Narrative Review to Meta-Analysis: A Cookbook Approach to Evidence Synthesis in Surgical Research.

Evidence synthesis is a complex approach to research that can consolidate the current understanding of a particular topic from various sources. A design hierarchy based upon reliability is described in detail. Methodology is described explicitly to provide readers with a foundation for performing and understanding published evidence synthesis. Resources that detail access to the comprehensive database are presented and explained. Special care is taken to discuss appraisal of studies prior to analysis.

Polyp characteristics at screening colonoscopy and post-colonoscopy colorectal cancer mortality: a retrospective cohort study.

BACKGROUND AND AIMS: Polyp size and high-grade dysplasia in polyps at screening colonoscopy are considered risk factors for post-colonoscopy colorectal cancer (PCCRC) development and death, which might be averted by surveillance colonoscopy. However, robust evidence backing these risk factors is lacking. We aimed to investigate whether polyp size or dysplasia grade is associated with PCCRC mortality. METHODS: This was a retrospective study including individuals of the Austrian Quality Certificate for Screening Colonoscopy who underwent a colonoscopy between January 2007 and December 2020. We investigated the association of polyp size and dysplasia in polyps with PCCRC mortality according to Cox regression analysis. In addition, whether patients with certain polyp characteristics had similar risk for CRC death compared with the Austrian population was assessed by calculating standardized mortality ratios (SMRs). RESULTS: A total of 316,001 individuals were included. After a median follow-up time of 5.27 years (95% confidence interval [CI], 5.25-5.29), a significant association of polyps 10 to 20 mm (hazard ratio, 4.00; 95% CI, 2.46-6.50; P < .001) as well as high-grade dysplasia (hazard ratio, 6.61; 95% CI, 3.31-13.2; P < .001) with PCCRC death was observed. PCCRC mortality was significantly lower than the expected CRC mortality in the general population in patients with polyps <10 mm and without high-grade dysplasia (SMR, .27; 95% CI, .21-.33; P < .001), which was not observed for patients with polyps ≥10 mm or with high-grade dysplasia (SMR, 2.05; 95% CI, 1.64-2.57; P < .001). CONCLUSIONS: Polyp size ≥10 mm and high-grade dysplasia are associated with PCCRC mortality in screening patients. The data suggest that these patients might benefit most from surveillance colonoscopy.

Comparison of adenoma detection rate and proximal serrated polyp detection rate and their effect on post-colonoscopy colorectal cancer mortality in screening patients.

BACKGROUND: Patients with serrated polyps are at increased risk for post-colonoscopy colorectal cancer (PCCRC); however, evidence for a dedicated serrated polyp detection rate is lacking. The aim of this study was to investigate the association of the proximal serrated polyp detection rate (PSDR) and adenoma detection rate (ADR) with PCCRC death. METHODS: This was a retrospective analysis within the Austrian quality assurance program for screening colonoscopy. Spearman's rank coefficient was calculated for the assessment of association between ADR and PSDR. Whether ADR or PSDR were associated with colorectal cancer mortality was assessed by Cox proportional hazards model. RESULTS: 229/729 screening colonoscopies performed by 308 endoscopists were analyzed. The ADR (hazard ratio [HR] per 1 percentage point increase 0.98, 95 %CI 0.96-0.99) as well as the PSDR (HR per 1 percentage point increase 0.97, 95 %CI 0.94-0.99) were significantly associated with PCCRC death. The correlation coefficient of the ADR and PSDR calculated at every colonoscopy was 0.70 (95 %CI 0.70-0.71), and the corresponding PSDR value for an ADR performance standard of 25 % was 11.1 %. At the end of the study period, 86 endoscopists (27.9 %) reached an ADR of > 25 % and a PSDR of > 11.1 %. CONCLUSIONS: The ADR as well as the PSDR were associated with PCCRC death. Striving for a high PSDR in addition to a high ADR might reduce the risk for PCCRC mortality in patients undergoing screening colonoscopy.

Tibial Component Subsidence in a Total Ankle System Comparing Standard Technique Versus a Hybrid Technique.

Total ankle arthroplasty (TAA) is a viable treatment option for end-stage ankle arthritis. However, implant survivorship remains an important consideration. Concerns regarding early component loosening with the low-profile tibial tray utilized by fourth-generation TAA systems have been raised in the literature. We have previously described our preliminary outcomes of a hybrid technique combining a stemmed intramedullary tibial component with a chamfer-cut talar component for TAA. A retrospective study comparing short-term outcomes of the tibial component between a standard fourth-generation TAA system versus our hybrid technique was performed. 46 patients with a minimum of 1-year follow up were included in the analyses. There were 25 subjects in the standard implant cohort utilizing a low-profile tibial tray, and 21 subjects in the hybrid group utilizing a stemmed intramedullary tibial component. No statistically significant difference between the demographics of each group was found. The rate of tibial component subsidence was 8% (n = 2) in the standard implant group, and 0% (n = 0) in the hybrid group, though this did not meet statistical significance (p = .49). Mean time to subsidence was 6 months, and revision rate due to tibial component subsidence was 2.1% (n = 1). Periprosthetic lucency was present on most recent follow-up radiographs in 32% and 9.5% of ankles in the standard and hybrid groups, respectively (p = .08). Despite prior concerns for tibial component subsidence with the standard fourth-generation system, we demonstrated low rates in both implant groups. Additional studies are needed to further explore factors that may predispose patients to early tibial component subsidence and resulting implant failure.

The very small angle neutron scattering instrument at the National Institute of Standards and Technology.

A description and the performance of the very small angle neutron scattering diffractometer at the National Institute of Standards and Technology are presented. The measurement range of the instrument extends over three decades of momentum transfer q from 2 × 10-4 to 0.7 Å-1. The entire scattering angle range from 8 × 10-5 to π/6 rad (30°) can be measured simultaneously using three separate detector carriages on rails holding nine 2D detector arrays. Versatile choices of collimation options and neutron wavelength selection allow the q resolution and beam intensity to be optimized for the needs of the experiment. High q resolution is achieved using multiple converging-beam collimation with circular pinholes combined with refractive lenses and prisms. Relaxed vertical resolution with much higher beam intensity can be achieved with narrow slit collimation and a broad wavelength range chosen by truncating the moderator source distribution below 4 Šwith a Be crystalline filter and above 8 Šwith a supermirror deflector. Polarized beam measurements with full polarization analysis are also provided by a high-performance supermirror polarizer and spin flipper, capable of producing flipping ratios of over 100, along with a high-efficiency 3He polarization analyzer.

Risk Stratification for Revision Surgery Following Total Ankle Replacement.

As a result of improved implants total ankle replacement (TAR) is becoming a more reliable option for end stage ankle arthritis. As with any surgery there are numerous complications that can occur intraoperatively and postoperatively with TAR. The primary aim of this study is to use recent data on implants currently on the market to develop a well-defined and comprehensive complication classification system which stratifies risk of subsequent surgery for TAR. A systematic review of studies on TARs from 2013 to 2018 was performed. Inclusion criteria were studies published between 2013 and August 2018, studies having at least 20 patients, data with at least 1-year follow-up and use of implants currently on the market. Studies were excluded if they involved revision cases, case reports, basic science articles and studies published in non-peer-reviewed journals. Sixteen studies fit inclusion criteria involving 3,305 implants. Overall survival of all implants was found to be 93% with a pooled complication rate of 75.6% using criteria for classifying complications by Glazebrook et al. Previously published classification systems did not clearly define complication categories leading to inconsistency in complication reporting and inaccurate complication rates. There are also several complications that are unclassifiable with the classifications developed by Gadd et al and Glazebrook et al. Our proposed updated classification system provides more inclusive tier profiles to capture the complications that can occur with implants currently on the market. Furthermore, this system provides a stratification of risk that these complications pose to ultimate procedure success.

Autonomous Surface and Underwater Vehicles as Effective Ecosystem Monitoring and Research Platforms in the Arctic-The Glider Project.

Effective ocean management requires integrated and sustainable ocean observing systems enabling us to map and understand ecosystem properties and the effects of human activities. Autonomous subsurface and surface vehicles, here collectively referred to as "gliders", are part of such ocean observing systems providing high spatiotemporal resolution. In this paper, we present some of the results achieved through the project "Unmanned ocean vehicles, a flexible and cost-efficient offshore monitoring and data management approach-GLIDER". In this project, three autonomous surface and underwater vehicles were deployed along the Lofoten-Vesterålen (LoVe) shelf-slope-oceanic system, in Arctic Norway. The aim of this effort was to test whether gliders equipped with novel sensors could effectively perform ecosystem surveys by recording physical, biogeochemical, and biological data simultaneously. From March to September 2018, a period of high biological activity in the area, the gliders were able to record a set of environmental parameters, including temperature, salinity, and oxygen, map the spatiotemporal distribution of zooplankton, and record cetacean vocalizations and anthropogenic noise. A subset of these parameters was effectively employed in near-real-time data assimilative ocean circulation models, improving their local predictive skills. The results presented here demonstrate that autonomous gliders can be effective long-term, remote, noninvasive ecosystem monitoring and research platforms capable of operating in high-latitude marine ecosystems. Accordingly, these platforms can record high-quality baseline environmental data in areas where extractive activities are planned and provide much-needed information for operational and management purposes.

Mitigating background caused by extraneous scattering in small-angle neutron scattering instrument design.

Measurements, calculations and design ideas to mitigate background caused by extraneous scattering in small-angle neutron scattering (SANS) instruments are presented. Scattering includes processes such as incoherent scattering, inelastic scattering and Bragg diffraction. Three primary sources of this type of background are investigated: the beam stop located in front of the detector, the inside lining of the detector vessel and the environment surrounding the sample. SANS measurements were made where materials with different albedos were placed in all three locations. Additional measurements of the angle-dependent scattering over the angular range of 0.7π-0.95π rad were completed on 16 different shielding materials at five wavelengths. The data were extrapolated to cover scattering angles from π/2 to π rad in order to estimate the materials' albedos. Modifications to existing SANS instruments and sample environments to mitigate extraneous scattering from surfaces are discussed.

Intraosseous Anchorage of a Collagen Matrix Graft to Enhance Repair of Peroneus Brevis Tendon Degeneration.

INTRODUCTION: Chronic degeneration of the peroneus brevis tendon (PBT) at its insertion to the base of the fifth metatarsal is uncommon; however, when present it can be a challenge to treat. Repair of the PBT often requires tubularization with or without a peroneus longus tendon transfer. These repairs, however, may not provide resultant full muscle strength, especially if ostectomy of the fifth metatarsal base is required. We report outcomes following a novel technique for anatomic repair of degenerative PBT with intraosseous fifth metatarsal base fixation of a collagen matrix graft. METHODS: Thirteen consecutive patients (14 procedures) with degeneration of PBT that underwent tendon repair augmented with collagen matrix graft from 2011 to 2019 were reviewed retrospectively. We present outcome data of these 13 patients that were followed for at least 12 months. RESULTS: Muscle strength, complications, and patient-reported subjective outcomes were reported. There were 10 females and 3 males. Average age was 49.1 years, and average follow-up was 34.9 months. Muscle strength was reported at 5/5 to the PBT by the final follow-up for 92% of patients. There were minimal complications, 84.6% (11/13) of patients had no limitation in activity level, and 92% (12/13) would recommend this procedure to a friend. CONCLUSION: Outcomes for this novel repair technique for insertional degenerative PBT have never been reported before and show excellent results with long-term follow-up.

Total Ankle Arthroplasty Survivorship: A Meta-analysis.

The gold standard for management of end-stage ankle arthritis was previously ankle arthrodesis; however, improvements in total ankle replacements are making this a more viable treatment option. The primary aim of this meta-analysis was to evaluate the survivorship of total ankle replacement implants currently in use. An extensive search strategy initially captured 20,842 citations that were evaluated for relevance. Abstract screening produced 97 articles to be read in entirety, of which 10 articles studying 1963 implants met all prospective inclusion criteria for analysis. Overall survivorship of all implants was 93.0% (95% confidence interval, 85.2-96.9) using a random effect model. There was significant heterogeneity between the studies (Q = 131.504). Meta-regression identified an inverse relationship between survivorship and study follow-up duration (p < .0001). Furthermore, age (p = .36) and implant type (fixed-bearing [95.6%, 95% confidence interval, 85.9-98.7] versus mobile-bearing ]89.4%, 95% confidence interval, 79.6%-94.8%]) did not have a statistically significant impact on survivorship, p = .213. However, patients with higher preoperative functional scores had improved survivorship (p = .001). Complications were inconsistently reported with varied definitions. In order of reported frequency, complications were classified into technical error (28.15%), subsidence (16.89%), implant failure (13.28%), aseptic loosening (6.3%), intraoperative fracture (5.67%), wound problems (4.3%), deep infection (1%), and postoperative fracture (0.0001%). Overall study quality was low, with only 10% being prospective and 90% from nonregistry data. The results from this meta-analysis revealed a promising overall survivorship of current implants in use for total ankle replacement; however higher quality studies with standardized outcomes measures are needed.

One-Year Outcome Study of Anatomic Reconstruction of Lesser Metatarsophalangeal Joints.

Background: Lesser metatarsophalangeal joint (MTPJ) and plantar plate pathologies are commonly seen forefoot conditions. Traditional rebalancing techniques are commonly used but can have concerning adverse effects. The purpose of this study was to analyze the 1-year outcomes of a new technique consisting of anatomic repair of the plantar plate and collateral ligaments involving lesser MTPJs. Methodology: A retrospective cohort study of 50 consecutive patients treated with anatomic plantar plate and collateral ligament reconstruction were evaluated for lesser MTPJ imbalances between 2013 and 2016. The primary outcome was postoperative digital stability defined as a normal dorsal drawer test and normal paper pull-out test. Secondary outcomes included pre- and postoperative visual analogue scale pain measurements, MTPJ radiographic alignment, and ACFAS Forefoot module scores. Results: All patients had digital instability prior to the surgical intervention. Final follow-up revealed that 92% of patients showed improved digital stability, P = .0005. Multivariate regression found statistically significant improvement in pain reduction via the visual analogue scale of 51.2 mm (P < .0001) and ACFAS Forefoot module scores improved to 92 (P < .0001). The 45 joints with preoperative abnormal transverse plane deformity, had either complete (n = 29) or partial (n = 16) radiographic MTPJ correction. Conclusion: These results suggest that anatomic repair of lesser MTPJ improved digital stability, pain, function and radiographic alignment with greater than one year of follow-up.Levels of Evidence: Level IV: Retrospective cohort study.

Long-Term Outcomes of Corrective Osteotomies Using Porous Titanium Wedges for Flexible Flatfoot Deformity Correction.

Common corrective osteotomies used in flexible flatfoot deformity reconstruction include Cotton and Evans osteotomies, which require structural graft to maintain correction. Auto-, allo-, and xenografts are associated with a number of limitations, including disease transmission, rejection, donor site morbidity, technical challenges related to graft fashioning, and graft resorption. Porous titanium is a synthetic substance designed to address these flaws; however, few studies have been reported on the efficacy, safety, and long-term outcomes. A multicenter retrospective cohort of 63 consecutive preconfigured porous titanium wedges (PTWs) used in flexible flatfoot reconstructions from June 1, 2009 to June 30, 2015 was evaluated. The primary outcome measure was the pre- to postdeformity correction efficacy. The secondary outcomes included maintenance of correction at a minimum follow-up point of 12 months, complications, graft incorporation, and graft safety profile. Multivariate linear regression found a statistically significant improvement in all radiographic parameters from preoperatively to the final weightbearing radiographs (calcaneocuboid 18.850 ± 4.020 SE, p < .0001; Kite's, 7.810 ± 3.660 SE, p = .04; Meary's 13.910 ± 3.100 SE, p = .0001; calcaneal inclination, 5.550 ± 2.140 SE, p = .015). When restricted to patients with >4 years of follow-up data, maintenance of correction appeared robust in all 4 measurements, demonstrating a lack of bone or graft resorption. No patients were lost to follow-up, no major complications or implant explantation or migration occurred, and all implants were incorporated. Minor complications included hardware pain from plates over grafts (8%), 1 case of scar neuritis, and a 5% table incidence of transfer pain associated with the PTWs. These results support the use of PTWs for safety and degree and maintenance of correction in flatfoot reconstruction.

Anatomic Reconstruction Versus Traditional Rebalancing in Lesser Metatarsophalangeal Joint Reconstruction.

Traditional rebalancing techniques, such as capsulotomies and capsulorrhaphies, are commonly performed during complex hammertoe and lesser metatarsal osteotomy procedures involving metatarsophalangeal joint (MTPJ) contractures; however, floating toes, digital instability, and malalignment are concerns. We critically analyzed the outcomes after anatomic reconstruction of the plantar plate and collateral ligaments compared with those after traditional rebalancing techniques. A case-control study was conducted of 54 patients who had undergone surgical correction of lesser MTPJ imbalances due to complex hammertoe deformities (power 80%, type I error = 0.05). Cases were defined as consecutive patients treated with anatomic plantar plate and collateral ligament reconstruction. Controls had undergone traditional lesser MTPJ rebalancing and were matched to cases by age, gender, follow-up duration (minimum 12 months), and concomitant procedures of the same lesser ray. Multivariate logistic regression demonstrated that patients treated with anatomic reconstruction had greater digital stability (negative dorsal drawer and negative paper pull-out test findings) at final follow-up examination compared with the controls. American College of Foot and Ankle Surgeons (ACFAS) forefoot module scores were greater in the anatomic group in all domains (p ≤ .05). Controls had greater postoperative radiographic MTPJ angles than the cases, with no differences detected between the 2 groups in visual analog scale scores or proximal interphalangeal joint angles. The importance of restoration of the plantar plate and collateral ligament integrity as a digital stabilizer is generally accepted but has not been well studied. We found that anatomic reconstruction yielded greater digital stability, greater ACFAS Forefoot module scores, and better radiographic MTPJ alignment than controls. Additional studies are warranted to assess the long-term viability of anatomic lesser MTPJ reconstruction.

Development and Validation of the Foot Union Scoring Evaluation Tool for Arthrodesis of Foot Structures.

Reliable evaluation of osseous consolidation after pedal arthrodesis can be difficult, and the presence or absence of radiographic healing often dictates care. Plain radiographs remain the mainstay imaging tool owing to their cost, efficiency, and low radiation exposure. Applying radiographic parameters that can reliably determine osseous healing is essential. However, currently, no reliable or validated measures are available to determine osseous union of any joint in the foot or ankle. The purpose of the present study was to develop a radiographic healing scoring system that would enhance the diagnostic healing assessment after joint arthrodesis of the foot or ankle. We adapted several existing scales previously validated for fracture healing in the leg, because no study has attempted to apply this to a joint fusion model. A total of 150 cases were evaluated by 6 blinded assessors to test the interrater reliability of the subjective healing assessment compared with the proposed scoring system. The radiographs were classified by the postoperative period: ≤4 weeks, 5 to 12 weeks, and >12 weeks. The initial proposed scale was found to have high interrater reliability but was burdensome. Using a priori item reduction protocols, a limited 5-item scale further improved the internal consistency and reduced the burden. The result was excellent interrater reliability (α = 0.978, standard deviation 0.02, 95% confidence interval 0.96 to 0.99) among all assessors compared with the reduced reliability (α = 0.752) for subjective arthrodesis healing. Intrarater reliability was also found to be superior using a test-retest method. The reliability of this system appeared superior to the subjective assessment of arthrodesis healing, even in the absence of clinical correlates, after foot arthrodesis.

Radiographic Union Scoring Scale for Determining Consolidation Rates in the Calcaneus.

The reliable evaluation of osseous consolidation after hindfoot osteotomy can be difficult. Concomitant hindfoot osteotomies often dictate the advancement of weightbearing, and radiographs are the mainstay imaging tool owing to cost, efficiency, and radiation exposure. Understanding the radiographic parameters that can be used to reliably determine osseous healing is paramount. However, currently, no reliable or validated method is available to determine osseous healing of hindfoot osteotomies in irregular bones of the foot. The purpose of the present study was to develop a radiographic healing scoring system that would enhance the diagnostic healing assessment after elective calcaneal osteotomy. We adapted existing orthopedic scales validated for healing in the leg for application in the irregular bones of the foot. A total of 168 cases were evaluated by 6 blinded assessors to test the interrater reliability of subjective healing assessment compared with the proposed scoring system. The radiographs were classified by postoperative period: ≤4 weeks, 5 to 12 weeks, and >12 weeks. The proposed scale had high interrater reliability but was burdensome. Using a priori item reduction protocols, a limited 6-item scale further improved internal consistency and reduced the burden. The result was excellent interrater reliability (α = 0.98, standard deviation 0.02, 95% confidence interval 0.91 to 0.96) among all assessors when using the scoring scale compared with unacceptable reliability (α = 0.438) for subjective osteotomy healing. The reliability of our system appeared superior to that of subjective assessment of osseous healing alone, even in the absence of clinical correlates after osteotomy of the calcaneus.

Peropsin modulates transit of vitamin A from retina to retinal pigment epithelium.

Peropsin is a non-visual opsin in both vertebrate and invertebrate species. In mammals, peropsin is present in the apical microvilli of retinal pigment epithelial (RPE) cells. These structures interdigitate with the outer segments of rod and cone photoreceptor cells. RPE cells play critical roles in the maintenance of photoreceptors, including the recycling of visual chromophore for the opsin visual pigments. Here, we sought to identify the function of peropsin in the mouse eye. To this end, we generated mice with a null mutation in the peropsin gene (Rrh). These mice exhibited normal retinal histology, normal morphology of outer segments and RPE cells, and no evidence of photoreceptor degeneration. Biochemically, Rrh-/- mice had ∼2-fold higher vitamin A (all-trans-retinol (all-trans-ROL)) in the neural retina following a photobleach and 5-fold lower retinyl esters in the RPE. This phenotype was similar to those reported in mice that lack interphotoreceptor retinoid-binding protein (IRBP) or cellular retinol-binding protein, suggesting that peropsin plays a role in the movement of all-trans-ROL from photoreceptors to the RPE. We compared the phenotypes in mice lacking both peropsin and IRBP with those of mice lacking peropsin or IRBP alone and found that the retinoid phenotype was similarly severe in each of these knock-out mice. We conclude that peropsin controls all-trans-ROL movement from the retina to the RPE or may regulate all-trans-ROL storage within the RPE. We propose that peropsin affects light-dependent regulation of all-trans-ROL uptake from photoreceptors into RPE cells through an as yet undefined mechanism.

Development of a Radiographic Union Score for Determining Osteotomy Union Rates in Long Bones of the Foot.

Determining the status of bone healing after osteotomy can be challenging and has implications ranging from clinical decision-making to standardization of research outcomes without the use of computed tomography. To date, no method has been validated for determining osseous healing of an osteotomy site of the long bones of the foot. The purpose of the present study was to develop a radiographic union scoring system that would enhance the diagnostic healing assessment. We adapted existing orthopedic scales that had been validated for healing in the leg for application in the long bones of the foot. One hundred cases were evaluated by 6 blinded assessors to test the inter- and intrarater reliability of the subjective healing assessment compared with the proposed scoring system. The radiographs were classified by postoperative period: ≤4, 5 to 12, and >12 weeks. The proposed scale had a high interrater reliability but was burdensome. Using a priori item reduction protocols, the scale was limited to the 5 items with the best internal consistency, which significantly reduced the burden. The result was excellent interrater reliability (α = 0.87) among all assessors compared with acceptable reliability (α = 0.66) for the subjective osteotomy healing assessment. The intrarater reliability during the subsequent retest phase demonstrated similar relationships, with low agreement (r = 0.38) for subjective healing. Each of the items included in the final scoring scale had moderate to good agreement across all assessors (r = 0.51 to 0.63). The reliability of this system appeared superior to the subjective assessment of osseous healing alone, even in the absence of clinical correlates after an osteotomy in the foot.

Healing in the new millennium: bone stimulators: an overview of where we've been and where we may be heading.

Electromagnetic fields and their uses in bone healing have been fairly well studied, with most results showing improvement in healing of both bone and cartilage. Most supportive data are found in relation to the spine, femur, and tibia, but there is increasing evidence for its use in the foot and ankle for treatment of nonunions and as an adjunctive device in arthrodeses, particularly in high-risk populations. There are varying data and a significant variety of quality in the current research and publications concerning the use of electrical bone stimulation in the treatment of the foot and ankle. Thus, there is a definite need for further investigation and high-quality study designs to determine the most effective treatment modalities and pathologies best used with bone stimulation. Bone stimulation should be viewed as an adjunctive procedure in which the surgeon optimizes the high-risk patient both medically or surgically whenever possible. But when used appropriately, bone stimulation has the potential to influence outcomes and aid in bone healing when complications arise and in high-risk populations.

A prospective, multicenter, randomized, controlled clinical trial comparing a bioengineered skin substitute to a human skin allograft.

An estimated 25% of all people with diabetes may experience a foot ulcer in their lifetime, which may lead to serious complications including infection and amputation. A prospective, multicenter, randomized, controlled clinical trial was conducted to compare an in vitro-engineered, human fibroblast-derived dermal skin (HFDS) substitute and a biologically active cryopreserved human skin allograft (HSA) to determine the relative number of diabetic foot ulcers (DFUs) healed (100% epithelialization without any drainage) and the number of grafts required by week 12. Secondary variables included the proportion of healed patients at weeks 16 and 20, time to healing during the study, and wound size progression. The 23 eligible participants (11 randomized to the HSA, 12 to the HFDS group) were recruited from two hospital-based outpatient wound care centers. Baseline patient (body mass index, age, gender, race, type and duration of diabetes, presence of neuropathy and/or peripheral arterial disease, tobacco use) and wound characteristics (size and duration) were recorded, and follow-up visits occurred every week for up to 20 weeks. Descriptive and multivariate regression analyses were used to compare wound outcomes. At baseline, no statistically significant differences between patients and wounds were observed. At week 12, seven (63.6%) patients in the HSA and four (33.3%) in the HFDS group were healed (P = 0.0498). At the end of the 20-week evaluation period, 90.91% of HSA versus 66.67% of HFDS were healed (P = 0.4282). Among the subset of wounds that healed during the first 12 weeks of treatment, an average of 4.36 (range 2-7) HSA grafts were applied versus 8.92 (range 6-12) in the HFDS subset (P <0.0001, SE 0.77584). Time to healing in the HSA group was significantly shorter (8.9 weeks) than in the HFDS group (12.5 weeks) (log-rank test, P = 0.0323). The results of this study are similar to previous outcomes reported using these treatment modalities and suggest that, after 12 weeks of care, DFUs managed with HSA are approximately twice as likely to heal as DFUs managed with HFDS with approximately half the number of grafts required. Research confirming these results with a larger sample size and inpatients with different types of wounds is warranted.

Identification of the 11-cis-specific retinyl-ester synthase in retinal Müller cells as multifunctional O-acyltransferase (MFAT).

Absorption of a photon by a rhodopsin or cone-opsin pigment isomerizes its 11-cis-retinaldehyde (11-cis-RAL) chromophore to all-trans-retinaldehyde (all-trans-RAL), which dissociates after a brief period of activation. Light sensitivity is restored to the resulting apo-opsin when it recombines with another 11-cis-RAL. Conversion of all-trans-RAL to 11-cis-RAL is carried out by an enzyme pathway called the visual cycle in cells of the retinal pigment epithelium. A second visual cycle is present in Müller cells of the retina. The retinol isomerase for this noncanonical pathway is dihydroceramide desaturase (DES1), which catalyzes equilibrium isomerization of retinol. Because 11-cis-retinol (11-cis-ROL) constitutes only a small fraction of total retinols in an equilibrium mixture, a subsequent step involving selective removal of 11-cis-ROL is required to drive synthesis of 11-cis-retinoids for production of visual chromophore. Selective esterification of 11-cis-ROL is one possibility. Crude homogenates of chicken retinas rapidly convert all-trans-ROL to 11-cis-retinyl esters (11-cis-REs) with minimal formation of other retinyl-ester isomers. This enzymatic activity implies the existence of an 11-cis-specific retinyl-ester synthase in Müller cells. Here, we evaluated multifunctional O-acyltransferase (MFAT) as a candidate for this 11-cis-RE-synthase. MFAT exhibited much higher catalytic efficiency as a synthase of 11-cis-REs versus other retinyl-ester isomers. Further, we show that MFAT is expressed in Müller cells. Finally, homogenates of cells coexpressing DES1 and MFAT catalyzed the conversion of all-trans-ROL to 11-cis-RP, similar to what we observed with chicken-retina homogenates. MFAT is therefore an excellent candidate for the retinyl-ester synthase that cooperates with DES1 to drive synthesis of 11-cis-retinoids by mass action.