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Matthew Sniegowski, Michael Erlanger, Raul Velez-Montoya, Jeffrey L Olson Ophthalmology Department, University of Colorado School of Medicine, Rocky Mountain Lions Eye Institute, Aurora, CO, USA Purpose: To assess the change in ocular surface temperature between healthy phakic and pseudophakic patients.Methods: We included patients with no history of ocular disease other than cataract. Patients were divided into three groups: clear lens, cataract, and pseudophakic. All patients had two ocular surface digital thermal scans. An average of five surface points was used as the mean ocular surface temperature. Results were analyzed with a one-way analysis of variance and a Tukey’s least significance difference test. The patients were further divided into phakic and pseudophakic groups. Correlation coefficients between several variables were done in order to assess dependencies.Results: Fifty-six eyes (28 cataracts, 12 clear lenses, 16 pseudophakic) were enrolled. The mean ocular surface temperature in the cataract group was 34.14°C±1.51°C; clear lens: 34.43°C±2.27°C; and pseudophakic: 34.97°C±1.57°C. There were no statistical differences among the study groups (P=0.3). There was a nonsignificant negative correlation trend between age and surface temperature in the phakic group. The trend inverted in the pseudophakic group but without statistical significance.Conclusion: Although cataract extraction and intraocular lens implantation seem to induce a mild increase in ocular surface temperature, the effect is not clear and not significant. Keywords: digital thermal scans, intraocular lens implantation, cataract extraction

Kesenia Stafeeva, Michael Erlanger, Raul Velez-Montoya, Jeffrey L OlsonDepartment of Ophthalmology, University of Colorado School of Medicine, Rocky Mountain Lions Eye Institute, Colorado, CO, USAAbstract: This case report describes the clinical, autofluorescence, and optical coherent tomography findings in a patient with panocular argyrosis secondary to chronic intake of diluted silver nitrate salts in his water supply. An 86-year-old Caucasian male with a distinctive gray-bluish hue of the skin presented to our clinic, having developed a slow decrease in visual acuity in both eyes and nyctalopia for the past 2 years. Based on the patient's history of chronic intake of silver nitrate salts and a positive skin biopsy (performed by the dermatology department, data not shown), a diagnosis of panocular argyrosis was made. Fluorescein angiography showed choroidal blockage with a completely dark choroid. Fundus autofluorescence was within normal limits. Optical coherent tomography showed multiple excrescences of retinal pigment epithelium in both eyes. Although the drusen-like changes on fundus examination and retinal pigment epithelium changes may account for the diminished vision, the presence of concomitant nyctalopia suggests underlying damage of the photoreceptors.Keywords: silver nitrate, argyria, ocular argyrosis, fundus autofluorescence, optical coherent tomography

Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has i

Introduction: Digital health tools can be beneficial in the care of patients with chronic conditions and have the potential for widespread impact as readily scalable and cost-effective health interventions. However, benefits are often contingent on users sustaining their engagement with these tools over time. Sustained engagement with digital health tools can be challenging, and high rates of attrition from digital interventions are common. Inflammatory Bowel Disease (IBD) and irritable bowel syndrome (IBS) are prominent gastrointestinal conditions resulting in significant burdens for individuals and society. Emerging evidence suggests digital health tools can be beneficial for IBD and IBS management; however, it is not clear what barriers and enablers are experienced by people living with these conditions to sustaining their engagement with these tools, when necessary. Such knowledge could inform the tailoring of new and existing digital health tools to the needs of people living with IBD and/or IBS. This study will seek to identify the barriers and enablers of sustained engagement with digital health tools among adults living with IBD and/or IBS., Methods and Analysis: We will conduct semistructured interviews with a purposive sample of approximately 30 adults (>18 years) who (a) reside in Canada, (b) self-report that they have been diagnosed with IBD and/or IBS, (c) have ever used a digital health tool (ie, any application/platform) to manage their condition and (d) are capable of providing informed consent. Interviews will be audio and video recorded and transcribed verbatim. Data will be coded deductively and barriers and enablers to sustained engagement will be categorised in accordance with the Theoretical Domains Framework. Data analysis will be verified by a patient research partner., Ethics and Dissemination: The study has been approved by the Ottawa Health Science Network Research Ethics Board. The findings will inform the codevelopment of strategies to overcome modifiable barriers and leverage identified enablers of sustained engagement with digital health tools for IBD and IBS care. These strategies can inform the design of new, or modifications to existing, digital health tools for IBD and IBS care where sustained engagement is desirable. Strategies will be compiled into a guidebook and disseminated via the Inflammation, Microbiome and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) Strategy for Patient Oriented Research chronic disease network in Canada., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Process evaluations conducted alongside clinical trials can improve understanding of treatment fidelity and provide contextual knowledge to aide interpretations of trial outcomes. We adopted a multiple-goals perspective to investigate treatment fidelity in two related pilot clinical trials of an adjuvant treatment for pediatric-onset Inflammatory Bowel Disease. This included a focus on barriers and enablers of performing trial-specific activities and of integrating those activities into daily life., Methods: We conducted one-time semi-structured interviews with a sub-sample of participants of the Resistant Starch in Pediatric Inflammatory Bowel Disease (NCT04522271) and Optimized Resistant Starch in Inflammatory Bowel Disease pilot trials (NCT04520594) and their caregivers (N = 42). The trials examined the effects of personalized food-derived resistant starches as an adjuvant therapy on intestinal microbiome functioning. Interviews were conducted within 3-months of participants completing or withdrawing from the trials. Interview guides with age-appropriate language were developed and pilot tested. Codes were identified inductively though conventional content analysis and then mapped to personal projects analysis, to explore how participants navigated between activities., Results: Three themes were identified. The first described the potential impact of living with inflammatory bowel disease and taking prescribed medications. The second described characteristics of trial-specific activities that might impact on their enactment, including perceived difficulty, and challenges following procedures or using trial materials. The third described the integration of trial-specific activities with school, work, household demands, and social, and extracurricular activities., Conclusions: Adjusting to living with inflammatory bowel disease and managing its treatment can impact trial participation. Integrating trial-related activities into daily life can be challenging, which could heighten perceptions of goal conflict. Findings can inform interpretations of trial outcomes and development of strategies for trial optimization and implementation of the adjuvant therapy into clinical practice., Competing Interests: AS and DM are co-founders of MedBiome, a clinical microbiomics company. The other authors have no competing interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Olson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Wearable devices are increasingly being integrated to improve prevention, chronic disease management and rehabilitation. Inferences about individual differences in device-measured physical activity depends on devices being worn long enough to obtain representative samples of behavior. Little is known about how psychological factors are associated with device wear time adherence. This study evaluated associations between identity, behavioral regulations, and device wear adherence during an ambulatory monitoring period. Young adults who reported insufficient physical activity (N = 271) were recruited for two studies before and after the SARS-COVID-19 pandemic declaration. Participants completed a baseline assessment and wore an Actigraph GT3X + accelerometer on their waist for seven consecutive days. Multiple linear regression indicated that wear time was positively associated with age, negatively associated with integrated regulation for physical activity, and greater after (versus before) the pandemic declaration. Overall, the model accounted for limited variance in device wear time. Exercise identity and exercise motivation were not associated with young adults' adherence to wearing the physical activity monitors. Researchers and clinicians can use wearable devices with young adults with minimal concern about systematic motivational biases impacting adherence to device wear., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases., Design: Experimental study., Subjects: Brown Norway rats and New Zealand White Cross rabbits., Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents., Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101., Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo., Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background: Restoration of shoulder function in obstetrical brachial plexus injury is paramount. There remains debate as to the optimal method of upper trunk reconstruction. The purpose of this study was to test the hypothesis that spinal accessory nerve to suprascapular nerve transfer leads to improved shoulder external rotation relative to sural nerve grafting., Methods: A systematic review of Medline, EMBASE, EBSCO CINAHL, SCOPUS, Cochrane Library, and TRIP Pro from inception was conducted. Our primary outcome was shoulder external rotation., Results: Four studies were included. Nerve transfer was associated with greater shoulder external rotation relative to nerve grafting (mean difference: 0.82 AMS 95% confidence interval [CI]: 0.27-1.36, P < .005). Patients undergoing nerve grafting were more likely to undergo a secondary shoulder stabilizing procedure (odds ratio [OR]: 1.27, 95% CI: 0.8376-1.9268)., Conclusion: In obstetrical brachial plexus injury, nerve transfer is associated with improved shoulder external rotation and a lower rate of secondary shoulder surgery., Level of Evidence: Level III; Therapeutic.

Background: The aim of this work was to develop a National Evaluation Framework to facilitate the standardization of delivery, quality, reporting, and evaluation of diabetes education and support programs delivered throughout Australia through the National Diabetes Services Scheme (NDSS). The NDSS is funded by the Australian Government, and provides access to diabetes information, education, support, and subsidized product across diverse settings in each state and territory of Australia through seven independent service-providers. This article reports the approach undertaken to develop the Framework., Methods: A participatory approach was undertaken, focused on adopting nationally consistent outcomes and indicators, nominating objectives and measurement tools, specifying evaluation processes, and developing quality standards. Existing programs were classified based on related, overarching indicators enabling the adoption of a tiered system of evaluation., Results: Two outcomes (i.e., improved clinical, reduced cost) and four indicators (i.e., improved knowledge and understanding, self-management, self-determination, psychosocial adjustment) were adopted from the Eigenmann and Colagiuri national consensus position statement for diabetes education. This allowed for the identification of objectives (i.e., improved empowerment, reduced distress, autonomy supportive program delivery, consumer satisfaction) and related measurement instruments. Programs were categorized as comprehensive, topic-specific, or basic education, with comprehensive programs allocated to receive the highest-level of evaluation. Eight quality standards were developed, with existing programs tested against those standards. Based on the results of testing, two comprehensive (OzDAFNE for people with type 1 diabetes, DESMOND for people with type 2 diabetes), and eight topic-specific (CarbSmart, ShopSmart, MonitorSmart, FootSmart, MedSmart, Living with Insulin, Insulin Pump Workshop, Ready Set Go - Let's Move) structured diabetes self-management education and support programs were nominated for national delivery., Conclusions: The National Evaluation Framework has facilitated consistency of program quality, delivery, and evaluation of programs delivered by multiple service providers across diverse contexts. The Framework could be applied by other service providers who facilitate multiple diabetes education and support programs and could be adapted for use in other chronic disease populations where education and support are indicated., (© 2022. The Author(s).)

Background: Recent evidence shows that sport settings can act as a powerful draw to engage men in weight loss. The primary objective of this pilot study was to test the feasibility of delivering and to evaluate preliminary efficacy of Aussie-FIT, a weight-loss program for men with overweight/obesity delivered in Australian Football League (AFL) settings, in preparation for a future definitive trial., Methods and Findings: This 6-month pilot trial took place in Perth, Australia. Participants were overweight/obese (Body Mass Index [BMI] ≥ 28 kg/m2), middle-aged (35-65 years old) men. Participants were recruited in May 2018, and the intervention took place between June and December 2018. The intervention involved 12 weekly 90-min face-to-face sessions, incorporating physical activity, nutrition, and behaviour change information and practical activities delivered by coaches at 2 clubs. Data were collected at baseline and immediately postintervention. For trial feasibility purposes, 6-month follow-ups were completed. Outcomes were differences in weight loss (primary outcome) and recruitment and retention rates, self-reported measures (for example, psychological well-being), device-measured physical activity, waist size, and blood pressure at 3 months. Within 3 days of advertising at each club, 426 men registered interest; 306 (72%) were eligible. Men were selected on a first-come first-served basis (n = 130; M age = 45.8, SD = 8; M BMI = 34.48 kg/m2, SD = 4.87) and randomised by a blinded researcher. Trial retention was 86% and 63% at 3- and 6-month follow-ups (respectively). No adverse events were reported. At 3 months, mean difference in weight between groups, adjusted for baseline weight and group, was 3.3 kg (95% CI 1.9, 4.8) in favour of the intervention group (p < 0.001). The intervention group's moderate-to-vigorous physical activity (MVPA) was higher than the control group by 8.54 min/day (95% CI 1.37, 15.71, p = 0.02). MVPA among men attracted to Aussie-FIT was high at baseline (intervention arm 35.61 min/day, control arm 38.38 min/day), which may have limited the scope for improvement., Conclusions: Aussie-FIT was feasible to deliver; participants increased physical activity, decreased weight, and reported improvements in other outcomes. Issues with retention were a limitation of this trial. In a future, fully powered randomised controlled trial (RCT), retention could be improved by conducting assessments outside of holiday seasons., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12617000515392., Competing Interests: The authors have declared that no competing interests exist.

Background: In order to increase one's competitiveness in the current job market, Canadian plastic surgery graduates may complete additional degrees and multiple fellowships. The authors sought to determine the impact of this additional training on the practice profile of recent graduates and determine the current state of job satisfaction among this group., Methods: An anonymous cross-sectional online survey was created and sent to all 250 graduates of Canadian plastic surgery residencies from 2005 to 2015. Demographics were collected and questions grouped into clinical, teaching, research, and administrative components. Questions pertaining to job satisfaction were also included., Results: The response rate to the survey was 39%. Sixty-nine (71%) respondents had permanent attending positions at the time of survey completion, while the remaining 28 respondents did not. Among those with permanent positions, 59 (86%) completed at least one fellowship and 30 (43%) have an advanced degree. Of those who did fellowship training, 76% practice primarily in their area of subspecialty. Having an advanced degree showed a trend to a higher percentage of practice dedicated to research (5.6% vs 1.9%; P = .074) and more publications per year were seen among this group (1.31 vs 0.30; P = .028). Eighty-six percent of respondents are satisfied with their current attending position., Conclusions: The majority of recent Canadian plastic surgery graduates are undergoing fellowship training and are practicing primarily in their fields of subspecialty training. Having a postgraduate degree was associated with a higher number of publications per year as an attending surgeon. Job satisfaction is high among recent graduates., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This article introduces changes occurring in the Veterans Health Administration (VHA) with respect to the delivery of acupuncture. The VHA has published a new occupation code and job qualification standard allowing licensed acupuncturists to practice at the VHA medical centers. This policy shift comes at a time of great need for complementary and integrative health (CIH) options for veterans as identified by the advancing research, policies, and legislation that support CIH. The VHA initiatives include fostering an understanding of the distinct profession of licensed acupuncturists, developing an appreciation of the emerging evidence for acupuncture, and creating the cultural shift to support a wider view of CIH services. Historically, acupuncture was provided in the VHA mostly by physician-acupuncturists and chiropractic acupuncturists. The publication of a qualification standard for licensed acupuncturists allows the VHA to increase its provider base and create cost savings for the delivery of acupuncture. This move requires overcoming barriers to the integration of licensed acupuncturists into the VHA system. The goal is to increase the utilization of acupuncture among veterans., Competing Interests: No competing financial interests exist.

Introduction: The current standard of treatment for glaucoma is trabeculectomy. The use of glaucoma drainage devices has increased in recent years since its efficacy and safety was established as it provides an alternative surgical option. A downfall of these devices is the lack of proper flow rate control. Areas covered: In this paper we describe a glaucoma drainage device regulator that has already been protoyped and undergone initial testing. It consists of an implantable device with a semipermeable membrane that is used during glaucoma surgery and can be opened with either thermal or photodisruptive laser to adjust the amount of flow precisely and non-invasively, addressing the current difficulties of glaucoma surgeries. A literature search was conducted using MEDLINE and manuscript references for studies published in English between 2000 and 2015 using the terms glaucoma, trabeculectomy and glaucoma drainage devices. Expert commentary: The GDDR device can decrease surgical risk and allow surgeons to post-operatively adjust flow as clinically needed using a non-invasive method. Further testing is planned to substantiate these initial results and evaluate the device's biocompatibility, tunability and efficacy.

PurposeWe report the in vivo testing of a large-lumen glaucoma drainage (LL-GDD) device equipped with a flow regulator. The device's membrane can be non-invasively opened with laser in the postoperative period to adjust aqueous flow and intraocular pressure.MethodsThe initial LL-GDD prototypes were constructed using 22 G silicone angiocatheters cut down to size. A 10 nm PVDF membrane was then affixed to the end using cyanoacrylate. The LL-GDD was tested first in a model eye equipped with ports for infusion and pressure measurement and in New Zealand rabbits.ResultsNew Zealand white satin cross rabbits were used, two eyes receiving the LL-GDD and the two fellow eyes serving as the control group with no intervention performed. After the procedure, the IOP in the LL-GGD surgical group dropped an average of 5.5 mm Hg (P=0.001), which was maintained until the membrane laser procedure at week 5 resulting in an average IOP reduction of 1.8 mm Hg. At week 7, the average IOP in the surgical group was 11 mm Hg compared with 18 mm Hg in the control group (P<0.001). A second laser procedure was done to completely open the membrane face, which resulted in an immediate drop in the average IOP of the surgical group by another 2.7 mm Hg, which was maintained until the study termination at day 55.ConclusionsThe large-lumen glaucoma drainage device demonstrated an ability both to prevent immediate postoperative hypotony and to allow progressively lower IOP on demand in this proof-of-concept study.

A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients' combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70-associated autoimmune disease., (© 2016 Chan et al.)

Protein disulfide isomerase (PDI) family members regulate protein folding and calcium homeostasis in the endoplasmic reticulum (ER). The PDI family member anterior gradient (AGR) 3 is expressed in the airway, but the localization, regulation, and function of AGR3 are poorly understood. Here we report that AGR3, unlike its closest homolog AGR2, is restricted to ciliated cells in the airway epithelium and is not induced by ER stress. Mice lacking AGR3 are viable and develop ciliated cells with normal-appearing cilia. However, ciliary beat frequency was lower in airways from AGR3-deficient mice compared with control mice (20% lower in the absence of stimulation and 35% lower after ATP stimulation). AGR3 deficiency had no detectable effects on ciliary beat frequency (CBF) when airways were perfused with a calcium-free solution, suggesting that AGR3 is required for calcium-mediated regulation of ciliary function. Decreased CBF was associated with impaired mucociliary clearance in AGR3-deficient airways. We conclude that AGR3 is a specialized member of the PDI family that plays an unexpected role in the regulation of CBF and mucociliary clearance in the airway.

Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC), in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

Purpose: To assess the capabilities of a new glaucoma drainage device regulator in controlling fluid flow as well as to demonstrate that this effect may be titratable by noninvasive means., Methods: A rigid eye model with two main ports was used. On the first port, we placed a saline solution column. On the second, we placed a glaucoma shunt. We then measured the flow and flow rate through the system. After placing the regulator device on the tip of the tube, we measured again with the intact membrane and with the membrane open 50% and 100%. For the ex vivo testing we used a similar setting, using a cadaveric porcine eye, we measured again the flow and flow rate. However, this time we opened the membrane gradually using laser shots. A one-way analysis of variance and a Fisher's Least Significant Difference test were used for statistical significance. We also calculated the correlation between the numbers of laser shots applied and the main outcomes., Results: The flow through the system with the glaucoma drainage device regulator (membrane intact and 50% open) was statistically lower than with the membrane open 100% and without device ( P < 0.05). The flow was successfully controlled by the number of laser shots applied, and showed a positive correlation (+ 0.9). The flow rate was almost doubled every 10 shots and statistically lower than without device at all time ( P < 0.05)., Conclusions: The glaucoma drainage device regulator can be controlled noninvasively with laser, and allows titratable control of aqueous flow., Translational Relevance: Initial results and evidence from this experiment will justify the initiation of in vivo animal trials with the glaucoma drainage device regulator; which brings us closer to possible human trials and the chance to significantly improve the existing technology to treat glaucoma surgically.

We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation.

The hand is an integral component of the human body, with an incredible spectrum of functionality. In addition to possessing gross and fine motor capabilities essential for physical survival, the hand is fundamental to social conventions, enabling greeting, grooming, artistic expression and syntactical communication. The loss of one or both hands is, thus, a devastating experience, requiring significant psychological support and physical rehabilitation. The majority of hand amputations occur in working-age males, most commonly as a result of work-related trauma or as casualties sustained during combat. For millennia, humans have used state-of-the-art technology to design clever devices to facilitate the reintegration of hand amputees into society. The present article provides a historical overview of the progress in replacing a missing hand, from early iron hands intended primarily for use in battle, to today's standard body-powered and myoelectric prostheses, to revolutionary advancements in the restoration of sensorimotor control with targeted reinnervation and hand transplantation.

Traumatic brachial plexus root avulsions are devastating injuries, and are complex and challenging to reconstruct. Double free muscle transfer using the gracilis muscles is a potentially effective method of restoring upper extremity function. The authors report on the first two patients treated using this technique in Canada. Both sustained traumatic brachial plexus root avulsion injuries resulting in a flail arm. In the first step of this two-stage procedure, a gracilis muscle was transferred to restore elbow flexion, and wrist and digit extension. Months later, the transfer of the second gracilis muscle was performed to enhance elbow flexion and to enable wrist and digit flexion. Postoperatively, both patients achieved Medical Research Council grade 4 elbow flexion, functional handgrip and were able to return to gainful employment. Patient satisfaction was high and active range of motion improved substantially. The authors' experience supports the use of this technique following severe brachial plexus injury.

Background. To assess the peeling forces exerted by different calibers of microsurgical forceps on an experimental model of epiretinal membrane. Methods. A model of epiretinal membrane was constructed using thin cellulose paper and heptanes-isopropyl alcohol 1% mixture. The model was mounted on a force censoring device. Subsequently, flaps were created with three different microsurgical forceps of different calibers. We recorded the number of attempts, the duration of the event, and the pushing and the pulling forces during the peeling. The results were compared by a one-way ANOVA and a Fisher unprotected least significant difference test with an alpha value of 0.05 for statistically significance. Results. There was a statistical significant difference on the pulling and pushing forces between the 25 gauge (13.79 mN; -13.27 mN) and the 23 (6.63 mN; -5.76 mN) and 20 (5.02 mN; -5.30 mN) gauge, being greater in the first (P < 0.001). There were no differences in the duration of all events, meaning that all the forces were measured within the same period of time. Conclusions. The 25 gauge microsurgical forceps exerted the greatest mechanical stress over our simulated epiretinal membrane model and required more attempts to create a surgical suitable flap. The clinical implication of this finding is still to be determined.

Purpose: To study the intravitreal application of silicon quantum dots (QDs) and their capabilities to deliver electrical stimulation to the retinal cells and to assess the potential effect on retinal electrophysiology and anatomy., Methods: A Royal College of Surgeon rat model of retinal degeneration was used in this study. A total of 32 eyes were used, divided in four groups of 8 eyes each; the first group received the silicon-based QD, the second group received an inactive gold-based QD, the third group received a sham injection, and the fourth group was used as a control. An electroretinogram (ERG) was done at baseline and thereafter every week for 9 weeks. At the end of the follow-up, eyes were collected for further pathologic analysis and nuclei cell counts., Results: Eyes within the silicon-based QD group showed a definite but transient increase in the waves of the ERG, especially in the rod response compared with the sham and control groups (P < 0.05). The pathologic examination demonstrated a higher nuclei count in the QD group, consistent with a higher cell survival rate than that in the sham and control groups in which cells degenerated as expected., Conclusions: Intravitreal injection of silicon-based QD seems to be safe and well tolerated, with no evident toxic reaction and demonstrates a beneficial effect by prolonging cell survival rate and improving ERG patterns in a well-established model of retinal degeneration. (ClinicalTrials.gov numbers NCT00407602, NCT01490827.).

Background: . More than 150 000 neuroprostheses (NPs) have been implanted in people to restore bodily function in a variety of neural disorders. The authors developed a novel NP, the Stimulus Router System (SRS), in which only passive leads are implanted. Each lead picks up a portion of the current delivered through the skin by an external stimulator., Objective: . The authors report on the first human implant of an SRS., Methods: . The recipient was a tetraplegic man with bilateral hand paralysis. Three SRS leads were implanted in his right forearm to activate the finger extensors, finger flexors, and thumb flexor. A wristlet containing a surface stimulator and electrodes was used to pass trains of electrical pulses through the skin to each lead. Hand opening and grasp were controlled via a wireless earpiece that sensed small tooth-clicks and transmitted signals to the wristlet., Results: . The current required to activate the muscles was less than half that required prior to implantation and below perceptual threshold. Maximal grip force and hand opening aperture were both larger using the SRS. The implanted leads have remained functional for 3 years. The recipient reported various tasks of daily life that improved during SRS usage. An electronic counter revealed mean monthly usage of 18.5 hours, equivalent to 55 hours of continuous manual activity., Conclusions: . This first implant of the SRS indicates that it can be effective and reliable and has potential to provide an alternative to existing NPs.

Purpose: To evaluate the tolerance and biocompatibility of a preformed nitinol intraocular clip in an animal model after anterior segment surgery., Methods: Yucatan mini-pigs were used. A 30-gauge prototype injector was used to attach a shape memory nitinol clip to the iris of five pigs. Another five eyes received conventional polypropylene suture with a modified Seipser slip knot. The authors compared the surgical time of each technique. All eyes underwent standard full-field electroretinogram at baseline and 8 weeks after surgery. The animals were euthanized and eyes collected for histologic analysis after 70 days (10 weeks) postsurgery. The corneal thickness, corneal endothelial cell counts, specular microscopy parameters, retina cell counts, and electroretinogram parameters were compared between the groups. A two sample t-test for means and a P value of 0.05 were use for assessing statistical differences between measurements., Results: The injection of the nitinol clip was 15 times faster than conventional suturing. There were no statistical differences between the groups for corneal thickness, endothelial cell counts, specular microscopy parameters, retina cell counts, and electroretinogram measurements., Conclusions: The nitinol clip prototype is well tolerated and showed no evidence of toxicity in the short-term. The injectable delivery system was faster and technically less challenging than conventional suture techniques.

This case report describes the clinical, autofluorescence, and optical coherent tomography findings in a patient with panocular argyrosis secondary to chronic intake of diluted silver nitrate salts in his water supply. An 86-year-old Caucasian male with a distinctive gray-bluish hue of the skin presented to our clinic, having developed a slow decrease in visual acuity in both eyes and nyctalopia for the past 2 years. Based on the patient's history of chronic intake of silver nitrate salts and a positive skin biopsy (performed by the dermatology department, data not shown), a diagnosis of panocular argyrosis was made. Fluorescein angiography showed choroidal blockage with a completely dark choroid. Fundus autofluorescence was within normal limits. Optical coherent tomography showed multiple excrescences of retinal pigment epithelium in both eyes. Although the drusen-like changes on fundus examination and retinal pigment epithelium changes may account for the diminished vision, the presence of concomitant nyctalopia suggests underlying damage of the photoreceptors.

Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes--differentiated epithelial cells crucial for filtration--are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt-β-catenin pathways in podocyte proliferation and disease.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions., (© 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Novel therapies resulting from regenerative medicine and tissue engineering technology may offer new hope for patients with injuries, end-stage organ failure, or other clinical issues. Currently, patients with diseased and injured organs are often treated with transplanted organs. However, there is a shortage of donor organs that is worsening yearly as the population ages and as the number of new cases of organ failure increases. Scientists in the field of regenerative medicine and tissue engineering are now applying the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that can restore and maintain normal function in diseased and injured tissues. In addition, the stem cell field is a rapidly advancing part of regenerative medicine, and new discoveries in this field create new options for this type of therapy. For example, new types of stem cells, such as amniotic fluid and placental stem cells that can circumvent the ethical issues associated with embryonic stem cells, have been discovered. The process of therapeutic cloning and the creation of induced pluripotent cells provide still other potential sources of stem cells for cell-based tissue engineering applications. Although stem cells are still in the research phase, some therapies arising from tissue engineering endeavors that make use of autologous, adult cells have already entered the clinical setting, indicating that regenerative medicine holds much promise for the future.

Mole fraction and temperature studies of halogen bonding between 1-iodo-perfluorobutane, 1-iodo-perfluorohexane, or 2-iodo-perfluoropropane and pyridine were performed using noisy light-based coherent anti-Stokes Raman scattering (I((2)) CARS) spectroscopy. The ring breathing mode of pyridine both is highly sensitive to halogen bonding and provides a strong I((2)) CARS signal. As the lone pair electrons from the pyridinyl nitrogen interact with the sigma-hole on the iodine from the iodo-perfluoroalkane, the ring breathing mode of pyridine blue-shifts proportionately with the strength of the interaction. The measured blue shift for halogen bonding of pyridine and all three iodo-perfluoroalkanes is comparable to that for hydrogen bonding between pyridine and water. 2-Iodo-perfluoropropane displays thermodynamic behavior that is different from that of the 1-iodo-perfluoroalkanes, which suggests a fundamental difference at the molecular level. A potential explanation of this difference is offered and discussed.

Background: There are many methods available for coverage of both the volar and dorsal hand surfaces in traumatic injury. All of these surgical procedures allow for ample coverage of the defect, but have the major drawback of needing multiple donor sites. In the present report, a case of a complex crush injury to the hand in which both volar and dorsal surfaces received traumatic injury is presented. A bilobed groin flap pedicled on the superficial circumflex iliac artery was fashioned to cover the entire defect. Like many other described flaps, the bilobed groin flap resulted in a favourable functional and cosmetic result for the patient, but with the unique advantage of requiring a single donor site., Methods: A bipedicled groin flap was raised from distal to proximal, and the flaps inset onto both the dorsal and volar hand defects., Results: The patient regained adequate function of his hand, and was able to return to work full-time as a manual labourer., Conclusion: The bilobed groin flap appears to be a valuable option for covering complex hand injuries involving both the volar and dorsal surfaces of the hand.

Purpose: To investigate the efficacy of intravitreal triamcinolone as treatment for macular oedema in central retinal vein occlusion (CRVO)., Methods: We conducted a retrospective comparative case series of nine patients with macular oedema associated with CRVO (six non-ischaemic and three ischaemic) treated with an intravitreal injection of 4 mg triamcinolone acetonide, compared with 10 control (observation) patients (six non-ischaemic and four ischaemic). Examination included visual acuity (VA) tests and complete ophthalmic examinations at baseline, 1, 2 and 6 months postoperatively., Results: The mean baseline VA was 20/161 for CRVO treatment group patients and 20/75 for observation group patients (p = 0.15). No significant difference in VA between CRVO treatment group patients (20/99) and controls (20/282) was observed at the final 6-month visit (p = 0.33). Subgroup analysis of the non-ischaemic CRVO treatment patients compared with the non-ischaemic controls also showed no significant difference at the 6-month visit (20/59 and 20/100, respectively; p = 0.20). At 6 months, five of the six non-ischaemic treated patients had VA >or= 20/100, compared with five of the six non-ischaemic control patients. All patients tolerated the procedure well, but there was a significant increase in intraocular pressure by the 2-month visit (p = 0.015)., Conclusions: Intravitreal injection of triamcinolone may not be effective for treatment of macular oedema in all CRVO patients or all non-ischaemic CRVO patients. A trend towards VA improvement was noted but was not statistically significant. Although our treatment was not hindered by severe complications, there was a significant increase in IOP in the 2 months following treatment.

The role of antibody-mediated rejection (AMR) in pancreas transplantation is poorly understood. Here, we report on a patient who developed AMR of his pancreas allograft after receiving a simultaneous pancreas-kidney transplant. Pre-operative enhanced cytotoxicity and flow cytometry T-cell crossmatches were negative; B-cell crossmatches were not performed as per institutional protocol. The patient's post-operative course was significant for elevated serum amylase levels and development of hyperglycemia approximately 1 month after transplantation. A pancreatic biopsy at this time showed no cellular infiltrate but strong immunofluorescent staining for C4d in the interacinar capillaries. Analysis of the patient's serum identified donor-specific HLA-DR alloantibodies. He received intravenous immunoglobulin (IVIg), rituximab and plasmapheresis, and his pancreatic function normalized. We conclude that clinically significant AMR can develop in a pancreas allograft and recommend that pancreatic biopsies be assessed for C4d deposition if the patient has risk factors for AMR and/or the pathologic evidence for cell-mediated rejection is underwhelming.

Aims/hypothesis: In several other models of chronic renal disease, decreases in renal nitric oxide activity and nitric oxide synthase (NOS) protein abundance have been demonstrated. Here, we studied diabetic obese Zucker (ZDF Gmi fa/fa) rats that develop severe hyperglycaemia and renal disease, together with their lean control animals, to determine if renal nitric oxide deficiency also occurs in this model., Methods: Obese Zucker rats aged 10 to 12 weeks were maintained on Purina 5008 diet until 4, 8, or 11 months of age and compared with similarly maintained, 4- and 11-month-old lean Zucker rats. NOS activity and abundance of endothelial NOS (eNOS) and neuronal NOS (nNOS) were measured on homogenates of kidney cortex. Blood was analysed for glucose, lipids, creatinine, and blood urea nitrogen and kidney tissue was obtained for histology., Results: Obese rats exhibited severe hyperglycaemia from 4 months of age and developed increasing hyperlipidaemia, proteinuria, and decreasing renal function with age compared to lean counterparts. At 4 months cortical NOS activity and nNOS abundance were lower in obese rats than in lean ones. At 11 months NOS activity remained depressed and nNOS abundance had declined further in obese rats. Glomerulosclerosis in the obese rats was mild at 4 months, becoming severe by 11 months. Lean rats had only mild age-dependent increases in glomerular injury., Conclusions/interpretation: The chronic renal disease that occurs in hyperglycaemic, obese Zucker rats is associated with decreased renal cortical nitric oxide production and increasing renal injury, although the changes do not resemble those of diabetic nephropathy in man.

Background: Relatively few U.S.-based studies in chronic kidney disease have focused on Asian/Pacific Islanders. Clinical reports suggest that Asian/Pacific Islanders are more likely to be affected by IgA nephropathy (IgAN), and that the severity of disease is increased in these populations., Methods: To explore whether these observations are borne out in a multi-ethnic, tertiary care renal pathology practice, we examined clinical and pathologic data on 298 patients with primary glomerular lesions (IgAN, focal segmental glomerulosclerosis, membranous nephropathy and minimal change disease) at the University of California San Francisco Medical Center from November 1994 through May 2001. Pathologic assessment of native kidney biopsies with IgAN was conducted using Haas' classification system., Results: Among individuals with IgAN (N = 149), 89 (60%) were male, 57 (38%) white, 53 (36%) Asian/Pacific Islander, 29 (19%) Hispanic, 4 (3%) African American and 6 (4%) were of other or unknown ethnicity. The mean age was 37 +/- 14 years and median serum creatinine 1.7 mg/dL. Sixty-six patients (44%) exhibited nephrotic range proteinuria at the time of kidney biopsy. The distributions of age, gender, mean serum creatinine, and presence or absence of nephrotic proteinuria and/or hypertension at the time of kidney biopsy were not significantly different among white, Hispanic, and Asian/Pacific Islander groups. Of the 124 native kidney biopsies with IgAN, 10 (8%) cases were classified into Haas subclass I, 12 (10%) subclass II, 23 (18%) subclass III, 30 (25%) subclass IV, and 49 (40%) subclass V. The distribution of Haas subclass did not differ significantly by race/ethnicity. In comparison, among the random sample of patients with non-IgAN glomerular lesions (N = 149), 77 (52%) patients were male, 51 (34%) white, 42 (28%) Asian/Pacific Islander, 25 (17%) Hispanic, and 30 (20%) were African American., Conclusions: With the caveats of referral and biopsy biases, the race/ethnicity distribution of IgAN differs significantly from that of other major glomerulonephridities. However, among individuals undergoing native kidney biopsy, we see no evidence of a race/ethnicity association with severity of disease in IgAN by clinical and IgAN-specific histopathologic criteria. Further studies are needed to identify populations at higher risk for progressive disease in IgAN.

To better understand the contributions of various genetic backgrounds to complex quantitative phenotypes, we have measured several quantitative traits of cardiovascular interest [i.e., systolic blood pressure, weight (corrected by body weight) of several cardiac compartments and adrenals and kidneys, and histological correlates for kidneys and adrenals] in male and female mice from 13 different inbred strains. We selected strains so that each major genealogical group would be represented and to conform to priorities set by the Mouse Phenome Database project. Interstrain comparisons of phenotypes made it possible to identify strains that displayed values that belonged to either the low or the high end of the interstrain variance for quantitative traits, such as systolic blood pressure, body weight, left ventricular weight, and/or adrenocortical structure. For instance, both male and female C3H/HeJ and A/J mice displayed either low systolic blood pressure or low cardiac ventricular mass, respectively, and male C57BL6/J displayed low adrenal weight. Likewise, intersex comparisons made it possible to identify phenotypic values that were sexually dimorphic for some of the same traits. For instance, female AKR/J mice had relatively higher body weight and systolic blood pressure values than their male counterparts, perhaps constituting an animal model of the metabolic X syndrome. These strain- and sex-specific features will be of value both for future genetic and/or developmental studies and for the development of new animal models that will help in the generation of mechanistic hypotheses. All data have been deposited to the Mouse Phenome Database for future integration with the Mouse Genome Database and can be further analyzed and compared with tools available on the site.

The Wistar-Furth (WF) rat is protected against chronic renal disease (CRD) following 5/6th ablation/infarction vs. the Sprague-Dawley (SD) rat, and protection was associated with preserved renal nitric oxide (NO) production. This study examined CRD induced with repeated administration of puromycin aminonucleoside (PAN). SD PAN developed nephrotic range proteinuria (>1 g/24 h), and at 15 wk severe renal injury developed and the glomerular filtration rate (GFR) was reduced to approximately 10% of sham. Total NO production, renal NO synthase (NOS) activity, and renal neuronal (n) and medullary endothelial (e)NOS abundance were reduced in the SD PAN. WF PAN exhibited less severe initial proteinuria (>400 mg/24 h), which abated within weeks, whereas GFR was normal and injury was minimal at 15 wk. Total NO production and renal NOS activity and abundance were significantly elevated compared with SD PAN. NOS mRNA (nNOS, eNOS, and inducible NOS) was not altered in WF, whereas SD showed significant increases in NOS gene expression with PAN. In conclusion, WF showed resistance to a second model of CRD with maintained renal NOS activity compared with SD.