The Relevance of Advanced Therapy Medicinal Products in the Field of Transplantation and the Need for Academic Research Access: Overcoming Bottlenecks and Claiming a New Time.

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research.

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy.

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Development and Application of a Semi quantitative Scoring Method for Ultrastructural Assessment of Acute Stress in Pancreatic Islets.

BACKGROUND: Pancreas and islet transplantation outcomes are negatively impacted by injury to the endocrine cells from acute stress during donor death, organ procurement, processing, and transplant procedures. Here, we report a novel electron microscopy scoring system, the Newcastle Pancreas Endocrine Stress Score (NPESS). METHODS: NPESS was adapted and expanded from our previously validated method for scoring pancreatic exocrine acinar cells, yielding a 4-point scale (0-3) classifying ultrastructural pathology in endocrine cell nuclei, mitochondria, endoplasmic reticulum, cytoplasmic vacuolization, and secretory granule depletion, with a maximum additive score of 15. We applied NPESS in a cohort of deceased organ donors after brainstem (DBD) and circulatory (DCD) death with a wide range of cold ischemic times (3.6-35.9 h) including 3 donors with type 1 and 3 with type 2 diabetes to assess islets in situ (n = 30) in addition to pancreata (n = 3) pre- and postislet isolation. RESULTS: In DBD pancreata, NPESS correlated with cold ischemic time (head: r = 0.55; P = 0.02) and mirrored exocrine score (r = 0.48; P = 0.01). When stratified by endocrine phenotype, cells with granules of heterogeneous morphology had higher scores than α, ß, and δ cells (P < 0.0001). Cells of mixed endocrine-exocrine morphology were observed in association with increased NPESS (P = 0.02). Islet isolation was associated with improved NPESS (in situ: 8.39 ± 0.77 [Mean ± SD]; postisolation: 5.44 ± 0.31; P = 0.04). CONCLUSIONS: NPESS provides a robust method for semiquantitative scoring of subcellular ultrastructural changes in human pancreatic endocrine cells in situ and following islet isolation with utility for unbiased evaluation of acute stress in organ transplantation research.

Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation.

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC® ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1ß (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.

Development and validation of a quantitative electron microscopy score to assess acute cellular stress in the human exocrine pancreas.

The pancreas is particularly sensitive to acute cellular stress, but this has been difficult to evaluate using light microscopy. Pancreatic ischaemia associated with deceased organ donation negatively impacts whole-organ and isolated-islet transplantation outcomes. Post-mortem changes have also hampered accurate interpretation of ante-mortem pancreatic pathology. A rigorous histological scoring system accurately quantifying ischaemia is required to experimentally evaluate innovations in organ preservation and to increase rigour in clinical/research evaluation of underlying pancreatic pathology. We developed and validated an unbiased electron microscopy (EM) score of acute pancreatic exocrine cellular stress in deceased organ donor cohorts (development [n = 28] and validation [n = 16]). Standardised assessment led to clearly described numerical scores (0-3) for nuclear, mitochondrial and endoplasmic reticulum (ER) morphology and intracellular vacuolisation; with a maximum (worst) aggregate total score of 12. In the Validation cohort, a trend towards higher scores was observed for tail versus head regions (nucleus score following donation after brainstem death [DBD]: head 0.67 ± 0.19; tail 0.86 ± 0.11; p = 0.027) and donation after circulatory death (DCD) versus DBD (mitochondrial score: DCD (head + tail) 2.59 ± 0.16; DBD (head + tail) 2.38 ± 0.21; p = 0.004). Significant mitochondrial changes were seen ubiquitously even with short cold ischaemia, whereas nuclear and vacuolisation changes remained mild even after prolonged ischaemia. ER score correlated with cold ischaemia time (CIT) following DBD (pancreatic tail region: r = 0.796; p = 0.018). No relationships between CIT and EM scores were observed following DCD. In conclusion, we have developed and validated a novel EM score providing standardised quantitative assessment of subcellular ultrastructural morphology in pancreatic acinar cells. This provides a robust novel tool for gold standard measurement of acute cellular stress in studies evaluating surrogate measures of peri-transplant ischaemia, organ preservation technologies and in samples obtained for detailed pathological examination of underlying pancreatic pathology.

Normothermic machine perfusion of donor-lungs ex-vivo: promoting clinical adoption.

PURPOSE OF REVIEW: Lung transplantation offers the only realistic therapeutic option for patients with end-stage lung disease. However, this is impacted by a shortfall in availability of suitable donor-lungs. Normothermic machine perfusion of donor-lungs outside the donor body also known as ex-vivo lung perfusion (EVLP) offers a potential solution through objective assessment, reconditioning and treatment of donor-lungs initially deemed unsuitable for use. This review discusses key advances and challenges in the wider clinical adoption of this technology. RECENT FINDINGS: This review will summarize key research within the following areas: recent clinical trials utilizing EVLP, logistical challenges, EVLP protocol innovations, novel assessment methods and current research into therapeutic modulation of lung function during EVLP. SUMMARY: Normothermic machine perfusion of donor-lungs ex-vivo offers a promising platform to assess and modulate donor-lung quality prior to transplantation. Consensus on how and when to best utilize EVLP is yet to be reached, meaning that widespread clinical adoption of the technology has not yet become a reality. Further work is needed on agreed indications, perfusion protocols and organization of services before becoming a regularly used procedure prior to lung transplantation.

Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling.

BACKGROUND: All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS. METHODS: Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of ß-cell function and RNA sequencing to elucidate transcriptomic changes. RESULTS: Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability. CONCLUSIONS: These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved ß cell function.

Temperature profiles of different cooling methods in porcine pancreas procurement.

Porcine islet xenotransplantation is a promising alternative to human islet allotransplantation. Porcine pancreas cooling needs to be optimized to reduce the warm ischemia time (WIT) following donation after cardiac death, which is associated with poorer islet isolation outcomes. This study examines the effect of four different cooling Methods on core porcine pancreas temperature (n = 24) and histopathology (n = 16). All Methods involved surface cooling with crushed ice and chilled irrigation. Method A, which is the standard for porcine pancreas procurement, used only surface cooling. Method B involved an intravascular flush with cold solution through the pancreas arterial system. Method C involved an intraductal infusion with cold solution through the major pancreatic duct, and Method D combined all three cooling Methods. Surface cooling alone (Method A) gradually decreased core pancreas temperature to <10 °C after 30 min. Using an intravascular flush (Method B) improved cooling during the entire duration of procurement, but incorporating an intraductal infusion (Method C) rapidly reduced core temperature 15-20 °C within the first 2 min of cooling. Combining all methods (Method D) was the most effective at rapidly reducing temperature and providing sustained cooling throughout the duration of procurement, although the recorded WIT was not different between Methods (P = 0.36). Histological scores were different between the cooling Methods (P = 0.02) and the worst with Method A. There were differences in histological scores between Methods A and C (P = 0.02) and Methods A and D (P = 0.02), but not between Methods C and D (P = 0.95), which may highlight the importance of early cooling using an intraductal infusion. In conclusion, surface cooling alone cannot rapidly cool large (porcine or human) pancreata. Additional cooling with an intravascular flush and intraductal infusion results in improved core porcine pancreas temperature profiles during procurement and histopathology scores. These data may also have implications on human pancreas procurement as use of an intraductal infusion is not common practice.

Magnetic resonance imaging: a tool to monitor and optimize enzyme distribution during porcine pancreas distention for islet isolation.

Porcine islet xenotransplantation is emerging as a potential alternative for allogeneic clinical islet transplantation. Optimization of porcine islet isolation in terms of yield and quality is critical for the success and cost-effectiveness of this approach. Incomplete pancreas distention and inhomogeneous enzyme distribution have been identified as key factors for limiting viable islet yield per porcine pancreas. The aim of this study was to explore the utility of magnetic resonance imaging (MRI) as a tool to investigate the homogeneity of enzyme delivery in porcine pancreata. Traditional and novel methods for enzyme delivery aimed at optimizing enzyme distribution were examined. Pancreata were procured from Landrace pigs via en bloc viscerectomy. The main pancreatic duct was then cannulated with an 18-g winged catheter and MRI performed at 1.5-T. Images were collected before and after ductal infusion of chilled MRI contrast agent (gadolinium) in physiological saline. Regions of the distal aspect of the splenic lobe and portions of the connecting lobe and bridge exhibited reduced delivery of solution when traditional methods of distention were utilized. Use of alternative methods of delivery (such as selective re-cannulation and distention of identified problem regions) resolved these issues, and MRI was successfully utilized as a guide and assessment tool for improved delivery. Current methods of porcine pancreas distention do not consistently deliver enzyme uniformly or adequately to all regions of the pancreas. Novel methods of enzyme delivery should be investigated and implemented for improved enzyme distribution. MRI serves as a valuable tool to visualize and evaluate the efficacy of current and prospective methods of pancreas distention and enzyme delivery.

Persufflation (gaseous oxygen perfusion) as a method of heart preservation.

Persufflation (PSF; gaseous oxygen perfusion) is an organ preservation technique with a potential for use in donor heart preservation. Improved heart preservation with PSF may improve outcomes by maintaining cardiac tissue quality in the setting of longer cold ischemia times and possibly increasing the number of donor hearts available for allotransplant. Published data suggests that PSF is able to extend the cold storage times for porcine hearts up to 14 hours without compromising viability and function, and has been shown to resuscitate porcine hearts following donation after cardiac death. This review summarizes key published work on heart PSF, including prospective implications and future directions for PSF in heart transplantation. We emphasize the potential impact of extending preservation times and expanding donor selection criteria in heart allotransplant. Additionally, the key issues that need to be addressed before PSF were to become a widely utilized preservation strategy prior to clinical heart transplantation are summarized and discussed.

Practical community photoscreening in very young children.

OBJECTIVE: Recent US Preventive Services Task Force recommendations on vision screening reported insufficient data to recommend vision screening in children <3 years of age. The Iowa photoscreening program, KidSight, has screened children from 6 months of age and older since 2000. We report our experience with vision screening in these children and compare the results of the photoscreens in children younger than 3 years with those of children of preschool age and older. METHODS: A retrospective review of results from the Iowa KidSight database using the MTI PhotoScreener containing results of children screened between May 1, 2000, and April 30, 2011. RESULTS: During the 11 years of the study, 210 695 photoscreens on children were performed at 13 750 sites. In the <3-year age group, the unreadable rate was 13.0%, the referral rate was 3.3%, and the overall positive-predictive value was 86.6%. In the 3- to 6-year-old children, the unreadable rate was 4.1%, the referral rate was 4.7%, and the overall positive-predictive value was 89.4%. CONCLUSIONS: No statistically significant difference was found in screening children from 1 to 3 years old compared with screening children >3 years old. These results confirm that early screening, before amblyopia is more pronounced, can reliably detect amblyogenic risk factors in children younger than 3 years of age, and we recommend initiation of photoscreening in children aged 1 year and older.

Supplements in human islet culture: human serum albumin is inferior to fetal bovine serum.

Culture of human islets before clinical transplantation or distribution for research purposes is standard practice. At the time the Edmonton protocol was introduced, clinical islet manufacturing did not include culture, and human serum albumin (HSA), instead of fetal bovine serum (FBS), was used during other steps of the process to avoid the introduction of xenogeneic material. When culture was subsequently introduced, HSA was also used for medium supplementation instead of FBS, which was typically used for research islet culture. The use of HSA as culture supplement was not evaluated before this implementation. We performed a retrospective analysis of 103 high-purity islet preparations (76 research preparations, all with FBS culture supplementation, and 27 clinical preparations, all with HSA supplementation) for oxygen consumption rate per DNA content (OCR/DNA; a measure of viability) and diabetes reversal rate in diabetic nude mice (a measure of potency). After 2-day culture, research preparations exhibited an average OCR/DNA 51% higher (p < 0.001) and an average diabetes reversal rate 54% higher (p < 0.05) than clinical preparations, despite 87% of the research islet preparations having been derived from research-grade pancreata that are considered of lower quality. In a prospective paired study on islets from eight research preparations, OCR/DNA was, on average, 27% higher with FBS supplementation than that with HSA supplementation (p < 0.05). We conclude that the quality of clinical islet preparations can be improved when culture is performed in media supplemented with serum instead of albumin.

Energetic recovery in porcine grafts by minimally invasive liver oxygenation.

BACKGROUND: Gaseous insufflation of oxygen via the venous vascular system has proven to be an effective tool for preventing anoxic tissue injury after extended time periods of ischemic liver preservation. Most experimental studies so far have been undertaken in rat models and include a series of pinpricks into postsinusoidal venules as an outlet for the insufflated gas. Here, we describe a simplified technique for minimally invasive liver oxygenation in porcine grafts, representing a hassle-free access to organ oxygenation without vascular lesions. METHODS: We retrieved livers from Landrace pigs and cold-stored them in histidine-tryptophan-ketoglutarate solution. Subsequent to 18 h preservation, we treated some livers for an additional 2 h with gaseous oxygen, insufflated via silicone tubing inserted into the suprahepatic caval vein. Gas pressure was limited to 18 mm Hg. We occluded the infrahepatic caval vein with a bulldog clamp. Gas bubbles left the graft via the portal vein. We assessed liver integrity by energetic tissue status and by controlled in vitro reperfusion with autologous blood. RESULTS: Magnetic resonance imaging demonstrated homogeneous gas distribution in the persufflated tissue without major shunting. Biochemical analyses revealed effective and homogeneous restoration of energetic homeostasis in the ischemic graft before reperfusion. Sinusoidal endothelial clearance of hyaluronic acid was significantly improved upon reperfusion, as was hepatic arterial flow. Parenchymal enzyme loss was concordantly mitigated after minimally invasive liver oxygenation. CONCLUSIONS: Our results indicate that gaseous oxygen persufflation of the porcine liver is possible without tissue trauma, and significantly enhances post-preservation recovery of the graft.

Persufflation (or gaseous oxygen perfusion) as a method of organ preservation.

Improved preservation techniques have the potential to improve transplant outcomes by better maintaining donor organ quality and by making more organs available for allotransplantation. Persufflation, (PSF, gaseous oxygen perfusion) is potentially one such technique that has been studied for over a century in a variety of tissues, but has yet to gain wide acceptance for a number of reasons. A principal barrier is the perception that ex vivo PSF will cause in vivo embolization post-transplant. This review summarizes the extensive published work on heart, liver, kidney, small intestine and pancreas PSF, discusses the differences between anterograde and retrograde PSF, and between PSF and other conventional methods of organ preservation (static cold storage, hypothermic machine perfusion). Prospective implications of PSF within the broader field of organ transplantation, and in the specific application with pancreatic islet isolation and transplant are also discussed. Finally, key issues that need to be addressed before PSF becomes a more widely utilized preservation strategy are summarized and discussed.

Nine-year results of a volunteer lay network photoscreening program of 147 809 children using a photoscreener in Iowa.

PURPOSE: To present the largest cohort of preschool children screened by the MTI PhotoScreener over a 9-year period from a single, statewide vision screening effort. DESIGN: Cross-sectional study. PARTICIPANTS: We included 147,809 children screened between May 1, 2000, and April 30, 2009 by a photoscreening program. METHODS: Retrospective review of results from the Iowa photoscreening program using the MTI PhotoScreener. The photographs were taken by volunteers from local Lions clubs and sent to the University of Iowa for interpretation. Children who failed the photoscreening were referred to local eye care professionals, who preformed a comprehensive eye evaluation and forwarded the results to the Iowa KidSight program. MAIN OUTCOME MEASURES: Number of screenings, referral rate, positive predictive value (PPV), follow-up rate, and associated costs per year are described. RESULTS: Over the 9 years of the continuously operating program, 147,809 children underwent photoscreens to detect amblyopic risk factors at 9746 sites. Because of abnormal photoscreen results, 6247 children (4.2%) were referred. Of the children, 24.3% were evaluated by local ophthalmologists and 76.7% were seen by local optometrists. Between 2000 and 2009, the follow-up rate ranged from a low of 36.1% to a high of 89.5%, with an overall program follow-up rate after the addition of the follow-up coordinator of 81.3%. The overall PPV of the MTI PhotoScreener was 94.2%. Taking into account overall operating budget including salaries and associated costs, the cost of screening 1 child has been reduced to $US9 per child. CONCLUSIONS: The addition of a part-time follow-up coordinator to the photoscreening program produced 89.5% follow-up rate when screening 147,809 children for amblyopia risk factors over a 9-year period.

Pig pancreas anatomy: implications for pancreas procurement, preservation, and islet isolation.

BACKGROUND: Islet transplantation is emerging as a treatment option for selected patients with type 1 diabetes. The limited human islet supply from cadavers and poor islet yield and quality remain substantial impediments to progress in the field. Use of porcine islets holds great promise for large-scale application of islet transplantation. Consistent isolation of porcine islets is dependent on advances in pancreas procurement, pancreas preservation, and islet isolation, requiring detailed knowledge of the porcine pancreatic anatomy. The primary aim of this study was to describe the vascular and ductal anatomy of the porcine pancreas to guide and improve organ preservation and enzyme perfusion. METHODS: Pancreata were removed by en bloc viscerectomy from 65 female Landrace pigs. RESULTS: Fifteen percentage of organs exhibited inconsistent vascular branching from the celiac trunk. All organs showed uniform patterns of branching at the superior mesenteric artery. The superior and inferior mesenteric veins merged to become the portal vein in all but one case in which the inferior mesenteric vein drained into the splenic vein. Ninety-seven percent of pancreata had three lobes: duodenal lobe (DL), connecting lobe (CL), and splenic lobe (SL); 39% demonstrated ductal communication between the CL and the other two lobes; 50% had ductal communication only between the CL and duodenal lobe; and 11% presented other types of ductal delineation. CONCLUSIONS: Accounting for the variations in vascular and ductal anatomy, as detailed in this study, will facilitate development of protocols for preservation, optimal enzyme administration, and pancreas distention and digestion, and will ultimately lead to substantial improvements in isolation outcomes.

Transient acid exposure increases sevelamer HCl phosphate binding.

The patient-to-patient variability in the dosing of sevelamer HCl for phosphate control led us to test whether the binder's transient exposure to acidic environments (such as the stomach) might alter the compound so as to change its subsequent binding capacity in the more alkaline small intestine. We hypothesized that an acid milieu could either increase the reactive sites (protonated amine groups) or make the polymer more hydrophilic (hydration and swelling allowing more phosphate to reach those sites). Eight hundred milligrams of Renagel tablets were exposed to pHs 1, 2.3, and 7 (n = 7 each acidity level) for 1 h. NaCl was added to keep ionic strength the same. Measured by atomic emission phosphate uptake after 3 h at pH 7 was, respectively, 3.13 +/- 0.21, 2.72 +/- 0.35, and 1.85 +/- 0.46 mequiv./g (p = 0.0006, pH 1 vs. pH 7). Semi-automated computerized image analysis was then performed to measure swelling of the particles. We constructed a glass continuous-flow cell that allowed stationary particles and real-time photography. Using digitized optical measurements there was no difference (p > 0.8) between the swelling after 1 h of pH 1 or 7 solutions (60.2 +/- 14.8% vs. 59.5 +/- 9.8% increase in diameter). Our findings support the importance of transient acid exposure in enhancing phosphate binding, due to increased protonated sites rather than by more swelling. Patients with acquired or pharmacologic achlorhydria would not benefit from this unexpected in vivo reaction. Possibly manufacturing sevelamer with a higher degree of protonation or administering it with appropriately acidic vehicles or beverages remains to be investigated.

Recurrence of amblyopia after occlusion therapy.

PURPOSE: To determine the stability of visual acuity (VA) after a standardized occlusion regimen in children with strabismic and/or anisometropic amblyopia. DESIGN: Retrospective, population-based, consecutive observational case series. PARTICIPANTS: Four hundred forty-nine patients younger than 10 years who underwent an occlusion trial for amblyopia and were observed until there was a recurrence of amblyopia or for a maximum of 1 year after decrease or cessation of occlusion therapy. METHODS: We performed a retrospective chart review of all patients treated by occlusion therapy for strabismic and/or anisometropic amblyopia at our institution over a 34-year period. Of the 1621 patients identified in our database, 449 met the eligibility criteria and were included in this study. Patients having at least a 2 logarithm of the minimum angle of resolution (logMAR)-level improvement in VA by optotypes or a change from unmaintained to maintained fixation preference during the course of occlusion therapy were included. A recurrence of amblyopia was defined as > or =2 logMAR levels of VA reduction or reversal of fixation preference within 1 year after a decrease or cessation of occlusion therapy. MAIN OUTCOME MEASURE: Recurrence of amblyopia after a decrease or cessation of occlusion therapy and its relationship with patient age and VA of the amblyopic eye at the time of decrease or cessation of occlusion therapy. RESULTS: Of 653 occlusion trials, 179 (27%) resulted in recurrence of amblyopia. The recurrence was found to be inversely correlated with patient age. There was no statistically significant association between the recurrence of amblyopia and VA of the amblyopic eye at the end of maximal occlusion therapy. CONCLUSIONS: There is a clinically important risk of amblyopia recurrence when occlusion therapy is decreased before the age of 10 years. The risk of recurrence is inversely correlated with age (P<0.0001).

Lions Clubs International Foundation Core Four Photoscreening: results from 17 programs and 400,000 preschool children.

INTRODUCTION: Photoscreening programs for preschool vision screening have been promoted by Lions Clubs International Foundation (LCIF) via their 17 Core Four grant project awards since 1999. Results from 15 Core Four grant programs in the United States and one in Taiwan are presented here. METHODS: Photoscreening was modeled after the Tennessee program and instituted statewide in each area. Programs were given latitude with respect to screening instrument and referral criteria, but a partnering academic institution and medical director were expected. Preschool children were screened by volunteers; referred children were examined by community optometrists and ophthalmologists who returned results to each program's coordinating center. Outcome data included number of children screened, referral rate, follow-up rate, and positive predictive value, which was generally determined using AAPOS-defined vision screening criteria. RESULTS: All but one program used the MTI photoscreener (it chose not to participate); photoscreening referral criteria were standard for 13 programs. Through December 2004, more than 400,000 preschool children had been screened. The referral rate for programs using the MTI photoscreener averaged 5.2% (range, 3.7-12.6%). The predictive value of a positive photoscreen was 80%. Overall, 54% of referred children received follow-up examinations. Follow-up rate was the largest variable: 4 programs, screening nearly 250,000 children, had follow-up rates 70% or greater; 10 programs had follow-up data from fewer than 40% of referred children. CONCLUSIONS: Volunteer-led photoscreening programs can be instituted in other locations, including overseas, with high levels of effectiveness. Limitations include the possibility of poor success and variable attention to follow-up.