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This comparative case series presents 16 consecutively placed and temporized immediate implants in the maxillary esthetic zone. The implants have a novel, inverted body-shift design, intended to achieve high levels of primary stability via the tapered apical portion. The coronal narrow cylinder provides greater space between the implant platform and facial socket wall and adjacent teeth/implants, allowing a greater opportunity for augmentation. The restorative platform also features a subcrestal angle correction, which facilitates screw retention. The wider, facial platform-shift thus creates more room for augmentation via dual-zone bone grafting and the application of a dermal allograft, which yields greater soft tissue thickness after initial healing. This case series aimed to evaluate soft tissue thickness and compare the results to two previously published cohorts where implant design served as the only variable between groups.

IntroductionAccelerated by demands of the pandemic, Connected Care innovates across the paediatric health sector to leverage virtual solutions in addressing the pressing need for capacity building among home and community care (HCC) providers of children with medical complexity. Connected Care services supports a highly specialized and scarce paediatric home care workforce to deliver evidence-based nursing care when children transition from hospital to home. Family caregivers of children who depend on medical technology are integral to informing program development and guiding integration of new technologies and service lines. Aims Objectives Theory or MethodsVirtual care delivered by Connected Care aims to promote confidence and competence among home care providers of children with medical complexity through uptake of standardized, paediatric best practice. Connected Care engages hospital and home care administrators, interprofessional providers, and family advisors to inform integration of emerging technologies, testing of new virtual solutions, and usability of Connected Care’s information technology platforms. Services delivered by Connected Care from hospital to home undergo continuous quality improvement and include: 1) nurse led- 24/7 eConsultative services, 2) virtual simulation-based nursing education, and 3) cross-sector interprofessional virtual visits. Highlights or Results or Key FindingsConnected Care’s virtual community of practice has grown to include >800 homecare providers from >50 homecare organizations. In 2021, Connected Care will deliver >1000 paediatric virtual education sessions, across highly-accessible virtual platforms. The development of virtual simulation-based training modules for paediatric home ventilation have received very positive feedback among partners who describe appreciating the opportunity to practice their skills remotely. This year, Connected Care technologies will support remote access to >400 eConsultations and >1,500 self-directed resources. Consult types from homecare nurses vary with the majority reflecting their questions about medical technology trouble shooting. Real-time feedback indicates homecare nurses are highly satisfied with the eConsultation service giving it ‘thumbs up’ 99% of the time. Growth has been rapid in conduct of post- discharge virtual visits. In 2021, Connected Care will deliver >600 Virtual Visits bringing together hospital providers, family caregivers and homecare providers. ConclusionsDemand for Connected Care continues to build, aligned with recovery of paediatric homecare workforce and transition care gaps heightened through and beyond the pandemic. Experience with implementation of technologies linking hospital to home and community signal a high rate of acceptance and usability among diverse end-users across the sector. Implications for applicability/transferability sustainability and limitations Connected Care is well positioned to innovate in the use of cutting edge technologies to promote system integration. Leveraging partnerships and sharing resources will promote best practice and be scaled to build capacity in delivery of paediatric home care across expanding partnerships and geographies.

Pediatric nursing expertise in home care requires continuous development and maintenance of competencies. Through the pandemic, practice of essential "hands-on" skills was enabled by delivery of training mannequins from hospital to home care and a shift to virtual education. Learners (n = 57) included family caregivers of children with medical complexity and nurses new to home care. Evaluation informed iterative design of the service and signalled "Connected Care on the Go!" as desirable (100% highly satisfied), feasible (100% easily implemented) and viable. Now a sustainable service, this nurse-led innovation promotes partnership across leaders, sectors and geographies to address specialized training needs in pediatric home care.

The notion of physical activity during pregnancy has gained substantial momentum over the recent years. This is likely due to the increasing number of studies that have shown what the benefits exercise can have during this unique time in a woman's life. Pregnancy no longer needs to be thought of as a time to cease all activity, and it is important to counsel patients that there can be increased complications by not exercising. The goal of this chapter is to discuss the specific considerations and recommendations of exercise during pregnancy.

Objective: To evaluate the immediate and sustained knowledge retention and sense of self-efficacy of homecare nurses following completion of a standardized competency-based tracheostomy education course. Safe discharge of children requiring tracheostomy with or without ventilation relies on the competence of homecare nurses. Study Design: Pragmatic, randomized controlled trial of 44 homecare nurses. Participants were randomized into the intervention group (n=21), which received the tracheostomy course, or the control group (n=23), which received an enterostomy and vascular access course. Multiple-choice question (MCQ) knowledge assessments and self-efficacy questionnaires were administered to both groups pre-course and post-course at 6 week, 3 month, 6 month, and 12 month follow-ups. Results: Twenty participants in the intervention group and 19 in the control group were included. Four withdrew from the study and two crossed over from the control into the intervention arm. The change in mean self-efficacy scores (total score = 100) was significantly higher in the intervention group than in the control group at 6 weeks (intervention (mean ± SD): 18.6±14.5; control: 6.6±20.4; p=0.04) and 3 months (intervention: 19.6±14.2; control: 5.2±17.0; p=0.007), and trended higher at 6 months (intervention: 18.0±14.5; control: 6.9±24.1; p=0.1) and 12 months (intervention: 16.9±15.0; control: 16.8±20.5; p=1.0). The change in mean MCQ assessment scores (total score = 20) trended higher in the intervention group than in the control group at 6 weeks (intervention (mean ± SD): 1.8±2.2; control: 1.6, ±2.9; p=0.8). Conclusions: Homecare nurses who attended the tracheostomy course demonstrated a higher sense of self-efficacy at long-term follow-up.

Coeliac disease (CD) is an autoimmune disorder caused by the ingestion of gluten containing foods in genetically susceptible individuals, with a worldwide prevalence of up to 1%. Currently, the only available treatment is a gluten-free diet (GFD). Screening for CD is primarily performed using serum based testing for anti-tissue transglutaminase (tTG) antibodies. Patients must be on a gluten containing diet at the time of testing to ensure an accurate serological result. We investigated the prevalence of a GFD in hospital clinic settings and the general population using survey data to estimate the proportion of CD patients that may be misdiagnosed for CD based on serological tests. Data were collected at clinics of a metropolitan hospital in Sydney, Australia, and the general population. Data from Medicare Benefits Scheme and tTG results from a large Australian private laboratory were reviewed for comparison. Of 778 participants who responded to the survey, 58 (7.5%) were on a GFD. More patients attending the immunology (15.9%) and gastroenterology (12.1%) clinics adopted a GFD than those attending the diabetes (2.6%) or endocrinology (6.1%) clinics, or in the general population (4.3%). More females than males excluded gluten from their diet (p0.0001). Medicare statistics between 2013 and 2019 demonstrated an increase in CD serological testing; however, tTG data from a private pathology highlighted a stable level of elevated tTG antibodies of 3% of total tests performed. The high number of individuals on a GFD is likely impacting the ability to accurately diagnose CD using serum-based testing.

Purpose: This study investigated the involvement of NF-kB in regulating postoperative conjunctival inflammation.Methods: Experimental surgery was performed as described for the mouse model of conjunctival scarring. Expression of NF-κB in postoperative conjunctival tissues or conjunctival fibroblasts were assessed by real-time PCR, immunoblotting and immunofluorescence analyses. Downregulation of RelB was achieved using small interfering RNA. Cellular cytokine secretion was determined using multiplex cytokine assay.Results: RelB was the most highly induced member of the NF-kB family on day 2 post-surgery. Elevated RelB may be found associated with vimentin-positive cells and fibroblasts in vivo and in vitro. In conjunctival fibroblasts, RelB may be induced by TNF-α but not TGF-β2 while its silencing caused selective induction of CCL2 secretion by both basal and TNF-α-stimulated fibroblasts.Conclusions: High RelB induction in the inflammatory phase and the selective modulation of CCL2 suggest a specific anti-inflammatory role for RelB in the postoperative conjunctiva.

OBJECTIVE To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. METHODS We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection-related epilepsy syndrome (FIRES)/FIRES-related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. RESULTS The median age of onset of seizures was 2.4 years (range = 0.08-12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1-2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1-associated cytokines/chemokines (TNF-α, CXCL9, CXCL10, CXCL11), IL-6, CCL2, CCL19, and CXCL1 (P

Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45highF4/80low macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by ≥ 2.0-fold. VPA also specifically reduced tissue NF-кB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-α, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-кB2 p100. In corroboration, VPA suppressed TNF-α stimulation of NF-кB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva. Key messages VPA inhibited recruitment of a CD45highF4/80low macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues.VPA selectively suppressed tissue NF-кB2 p100 levels.VPA suppressed TNF-α induction of chemokines, cytokines and NF-кB2 p100 expression.VPA suppressed TNF-α stimulation of NF-кB reporter.

Purpose To identify the psychological impact of canceling cataract operations on patients during COVID-19 pandemic.Methods 99 participants aged from 59 years old who had their cataract surgeries postponed or as scheduled, were studied using the standardized patient health questionnaire (PHQ-9) and generalized anxiety disorder questionnaire (GAD-7) from April to June 2020 at Kowloon East Cataract Center, Tseung Kwan O Hospital, Hong Kong. ResultsNone of the patients who had the cataract surgeries rescheduled reached the cutoff score for major depression in PHQ-9, whereas for GAD-7, 5 patients had mild symptoms of anxiety, 1 had severe symptoms (p-value = 0.76). Conclusion There was no significant psychosocial impact of cancellation of cataract surgeries on patients.

PurposeTo determine the effect of valproic acid (VPA) on bleb morphology and scar characteristics in a rabbit model of minimally invasive glaucoma surgery (MIGS).MethodsNine New Zealand white rabbits were subjected to MIGS with intraoperative implantation of the PreserFlo MicroShunt. Rabbits were then administered with subconjunctival injections of phosphate buffered saline (PBS) (n=4) or with VPA (n=5). Bleb morphology was examined by slit-lamp biomicroscopy and in vivo confocal microscopy. Postoperative day 28 tissues were examined by immunohistochemical evaluation and label-free multiphoton microscopy to visualise the collagen matrix, by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay and immunofluorescent labelling for Ki67 expression to detect apoptosis and cell growth, and by real-time quantitative PCR to measure Col1a1, Fn, and Smad6 transcript expression.ResultsVPA-treated blebs were detectable on day 28, while the PBS-treated blebs were not detectable by day 14. VPA-treated blebs were diffuse, extended posteriorly with near normal conjunctival vascularity and featured a combination of reticular/blurred stromal pattern with evidence of relatively large stromal cysts. Instead of the deposition of thick, disorganised collagen fibres characteristic of the PBS bleb, the VPA bleb contained conspicuously thinner collagen fibres which were associated with similarly thinner fibronectin fibres. In corroboration, Col1a1 and Fn mRNA expression was reduced in the VPA blebs, while increased Smad6 expression implicated the disruption of the transforming growth factor beta pathway. Apoptosis and cell growth profiles appeared similar with both treatments.ConclusionsThe results support the application of VPA to enhance bleb morphology associated with good bleb function in MIGS with no apparent cytotoxicity.

Small interfering RNA (siRNA) therapy is a promising epigenetic silencing strategy. However, its widespread adoption has been severely impeded by its ineffective delivery into the cellular environment. Here, a biocompatible injectable gelatin-based hydrogel with positive-charge tuned surface charge is presented as an effective platform for siRNA protection and delivery. We demonstrate a two-step synthesis of a gelatin-tyramine (Gtn-Tyr) hydrogel with simultaneous charge tunability and crosslinking ability. We discuss how different physiochemical properties of the hydrogel interact with siSPARC (siRNA for secreted protein, acidic and rich in cysteine), and study the positive-charge tuned gelatin hydrogel as an effective delivery platform for siSPARC in anti-fibrotic treatment. Through in vitro studies using mouse tenon fibroblasts, the positive-charge tuned Gtn-Tyr hydrogel shows sustained siSPARC cellular internalization and effective SPARC silencing with excellent biocompatibility. Similarly, the same hydrogel platform delivering siSPARC in an in vivo assessment employing a rabbit model shows an effective reduction in subconjunctival scarring in post glaucoma filtration surgery, and is non-cytotoxic compared to a commonly used anti-scarring agent, mitomycin-C. Overall, the current siRNA delivery strategy involving the positive-charge tuned gelatin hydrogel shows effective delivery of gene silencing siSPARC for anti-fibrotic treatment. The current charge tunable hydrogel delivery system is simple to fabricate and highly scalable. We believe this delivery platform has strong translational potential for effective siRNA delivery and epigenetic silencing therapy. Ministry of Education (MOE) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This research was supported by an NTU internal grant (M4081851), Singapore Ministry of Education NTUitive Gap Fund (NGF-2019-07-004) and the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Programme (NMRC/TCR/008-SERI/2013). Animal studies were partially funded by the SERI core grant (NMRC/CG/015/2013). We would also like to acknowledge Nyein Chan Lwin from SingHealth Experimental Medicine Centre (SEMC), Singapore for assisting the in vivo studies.

Aim To determine the role of inflammation in pediatric transient focal cerebral arteriopathy using cerebrospinal fluid cytokine/chemokines as biomarkers. Methods We measured 32 cytokine/chemokines in acute cerebrospinal fluid collected from children with stroke due to focal cerebral arteriopathy (n = 5) using multiplex immunoassay and compared with two patients with arterial ischemic stroke due to other causes (non-focal cerebral arteriopathy group, vertebral dissection, n = 1; cryptogenic, n = 1), pediatric encephalitis (n = 43), and non-inflammatory neurological disease controls (n = 20). Results Median age in the focal cerebral arteriopathy group was 9.3 years (range, 2.8–13 years). In the focal cerebral arteriopathy group (n = 5), four patients had middle cerebral ± distal carotid arteriopathy; one patient had posterior circulation arteriopathy. The median time from symptom onset to cerebrospinal fluid sampling was four days (range, 0.6–7 days). Only IL-6, IL-8, CXCL1, and CXCL10 levels were significantly higher in the acute cerebrospinal fluid of focal cerebral arteriopathy patients compared to non-inflammatory neurological disease controls and non-focal cerebral arteriopathy stroke. In contrast to focal cerebral arteriopathy, a broad array of Th1, Th2, Treg, Th17, B-cell related, and other broad spectrum cytokine/chemokines were elevated in encephalitis. Conclusion The elevated cerebrospinal fluid cytokine/chemokines support innate, T cell, and granulocyte inflammatory mechanisms in children with focal cerebral arteriopathy. This warrants larger cohort studies to discriminate primary inflammatory signals of the arteriopathy from secondary inflammation due to the stroke itself.

BackgroundTo develop targeted antifibrotic therapy for glaucoma filtration surgery; this study determines the effectiveness of small interfering RNA (siRNA) to reduce in vivo secreted protein acidic and rich in cysteine (SPARC) expression using the mouse model of conjunctival scarring.MethodsExperimental surgery was performed as described for the mouse model of conjunctival scarring. Scrambled (siScram) or Sparc (siSparc) siRNAs, loaded on layer-by-layer (LbL) nanoparticles, were injected into the conjunctiva immediately after surgery. Expression ofSparc,Col1a1,Fn1andMmp14was measured by real-time PCR and immunoblotting on days 7 and 14 postsurgery. Live imaging of the operated eyes was performed using slit lamp, anterior segment-optical coherence tomography and confocal microscopy. Tissue pathology was evaluated by histochemical and immunofluorescent analyses of operated conjunctival cryosections. Tissue apoptosis was quantitated by annexin V assay.Results siSparc, delivered via expanded LbL nanoparticles, significantly inhibitedSparctranscription in both day 7 (2.04-fold) and day 14 (1.39-fold) treated tissues.Sparcsuppression on day 7 was associated with a significant reduction ofCol1a1(2.52-fold),Fn1(2.89-fold) andMmp14(2.23-fold) mRNAs. At the protein level, both SPARC and collagen 1A1 (COL1A1) were significantly reduced at both time points with siSparc treatment. Nanoparticles were visualised within cell-like structures by confocal microscopy, while overt tissue response or apoptosis was not observed.Conclusions SPARC targeted therapy effectively reduced both SPARC and collagen production in the operated mouse conjunctiva. This proof-of-concept study suggests that targeted treatment of fibrosis in glaucoma surgery is safe and feasible, with the potential to extend to a range of potential genes associated with fibrosis.

An acute care pediatric hospital and a university school of nursing joined forces to develop a comprehensive, interactive, online course in pediatric health assessment. The course was intended to increase nurses' knowledge and confidence in caring for children and families. The need for pediatric health assessment education varies depending on learners' prior experience. This article describes the course development and shares insights into the successful health care-academic partnership, which combined clinical, scholarly, and technological expertise. J Contin Educ Nurs. 2017;48(12):557–562.

Introduction We examined provider and regional variation in services provided and payments made to urologists by CMS (Centers for Medicare & Medicaid Services) by linking payments to individual beneficiaries and examining the proportion of submitted charges resulting in payments. Methods We analyzed Medicare Part B Provider Utilization and Payment Data released by CMS for 2012, the last year of the purely fee-for-service reimbursement model. For each provider we determined the ratio of number of services provided to individual beneficiaries as well as the ratio of total submitted charges-to-total Medicare payments. Each provider was stratified into deciles of total Medicare payments and the mean per decile of total Medicare payment was calculated. Finally, to elucidate the potential association between the ratio of services-to-beneficiaries, we conducted multivariate linear regressions. Results The 20th, 40th, 60th and 80th percentiles for the ratio of number of services per individual beneficiary ratios to total Medicare Part B payments are 2.8, 4.0, 5.2 and 7.4, respectively. Urologists with greater payments received provided more services to individual beneficiaries. Submitted charges exceeded payments by 3:1. Finally, female providers had lower ratios (p Conclusions We found significant variation in services and payment in CMS. Reimbursement models replacing fee-for-service should be tailored to ensure appropriate health care resource utilization.

To examine initial and longitudinal health-related quality of life (HRQOL) in adolescent sports-related concussion (SRC) patients, a prospective observational case-series study was conducted among adolescent SRC patients who were evaluated at a multi-disciplinary pediatric concussion program. Health-related quality of life was measured using the child self-report Pediatric Quality of Life Inventory (PedsQL) generic score scale (age 13-18 version) and the PedsQL Cognitive Functioning scale. Initial and longitudinal HRQOL outcomes were compared between patients who did and did not develop post-concussion syndrome (PCS). A total of 63 patients met the inclusion criteria during the study period. The mean age of the cohort was 14.57 years (standard deviation, 1.17) and 61.9% were male. The median time from injury to initial consultation was 6.5 days (interquartile range, 5, 11). At initial consultation, impairments in physical and cognitive HRQOL but not social or emotional HRQOL were observed. Initial symptom burden and length of recovery were associated with greater impairment in physical and cognitive HRQOL. Patients who went on to develop PCS had significantly worse physical and cognitive HRQOL at initial consultation and demonstrated a slower rate of recovery in these domains, compared with those who recovered in less than 30 days. Adolescent SRC was associated with HRQOL impairments that correlated with clinical outcomes. No persistent impairments in HRQOL were detected among patients who achieved physician-documented clinical recovery. Future studies are needed to evaluate the clinical utility of HRQOL measurement in the longitudinal management of adolescent SRC and PCS patients.

BACKGROUND: Concussion is an emerging public health concern, but care of patients with a concussion is presently unregulated in Canada. METHODS: Independent, blinded Google Internet searches were conducted for the terms "concussion" and "concussion clinic" and each of the Canadian provinces and territories. The first 10 to 15 concussion healthcare providers per province were identified. A critical appraisal of healthcare personnel and services offered on the provider's Web site was conducted. RESULTS: Fifty-eight concussion healthcare providers were identified using this search methodology. Only 40% listed the presence of an on-site medical doctor (M.D.) as a member of the clinical team. Forty-seven percent of concussion healthcare providers advertised access to a concussion clinic, program, or center on their Web site. Professionals designated as team leaders, directors, or presidents among concussion clinics, programs, and centers included a neuropsychologist (15%), sports medicine physician (7%), neurologist (4%), and neurosurgeon (4%). Services offered by providers included baseline testing (67%), physiotherapy (50%), and hyperbaric oxygen therapy (2%). CONCLUSIONS: This study indicates that there are numerous concussion healthcare providers in Canada offering diverse services with clinics operated by professionals with varying levels of training in traumatic brain injury. In some cases, the practices of these concussion clinics do not conform to current expert consensus guidelines. Language: en

IFIH1 gain-of-function causes a spectrum of neuroinflammatory phenotypes associated with enhanced type I interferon production and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation.1,2 Patients most often present in infancy, variably exhibiting spasticity, dystonia, seizures, and acquired microcephaly. We report the use of ruxolitinib, a JAK 1/2 blocker, in the treatment of early-onset, progressive neurologic disease due to an IFIH1 mutation.

Purpose Aquaporins (AQPs) facilitate transmembrane osmotic water transport and may play a role in iris fluid conductivity, which is implicated in the pathophysiology of glaucoma. In this study, we compared the iris expression of AQPs and aqueous osmolality between primary angle closure glaucoma (PACG), primary open-angle glaucoma (POAG), and nonglaucoma eyes. Methods AQP1-5 transcripts from a cohort of 36 PACG, 34 POAG and 26 nonglaucoma irises were measured by quantitative real-time PCR. Osmolality of aqueous humor from another cohort of 49 PACG, 50 POAG, and 50 nonglaucoma eyes were measured using an osmometer. The localization of AQP1 in both glaucoma and nonglaucoma irises was determined by immunofluorescent analysis. Results Of the five AQP genes evaluated, AQP1 and AQP2 transcripts were significantly upregulated in both PACG (3.48- and 8.07-fold, respectively) and POAG (3.12- and 11.58-fold, respectively) irises relative to nonglaucoma counterparts. The aqueous osmolalities of PACG (303.68 mmol/kg) and POAG (300.79 mmol/kg) eyes were significantly lower compared to nonglaucoma eyes (312.6 mmol/kg). There was no significant difference in expression of AQP transcripts or aqueous osmolality between PACG and POAG eyes. Conclusions PACG and POAG eyes featured significant increase in AQP1 and AQP2 expression in the iris and reduced aqueous osmolality compared to nonglaucoma eyes. These findings suggest that the iris may be involved in altered aqueous humor dynamics in glaucoma pathophysiology. Because PACG did not differ from POAG in both properties studied, it is likely that they are common to glaucoma disease in general.

Glaucoma filtration surgery (GFS) commonly fails due to excessive fibrosis. As collagen structure aberrations is implicated in adverse fibrotic progression, this study aims to uncover collagen organization alterations during postoperative scarring. Via quantitative second harmonic generation/ two photon excitation multiphoton imaging, we reveal the scar development and phenotype in the mouse model of conjunctival scarring. We also show that multiphoton imaging corroborated the collagen ultrastructure anomaly characteristic of the SPARC-/- mouse postoperative conjunctiva. These data improve our understanding of postoperative conjunctival scarring and further enhance the utility of this model for the development of anti-fibrotic therapeutics for GFS.

Overproduction of type I collagen is associated with a wide range of fibrotic diseases as well as surgical failure such as in glaucoma filtration surgery (GFS). Its modulation is therefore of clinical importance. Valproic acid (VPA) is known to reduce collagen in a variety of tissues with unclear mechanism of action. In this report, we demonstrate that VPA inhibited collagen production in both conjunctival fibroblasts and the mouse model of GFS. In fibroblasts, VPA decreased type I collagen expression which intensified with longer drug exposure and suppressed steady-state type I collagen promoter activity. Moreover, VPA decreased Smad2, Smad3 and Smad4 but increased Smad6 expression with a similar intensity-exposure profile. Reduction of Smad3 using small hairpin RNA and/or overexpression of Smad6 resulted in decreased collagen expression which was exacerbated when VPA was simultaneously present. Furthermore, fibrogenic TGF-β2 failed to induce collagen when VPA was present, as opposed to the myofibroblast markers, beta-actin, alpha-smooth muscle actin and tenascin-C, which were elevated by TGF-β2. VPA suppressed p3TP-Lux luciferase activity and selectively rescued Smad6 expression from suppression by TGF-β2. Notably, SMAD6 overexpression reduced the effectiveness of TGF-β2 in inducing collagen expression. In corroboration, VPA inhibited type I collagen but increased Smad6 expression in the late phase of wound healing in the mouse model of GFS. Taken together, our data indicate that VPA has the capacity to effectively suppress both steady-state and fibrogenic activation of type I collagen expression by modulating Smad expression. Hence, VPA is potentially applicable as an anti-fibrotic therapeutic by targeting collagen. Key message • VPA modulates type I collagen expression via members of the Smad family. •VPA suppresses Smad2, Smad3 and Smad4 but upregulates Smad6. •Smad3 and Smad6 are involved in VPA regulation of steady-state collagen expression. •Smad6 is involved in VPA modulation of TGF-β-stimulated collagen expression. •VPA reduces collagen and upregulates Smad6 in the mouse model of glaucoma filtration surgery.

Objective To report the use of telemedicine to deliver general urologic care to remote locations within the Veterans Affairs Greater Los Angeles Healthcare System. We describe the diagnoses managed, patient satisfaction, safety, and benefit to patients in terms of saved travel time and expense. Methods We conducted a retrospective chart review examining care delivered through urology telemedicine clinics over a 6-month period. We examined the urologic conditions, patient satisfaction, and emergency department visits within 30 days of the visit. We estimated patient benefit by calculating travel distance and time and the saved travel-associated costs using Google Maps and US Census income data. Results Ninety-seven unique telemedicine visits were conducted and a total of 171 urologic diseases were assessed. The most common conditions were lower urinary tract symptoms (35%), elevated prostate-specific antigen level (15%), and prostate cancer (14%). One patient was seen in the emergency department within 30 days with an unpreventable urologic complaint. Patient satisfaction was “very good” to “excellent” in 95% of cases, and 97% would refer another veteran to the urology telemedicine clinic. Patients saved an average of 277 travel miles, 290 minutes of travel time, $67 in travel expenses, and $126 in lost opportunity cost. Conclusion Telemedicine was successfully and safely used to evaluate and treat a wide range of urologic conditions within the Veterans Affairs Greater Los Angeles Healthcare System, and saves patients nearly 5 hours and up to $193 per visit. Further investigation of the potential of telemedicine for the delivery of urologic care in a cost-effective manner is warranted.

Objectives The objectives of this study are to better understand women's experience with pelvic organ prolapse (POP) and to compare this experience between English-speaking and Spanish-speaking women. Methods Women with POP were recruited from female urology and urogynecology clinics. Eight focus groups of 6 to 8 women each were assembled-4 groups in English and 4 in Spanish. A trained bilingual moderator conducted the focus groups. Topics addressed patients' perceptions, their knowledge and experience with POP symptoms, diagnostic evaluation, physician interactions, and treatments. Results Both English-speaking and Spanish-speaking women expressed the same preliminary themes-lack of knowledge regarding the prevalence of POP, feelings of shame regarding their condition, difficulty in talking with others, fear related to symptoms, and emotional stress from coping with POP. In addition, Spanish-speaking women included fear related to surgery and communication concerns regarding the use of interpreters. Two overarching concepts emerged-first, a lack of knowledge, which resulted in shame and fear and second, public awareness regarding POP is needed. From the Spanish speaking, an additional concept was the need to address language barriers and the use of interpreters. Conclusions Both English-speaking and Spanish-speaking women felt ashamed of their POP and were uncomfortable speaking with anyone about it, including physicians. Educating women on the meaning of POP, symptoms, and available treatments may improve patients' ability to discuss their disorder and seek medical advice; for Spanish-speaking women, access to translators for efficient communication is needed.

Aim: The purpose of this study was to examine academic achievement, absenteeism and school accommodations following adolescent sport-related concussion (SRC). Methods: A case-series was conducted among grade 8–12 students who suffered an SRC. The primary outcomes were change in pre- and post-concussion overall, core report card grade point average (GPA) and absenteeism due to concussion. The most helpful school accommodations were tabulated. Results: Pre- and post-concussion GPA was obtained from 33 students – 16 (48%) developed persistent post-concussion symptoms (symptoms lasting >4 weeks). There was no significant difference in pre- and post-concussion grades among students with a SRC for overall (p = 0.75) or core (p = 0.56) GPA. The median number of missed school days was 4 (interquartile range [IQR]: 2–8). Allowing for physical and cognitive rest was identified as the most helpful accommodation (30%). Conclusion: Larger studies should investigate the role that school accommodations and development of persistent post-concussion symptoms have on academic outcomes.

Purpose: Secreted protein acidic and rich in cysteine (SPARC) and Hevin are structurally related matricellular proteins involved in extracellular matrix assembly. In this study, we compared the anterior chamber biometric parameters and iris collagen properties in SPARC-, Hevin- and SPARC-/Hevin-null with wild-type (WT) mice. Methods: The right eyes of 53 WT, 35 SPARC-, 56 Hevin-, and 63 SPARC-/Hevin-null mice were imaged using the RTVue-100 Fourier-domain optical coherence tomography system. The parameters measured were anterior chamber depth (ACD), trabecular-iris space area (TISA), angle opening distance (AOD), and pupil diameter. Biometric data were analyzed using analysis of covariance and adjusted for age, sex, and pupil diameter. Expression of Col1a1, Col8a1, and Col8a2 transcripts in the irises was measured by quantitative polymerase chain reaction. Collagen fibril thickness was evaluated by transmission electron microscopy. Results: Mice that were SPARC- and SPARC-/Hevin-null had 1.28- and 1.25-fold deeper ACD, 1.45- and 1.53-fold larger TISA, as well as 1.42- and 1.51-fold wider AOD than WT, respectively. These measurements were not significantly different between SPARC- and SPARC-/Hevin-null mice. The SPARC-null iris expressed lower Col1a1, but higher Col8a1 and Col8a2 transcripts compared with WT. Collagen fibrils in the SPARC- and SPARC-/Hevin-null irises were 1.5- and 1.7-fold thinner than WT, respectively. The Hevin-null iris did not differ from WT in these collagen properties. Conclusions: SPARC-null mice have deeper anterior chamber as well as wider drainage angles compared with WT. Therefore, SPARC plays a key role in influencing the spatial organization of the anterior segment, potentially via modulation of collagen properties, while Hevin is not likely to be involved. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version

Excessive accumulation of collagen is often used to assess the development of fibrosis. This study aims to identify collagen genes that define fibrosis in the conjunctiva following glaucoma filtration surgery (GFS). Using the mouse model of GFS, we have identified collagen transcripts that were upregulated in the fibrotic phase of wound healing via RNA-seq. The collagen transcripts that were increased the most were encoded by Col8a1, Col11a1 and Col8a2. Further analysis of the Col8a1, Col11a1 and Col8a2 transcripts revealed their increase by 67-, 54- and 18-fold, respectively, in the fibrotic phase, compared with 12-fold for Col1a1, the most commonly evaluated collagen gene for fibrosis. However, only type I collagen was significantly upregulated at the protein level in the fibrotic phase. Type VIII and type I collagens colocalized in fibrous structures and in ACTA2-positive pericytes, and appeared to compensate for each other in expression levels. Type XI collagen showed low colocalization with both type VIII and type I collagens but can be found in association with macrophages. Furthermore, we show that both mouse and human conjunctival fibroblasts expressed elevated levels of the most highly expressed collagen genes in response to TGFβ2 treatment. Importantly, conjunctival tissues from individuals whose GF surgeries have failed due to scarring showed 3.60- and 2.78-fold increases in type VIII and I collagen transcripts, respectively, compared with those from individuals with no prior surgeries. These data demonstrate that distinct collagen transcripts are expressed at high levels in the conjunctiva after surgery and their unique expression profiles may imply differential influences on the fibrotic outcome., Summary: As well as providing an objective quantitative measure, distinct collagen genes may further aid in the characterization and definition of the development of fibrosis.

Schimke immuno-osseous dysplasia (SIOD) is a pleiotropic disorder caused by mutations in the SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like-1 ( SMARCAL1) gene, with multiple clinical features, notably end-stage renal disease. Here we characterize the renal pathology in SIOD patients. Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS). Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman’s capsule. To better understand the role of SMARCAL1 in the pathogenesis of FSGS, we defined SMARCAL1 expression in the developing and mature kidney. In the developing fetal kidney, SMARCAL1 is expressed in the ureteric epithelium, stroma, metanephric mesenchyme, and in all stages of the developing nephron, including the maturing glomerulus. In postnatal kidneys, SMARCAL1 expression is localized to epithelial tubules of the nephron, collecting ducts, and glomerulus (podocytes and endothelial cells). Interestingly, not all cells within the same lineage expressed SMARCAL1. In renal biopsies from SIOD patients, TUNEL analysis detected marked increases in DNA fragmentation. Our results highlight the cells that may contribute to the renal pathogenesis in SIOD. Further, we suggest that disruptions in genomic integrity during fetal kidney development contribute to the pathogenesis of FSGS in SIOD patients.

Failure after glaucoma filtration surgery is attributed to fibrosis at the operated site. To understand the wound healing process after glaucoma filtration surgery, we have developed a mouse model for glaucoma filtration surgery which closely mimics the clinical response. In this study, we describe a systematic analysis of the wound healing response in vivo. Our data revealed that the post-surgical tissue response was separable into two distinguishable phases. The early "acute inflammatory" phase was characterized by significantly increased transcript expression of Vegfa, Cxcl1, Cxcl5, Ccl2, Ccl3, Ccl4, Gmcsf and specific Mmps as well as greater infiltration of monocytes/macrophages and T cells. The late "fibrotic" phase was characterized by an increased expression of Tgfb2 and extracellular matrix genes as well as a notable reduction of infiltrating inflammatory cells. Significantly, more mitotic cells were observed at both time points post-surgery. Subconjunctival fibroblasts may be involved in both phases since they have the capacity to reiterate the in vivo gene expression profiles upon either pro-inflammatory or pro-fibrotic cytokine stimulation. Given that the cellular and molecular targets that govern the early and late phases of wound healing are distinct and time sensitive, a multi-targeted therapeutic approach to sequentially inhibit inflammation and fibrogenesis at the critical time point may lead to improved surgical outcomes in glaucoma filtration surgery.