit, leaving 15 subjects for end point analysis. Average IOP went from 21.6 mmHg (range 12.0-31.0, SD 6.6) at baseline to 12.5 mmHg (range 7.0-19.0, SD 3.6), a 42.1% reduction (p < 0.007). All subjects decreased the number of medication classes they were taking with an average reduction of 3.8 (range 2-5, SD 0.9) to 1.3 (range 0-3, SD 1.0) classes, or a 65.8% decrease (p < 0.006). Crude surgical success was 80.0% for the 15 subjects that followed up at 12 months. The Kaplan-Meier cumulative probability of success for all 28 subjects at 12 months was 70.4% (95% CI: 44.7-85.8%). Regardless of the length of follow-up, 21.4% (6/28) met failure criteria: 3 subjects failed because they required secondary surgical intervention, and the other 3 did not have adequate IOP reduction. Initial bleb needling rate was 28.6% (8/28) and repeat was 17.9% (5/28). CONCLUSIONS: Compared to the reported literature with experienced ocular surgeons, ab interno gel stent placements by glaucoma fellowship trainees have similar mean IOP, topical medication reduction, surgical success, and needling rates at 12-month follow-up.

Utility and Feasibility of Teleophthalmology Using a Smartphone-Based Ophthalmic Camera in Screening Camps in Nepal.

PURPOSE: To determine whether use of a mobile device-based ophthalmic camera by ophthalmic technicians (OTs) in village screening camps in Nepal followed by remote image interpretation by an ophthalmologist can improve detection of ocular pathology and medical decision-making. DESIGN: Evaluation of mobile device-based ophthalmic camera through study of before and after clinical decision-making. METHODS: One hundred forty patients over 18 years of age presenting to remote screening camps with best-corrected visual acuity ≤20/60 in one or both eyes were enrolled. Participants were examined by an OT with direct ophthalmoscopy. The technician recorded a diagnosis for each eye and a disposition for each patient. Patients then had anterior segment and fundus photos and/or videos taken using a smartphone-based ophthalmic camera system. Photos and videos were uploaded to a secure, HIPAA-compliant, cloud-based server, and interpreted by masked ophthalmologists from XXX, who independently recorded diagnoses and a disposition for each patient. RESULTS: The diagnoses given by OTs and ophthalmologists differed in 42.4% of eyes. Diagnosis agreement was highest for cataract [k = 0.732, 95% confidence interval (CI) 0.65-0.81], but much lower for posterior segment (retina/optic nerve) pathology (k = 0.057, 95% CI -0.03-0.14). Ophthalmologists and OTs suggested different dispositions for 68.6% of patients. Agreement was highest for cataract extraction (k = 0.623, 95% CI 0.49-0.75), whereas agreement for referral to XXX was lower (k = 0.12, 95% CI 0.00-0.24). CONCLUSIONS: Remote ophthalmologist consultation utilizing a mobile device ophthalmic camera system is logistically feasible, easily scalable, and capable of capturing high-quality images in the setting of rural eye screening camps. Although OTs are well equipped to identify and triage anterior segment pathology, this technology may be helpful in the detection of and referral for posterior segment pathology.

Mindfulness-Based Interventions for University Students: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: University students are expressing an increased need for mental health support. Mindfulness-based interventions (MBIs) are being integrated into university stress-reduction programmes globally. We conducted a comprehensive systematic review and meta-analysis of randomised controlled trials (RCTs) assessing MBI effects on university students' mental and physical health. METHODS: We searched nine databases, including grey literature and trial registries. Two independent reviewers extracted data following a prospective public protocol. RESULTS: Fifty-one RCTs were included. In comparison with passive controls, and when measured shortly after intervention completion, MBIs improve distress, anxiety, depression, well-being, rumination, and mindfulness with small to moderate effect sizes, with no benefit found for blood pressure, sleep, life satisfaction, resilience, worry, and thought suppression. Evidence for self-compassion is inconclusive. Effects last beyond three months for distress and mindfulness, with no data on other outcomes. Compared with active control groups, MBIs significantly improve distress and state anxiety, but not mindfulness, depression, well-being, affect, trait anxiety, or emotion regulation. Results were robust to adjustment for multiple testing, but RCTs' risk of bias is generally high. Moderator analyses did not find differential intervention effects according to intervention duration, delivery mode, or sub-populations. CONCLUSIONS: MBIs may be helpful to students but higher-quality research is needed.

Corneal Biomechanics Using a Scheimpflug-Based Noncontact Device in Normal-Tension Glaucoma and Healthy Controls.

PURPOSE: To determine if a novel biomechanical parameter, corneal applanation velocity, as measured by the Corvis ST, is associated with a diagnosis of normal-tension glaucoma (NTG). DESIGN: Prospective, cross-sectional study. METHODS: Study and control subjects were recruited from the ophthalmology clinic of a university teaching hospital in Hong Kong over an 8-week period in 2013. A total of 80 eyes with NTG diagnosis and 155 healthy eyes randomly selected to be in the control group were included in the final analysis. All subjects underwent corneal biomechanical testing with the Oculus Corvis ST non-contact tonometer. Logistic regression analysis adjusted for age and central corneal thickness was conducted to assess the relationship between inward and outward applanation velocity and the risk of NTG. Secondary outcome variables included corneal applanation time, length, amplitude, and highest concavity. RESULTS: Inward applanation velocity was faster in the NTG eyes (0.15 ± 0.02 m/s) than in the control eyes (0.14 ± 0.02 m/s) (P = 0.016). The odds ratio for a 0.01 m/s increase in inward applanation velocity when comparing NTG eyes with control eyes adjusted for age and central corneal thickness was 1.15 (95% confidence interval, 1.03-1.30) (P = 0.016). There was no evidence that outward applanation velocity or any secondary corneal biomechanical variable differed between the NTG and control eyes. CONCLUSIONS: Normal-tension glaucoma eyes demonstrated a small, statistically significant faster corneal inward applanation velocity than normal control eyes.

Teleophthalmology through handheld mobile devices: a pilot study in rural Nepal.

BACKGROUND: To compare screening referral recommendations made by remotely located ophthalmic technicians with those of an ophthalmologist examining digital photos obtained by a portable ophthalmic camera system powered by an iOS handheld mobile device (iPod Touch). METHODS: Dilated screening eye exams were performed by ophthalmic technicians in four remote districts of Nepal. Anterior and posterior segment photographs captured with a Paxos Scope ophthalmic camera system attached to an iPod Touch 6th generation device were uploaded to a secure cloud database for review by an ophthalmologist in Kathmandu. The ophthalmic technicians' referral decisions based on slit-lamp exam were compared to the ophthalmologist's recommendation based on the transmitted images. RESULTS: Using the transmitted images, the ophthalmologist recommended referral for an additional 20% of the 346 total subjects screened who would not have been referred by the ophthalmic technician. Of those subjects, 34% were referred to the retina clinic. Conversely, among the 101 patients referred by the technician, the ophthalmologist concurred with the appropriateness of referral in more than 97% of cases but thought eight (2.8%) of those patients had variants of normal eye pathology. CONCLUSION: An ophthalmologist who reviewed data and photos gathered with the mobile device teleophthalmology system identified a significant number of patients whose need for referral was not identified by the screening technician. Posterior segment pathology was most frequently found by the remote reader and not by the technician performing dilated slit lamp examinations. These results are promising for further clinical implementation of handheld mobile devices as tools for teleophthalmic screening in resource-limited settings.

Impact of Possibly Oncogenic High-Risk Human Papillomavirus (HPV) Types in Triage for ASC-US Cervical Cytology Results.

OBJECTIVE: Current guidelines recommend including 13 or 14 high-risk human papillomavirus (HPV) types for triage of atypical squamous cells of undetermined significance (ASC-US) cervical cytology; however, at least 13 additional types are considered possibly oncogenic. We evaluated the effect of including possibly oncogenic HPV types in the test panel. METHODS: Outcomes for all women 30 years or older with ASC-US and positive HPV testing who underwent colposcopic biopsy at University of Washington Medical Center-affiliated clinics between 2010 and 2011 were reviewed. We compared biopsy results between cases that were HPV positive for 1 or more of 13 possibly oncogenic types only (26/53/55/62/64/67/69/71/73/82/83/84/IS39) versus 1 or more of the 14 established high-risk types (16/18/31/33/35/39/45/51/52/56/58/59/66/68). We used the Fisher exact test to compare cervical intraepithelial neoplasia grade 2 or higher (CIN2+) diagnoses between HPV risk groups. RESULTS: Three hundred twenty-six ASC-US HPV-positive cervical cytology results were identified, with 170 that were linked to subsequent cervical biopsy results. Among 51 cases positive for possibly oncogenic types only, 31 (61%) had no neoplasia, 20 (39%) had CIN1, and none had CIN2+. Among 119 controls positive for at least one established high-risk type, 64 (53%) had no neoplasia, 42 (35%) had CIN1, and 13 (11%) had CIN2+ (p = .01 for the comparison of CIN2+ diagnoses between groups). CONCLUSIONS: The inclusion of possibly oncogenic types in the HPV test panel led to an additional 51 colposcopy biopsies (33% increase), with no additional cases of CIN 2+. Our results suggest that including possibly oncogenic HPV types increases the number of colposcopy biopsies with minimal improvements in detection of CIN2 +.

Risk factors for epilepsy in children with neonatal encephalopathy.

We examined neonatal predictors of epilepsy in term newborns with neonatal encephalopathy (NE) by studying children enrolled in a longitudinal, single center cohort study. Clinical data were obtained through chart review, and MRI was performed in the neonatal period. We administered a seizure questionnaire to parents of children aged ≥ 12 mo (range, 12 mo to 16.5 y) to determine the outcome of epilepsy. The association between clinical predictors and time to onset of epilepsy was assessed using Cox proportional hazards regression. Thirteen of 129 children developed epilepsy: all had neonatal seizures and brain injury on neonatal MRI. Of the newborns with neonatal seizures, 25% (15.8/1000 person-years) developed epilepsy, with the highest hazard ratios (HRs) in the newborns with status epilepticus (HR, 35.8; 95% CI, 6.5-196.5). Children with severe or near-total brain injury were more likely to develop epilepsy compared with those with only mild or moderate injury (HR, 5.5; 95% CI, 1.8-16.8). In a multivariable analysis adjusting for degree of encephalopathy and severe/near-total brain injury, status epilepticus was independently associated with epilepsy. These data add to information regarding epilepsy pathogenesis and further aid clinicians to counsel parents regarding the likelihood that a newborn with NE will develop epilepsy.

Vascular phenotyping of brain tumors using magnetic resonance microscopy (µMRI).

Abnormal vascular phenotypes have been implicated in neuropathologies ranging from Alzheimer's disease to brain tumors. The development of transgenic mouse models of such diseases has created a crucial need for characterizing the murine neurovasculature. Although histologic techniques are excellent for imaging the microvasculature at submicron resolutions, they offer only limited coverage. It is also challenging to reconstruct the three-dimensional (3D) vasculature and other structures, such as white matter tracts, after tissue sectioning. Here, we describe a novel method for 3D whole-brain mapping of the murine vasculature using magnetic resonance microscopy (µMRI), and its application to a preclinical brain tumor model. The 3D vascular architecture was characterized by six morphologic parameters: vessel length, vessel radius, microvessel density, length per unit volume, fractional blood volume, and tortuosity. Region-of-interest analysis showed significant differences in the vascular phenotype between the tumor and the contralateral brain, as well as between postinoculation day 12 and day 17 tumors. These results unequivocally show the feasibility of using µMRI to characterize the vascular phenotype of brain tumors. Finally, we show that combining these vascular data with coregistered images acquired with diffusion-weighted MRI provides a new tool for investigating the relationship between angiogenesis and concomitant changes in the brain tumor microenvironment.