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Context: Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile -an episignature., Objective: We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing., Methods: Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature., Results: WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3., Conclusions: Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS's in the KDM6A gene., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI., (© 2024. The Author(s).)

Context: Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood., Objective: We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease., Methods: We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children., Results: We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy., Conclusion: We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Predicting the impact of neovascular age-related macular degeneration (nAMD) service disruption on visual outcomes following national lockdown in the UK to contain SARS-CoV-2., Methods and Analysis: This retrospective cohort study includes deidentified data from 2229 UK patients from the INSIGHT Health Data Research digital hub. We forecasted the number of treatment-naïve nAMD patients requiring anti-vascular endothelial growth factor (anti-VEGF) initiation during UK lockdown (16 March 2020 through 31 July 2020) at Moorfields Eye Hospital (MEH) and University Hospitals Birmingham (UHB). Best-measured visual acuity (VA) changes without anti-VEGF therapy were predicted using post hoc analysis of Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD trial sham-control arm data (n=238)., Results: At our centres, 376 patients were predicted to require anti-VEGF initiation during lockdown (MEH: 325; UHB: 51). Without treatment, mean VA was projected to decline after 12 months. The proportion of eyes in the MEH cohort predicted to maintain the key positive visual outcome of ≥70 ETDRS letters (Snellen equivalent 6/12) fell from 25.5% at baseline to 5.8% at 12 months (UHB: 9.8%-7.8%). Similarly, eyes with VA <25 ETDRS letters (6/96) were predicted to increase from 4.3% to 14.2% at MEH (UHB: 5.9%-7.8%) after 12 months without treatment., Conclusions: Here, we demonstrate how combining data from a recently founded national digital health data repository with historical industry-funded clinical trial data can enhance predictive modelling in nAMD. The demonstrated detrimental effects of prolonged treatment delay should incentivise healthcare providers to support nAMD patients accessing care in safe environments., Trial Registration Number: NCT00056836., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function 1 . This silencing is largely controlled by non-coding elements, and their disruption might cause human disease 2 . We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a 'disallowed gene' in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To report the end-of-study results from the Ladder clinical trial of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD)., Design: Multicenter, randomized, active treatment-controlled phase 2 clinical trial., Participants: Patients diagnosed with nAMD with a documented response to anti-vascular endothelial growth factor treatment who received study treatment (N = 220)., Methods: Patients were randomized 3:3:3:2 to treatment with the PDS filled with ranibizumab 10-mg/ml, 40-mg/ml, and 100-mg/ml formulations or monthly intravitreal ranibizumab 0.5-mg injections., Main Outcome Measures: End-of-study results for the time to first meeting refill criteria (first refill), mean change from baseline for best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety., Results: At study end, the mean time on study was 22.1 months (range, 10.8-37.6 months) for all PDS patients. Median time to first refill was 8.7 months, 13.0 months, and 15.8 months, and 28.9%, 56.0%, and 59.4% of patients went 12 months or longer without meeting refill criteria in the PDS 10-mg/ml, 40-mg/ml, and 100-mg/ml treatment arms, respectively. At month 22, the observed mean BCVA change from baseline was ‒4.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒2.3 ETDRS letters, +2.9 ETDRS letters, and +2.7 ETDRS letters in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg treatment arms, respectively. At month 22, the observed mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg treatment arms. No new safety signals were detected during the additional follow-up., Conclusions: Over a mean of 22 months on study, vision and anatomic outcomes were comparable between the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms, with a lower total number of ranibizumab treatments with the PDS. The Ladder end-of-study findings were consistent with the primary analysis, and the PDS generally was well tolerated throughout the entire study period. The PDS has the potential to reduce treatment burden in patients with nAMD while maintaining vision., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the feasibility of capturing and interpreting retinal images in a workplace environment using a multimodal, cloud-based, diabetic retinal screening program combined with electronic self-reported questionnaires. The burden of diabetic retinopathy (DR) and other retinal conditions, healthcare utilization, and visual function were also assessed., Methods: A cross-sectional feasibility study was conducted at the Genentech, Inc., Campus Health Center. Eyes of participants were imaged using ultra-widefield (UWF) color fundus photography (CFP) and spectral-domain optical coherence tomography (SD-OCT). A cloud-based platform was used for the automated, seamless transfer of images to a remote reading center for evaluation for DR and other retinal pathologies. Electronic surveys collected participants' self-reported medical histories, healthcare utilization, and visual function data., Results: Among 100 participants (mean age, 43.9 years; 44% male), 33% of them self-reported diabetes. Eye examinations within the past 12 months were reported by 71% of all participants (n = 71/100) and by 85% (n = 28/33) of those with self-reported diabetes. Among participants with complete screening images from both UWF-CFP and SD-OCT, 20% (n = 6/30) of those with self-reported diabetes and 8.5% (n = 5/59) of participants with no history of diabetes were unaware they had mild/moderate nonproliferative DR. Among all participants, 20% (20/100) had a retinal finding, on either UWF-CFP or SD-OCT, or both, which prompted a referral for further evaluation., Conclusions: A retinal screening program deployed via a secure, scalable, and interoperable cloud-based platform was feasible and conveniently integrated into the workplace., Translational Relevance: Cloud-based platforms could be used to promote a secure, scalable, and interoperable system for retinal screening in nontraditional environments.

This article aims to identify key opportunities for improvement in the diagnosis and treatment of retinal disease, and describe recent innovations that will potentially facilitate improved outcomes with existing intravitreal vascular endothelial growth factor (VEGF) therapies and lay the groundwork for new treatment approaches. The review begins with a summary of the key discoveries that led to the development of anti-VEGF therapies and briefly reviews their impact on clinical practice. Opportunities for improvements in diagnosis, real-world outcomes with existing therapies, long-acting therapeutics and personalised health care are discussed, as well as the need to identify new targets for therapeutic intervention. Low-cost, remote patient screening and monitoring using artificial intelligence (AI)-based technologies can help improve diagnosis rates and enable remote disease monitoring with minimal patient burden. AI-based tools can be applied to generate patient-level prognostic data and predict individual treatment needs, reducing the time needed to optimise a patient's treatment regimen. Long-acting therapeutics can help improve visual outcomes by reducing the treatment burden. When paired with AI-generated prognoses, long-acting therapeutics enable the possibility of vision loss prevention. Dual-acting drugs may help improve efficacy and/or durability beyond what is possible with anti-VEGF agents alone. Recent developments and ongoing innovations will help build upon the success of anti-VEGF therapies to further reduce vision loss owing to retinal disease while lowering the overall burden of care.

Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered., (Copyright © 2020 Nguyen, Vrabel, Mantooth, Hopkins, Wagner, Gabaldon and Zaharoff.)

Purpose: To develop deep learning (DL) models to predict best-corrected visual acuity (BCVA) from optical coherence tomography (OCT) images from patients with neovascular age-related macular degeneration (nAMD)., Methods: Retrospective analysis of OCT images and associated BCVA measurements from the phase 3 HARBOR trial (NCT00891735). DL regression models were developed to predict BCVA at the concurrent visit and 12 months from baseline using OCT images. Binary classification models were developed to predict BCVA of Snellen equivalent of <20/40, <20/60, and ≤20/200 at the concurrent visit and 12 months from baseline., Results: The regression model to predict BCVA at the concurrent visit had R 2 = 0.67 (root-mean-square error [RMSE] = 8.60) in study eyes and R 2 = 0.84 (RMSE = 9.01) in fellow eyes. The best classification model to predict BCVA at the concurrent visit had an area under the receiver operating characteristic curve (AUC) of 0.92 in study eyes and 0.98 in fellow eyes. The regression model to predict BCVA at month 12 using baseline OCT had R 2 = 0.33 (RMSE = 14.16) in study eyes and R 2 = 0.75 (RMSE = 11.27) in fellow eyes. The best classification model to predict BCVA at month 12 had AUC = 0.84 in study eyes and AUC = 0.96 in fellow eyes., Conclusions: DL shows promise in predicting BCVA from OCTs in nAMD. Further research should elucidate the utility of models in clinical settings., Translational Relevance: DL models predicting BCVA could be used to enhance understanding of structure-function relationships and develop more efficient clinical trials., Competing Interests: Disclosure: M.G. Kawczynski, Genentech, Inc. (E); T. Bengtsson, Genentech, Inc. (E); J. Dai, Genentech, Inc. (E); J.J. Hopkins, Genentech, Inc. (E); S.S. Gao, Genentech, Inc. (E); J.R. Willis, Genentech, Inc. (E), (Copyright 2020 The Authors.)

Background: Sarcopenia at time of diagnosis predicts worse survival outcomes. It is currently unknown how changes in muscle mass over time interact with sarcopenia in colorectal patients treated with curative intent. Objectives of this study were to quantify sarcopenia and skeletal muscle loss from time of diagnosis to end of surveillance and determine its effect on survival outcomes after completion of 2 years of surveillance., Methods: Retrospective cohort study of stage I-III colorectal cancer patients from 2007-2009, who underwent resection and had preoperative and 2-year surveillance computed tomography scans, without recurrence during that time. Body composition analysis was done at both time points to determine lumbar skeletal muscle index, radiodensity and adiposity. Change over time was standardized as a percentage per year. Cox proportional hazard regression modeling was used for survival analysis., Results: Of 667 patients included, median survival from surgery was 7.96 years, with 75 recurrences occurring after 2 years. On average patients lost muscle mass (-0.415%/year; CI -0.789, -0.042) and radiodensity (-5.76 HU/year; CI -6.74, -4.80), but gained total adipose tissue (7.06%/year; CI 4.34, 9.79). Patients with sarcopenia at diagnosis (HR 1.80; CI 1.13, 2.85) or muscle loss over time (HR 1.55; CI 1.01, 2.37) had worse overall survival, with significantly worse joint effect (HR 2.73; CI 1.32, 5.65)., Conclusions: Sarcopenia at diagnosis combined with ongoing skeletal muscle loss over time resulted in significantly worse survival. Patients with these features who are recurrence-free at 2 years are more likely to have a non-colorectal cancer cause of death.

Background: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer., Objective: This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer., Design: This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival., Settings: All patients were seen in a tertiary care cancer center., Patients: Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included., Intervention: Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity., Main Outcome Measures: Primary outcome measures were overall, recurrence-free, and cancer-specific survival., Results: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model., Limitations: The limitations of this study are inherent in retrospective observational studies., Conclusions: Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

Human interleukin-12 (hIL-12) is a heparin-binding cytokine whose activity was previously shown to be enhanced by heparin and other sulfated glycosaminoglycans. The current study investigated the mechanisms by which heparin increases hIL-12 activity. Using multiple human cell types, including natural killer cells, an IL-12 indicator cell line, and primary peripheral blood mononuclear and T cells, along with bioactivity, flow cytometry, and isothermal titration calorimetry assays, we found that heparin-dependent modulation of hIL-12 function correlates with several of heparin's biophysical characteristics, including chain length, sulfation level, and concentration. Specifically, only heparin molecules longer than eight saccharide units enhanced hIL-12 activity. Furthermore, heparin molecules with three sulfate groups per disaccharide unit outperformed heparin molecules with one or two sulfate groups per disaccharide unit in terms of enhanced hIL-12 binding and activity. Heparin also significantly reduced the EC 50 value of hIL-12 by up to 11.8-fold, depending on the responding cell type. Cytokine-profiling analyses revealed that heparin affected the level, but not the type, of cytokines produced by lymphocytes in response to hIL-12. Interestingly, although murine IL-12 also binds heparin, heparin did not enhance its activity. Using the gathered data, we propose a model of hIL-12 stabilization in which heparin serves as a co-receptor enhancing the interaction between heterodimeric hIL-12 and its receptor subunits. The results of this study provide a foundation for further investigation of heparin's interactions with IL-12 family cytokines and for the use of heparin as an immunomodulatory agent.

Use of cross-sectional imaging to identify whole-body lean soft-tissue mass has recently emerged as an attractive prognostic factor for chemotherapy toxicities. Beyond that, there is increasing interest in use of lean soft-tissue mass as a more accurate method for dosing chemotherapy, as compared to body surface area. In this review, we summarize the current evidence that supports interactions between skeletal muscle and chemotherapy, the role of lean soft tissue in predicting chemotherapy toxicities and potential use of an alternate method of chemotherapeutic dosing, all based on quantification of skeletal muscle mass by computed tomography.

Purpose: To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD)., Design: Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial., Participants: Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN)., Methods: Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter ≥250 μm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included., Main Outcome Measures: Macular atrophy incidence, best-corrected visual acuity (BCVA)., Results: At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters [95% confidence interval]: +6.7 [4.1-9.3]; +9.1 [8.0-10.2], respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 [60.3-63.7] and 64.7 [63.2-66.3] letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio [HR], 2.45 [1.76-3.42]) and fellow eye atrophy (HR, 2.02 [1.42-2.87]); subretinal fluid was associated with a lower MA risk (HR, 0.50 [0.33-0.74]). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 [0.99-1.68]), but was not statistically significant., Conclusions: New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Measurement of body composition by computed tomography (CT) is an advancing field. Sarcopenia, myosteatosis, and visceral obesity (VO) have been identified as predictive of survival in colorectal cancer (CRC). We performed a systematic review of contemporary studies to characterize this association and highlight methodological inconsistencies., Methods: MEDLINE and PubMed were queried for articles published from January 2000 on, with populations of resectable CRC and with CT-measured body composition and survival data. The study quality was assessed by two independent reviewers using the Newcastle-Ottawa Scale., Results: Twenty studies met inclusion criteria, with a total of 8895 patients. Only two of the studies scored as high quality and nine as moderate quality. The remaining nine studies scored as low quality. Ten studies considered sarcopenia and 12 considered visceral obesity (VO). Cutoff points to define sarcopenia, myosteatosis, and VO were identified by optimal stratification, quartiles, or median values. The prevalence of sarcopenia varied from 15 to 60%, which based on study population and cutoff value used. Sarcopenia was associated with worse overall and disease-free survival in eight of the included studies. Myosteatosis was considered in three studies with a prevalence of 19-78%. It was significantly predictive of worse overall and disease-free survival in all three studies. VO had a prevalence of 14-70% and was inconsistently predictive of survival outcomes., Conclusions: There is a lack of methodological consistency within the currently published literature. Despite this, sarcopenia and myosteatosis, but not VO, are consistently associated with worse survival outcomes, when population and cancer-specific cutoffs are utilized.

Introduction: Body surface area dosing of chemotherapeutic agents is based on limited scientific data, and often results in unpredictable plasma drug levels. Cross-sectional computed tomography (CT) imaging provides an accurate measurement of lean mass. This review summarizes emerging roles of lean mass in predicting pharmacokinetics and drug toxicities in cancer patients. Areas covered: A concise review of body composition measurement with CT cross-sectional imaging and its relationship to drug pharmacokinetics and toxicities. A comprehensive review of the predictive value of low lean mass (sarcopenia) in dose-limiting toxicities is also included. Expert commentary: Drug dosing in medical oncology faces many challenges, including heterogeneous body composition profiles. The emerging role of sarcopenia in predicting lean mass may provide the tool needed to more accurately dose patients and prevent dose-limiting toxicities.

Humans require resilient, rapidly renewable and sustainable supplies of food and many other plant-derived supplies. However, the combined effects of climate change and population growth compromise the provision of these supplies particularly in respect to global food security. Crop wild relatives (CWR) contain higher genetic diversity than crops and harbour traits that can improve crop resilience and yield through plant breeding. However, in common with most countries, CWR are poorly conserved in England. There is currently no provision for long-term CWR conservation in situ, and comprehensive ex situ collection and storage of CWR is also lacking. However, there is a commitment to achieve their conservation in England's Biodiversity Strategy and the UK has international commitments to do so as part of the Global Plant Conservation Strategy. Here, we identify a series of measures that could enhance the conservation of English CWR, thereby supporting the achievement of these national and international objectives. We provide an inventory of 148 priority English CWR, highlight hotspots of CWR diversity in sites including The Lizard Peninsula, the Dorset coast and Cambridgeshire and suggest appropriate sites for the establishment of a complementary network of genetic reserves. We also identify individual in situ and ex situ priorities for each English CWR. Based on these analyses, we make recommendations whose implementation could provide effective, long-term conservation of English CWR whilst facilitating their use in crop improvement.

Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

Purpose: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME)., Design: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years., Participants: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography., Methods: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary., Main Outcome Measures: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24., Results: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group., Conclusions: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity over time in 2 phase 3 clinical trials (RIDE, NCT00473382; RISE, NCT00473330) of ranibizumab for diabetic macular edema., Methods: Participants with diabetic macular edema (n=759) were randomized to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections. Macular laser was available per protocol-specified criteria. Fundus photographs, taken at baseline and periodically, were graded by a central reading center; clinical examinations were performed monthly. The main outcome measures of this report are secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic Retinopathy Study severity scale in the study eye and a composite DR progression outcome including photographic changes plus clinically important events such as occurrence of vitreous hemorrhage or need for panretinal laser., Results: At 2 years, the percentage of participants with DR progression (worsening by ≥ 2 or ≥ 3 steps) was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥ 2 or ≥ 3 steps) was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes., Conclusions: Intravitreal ranibizumab reduced the risk of DR progression in eyes with diabetic macular edema, and many ranibizumab-treated eyes experienced improvement in DR severity. Because these results are exploratory, the use of intravitreal ranibizumab specifically to reduce DR progression or cause DR regression requires further study.

Purpose: To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients., Design: Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies., Participants: Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT)., Intervention: Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria., Main Outcome Measures: Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months., Results: In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients., Conclusions: Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.

Background: A 57-year-old woman presented with distorted vision and decreased visual acuity (finger count only) in her left eye, 6 years after she had undergone a lumpectomy, lymph-node dissection, and radiation therapy for a 1.1 cm infiltrating ductal carcinoma of her right breast. A year before this presentation, she had completed 5 years of adjuvant tamoxifen therapy., Investigations: Physical examination, including a thorough ophthalmologic evaluation; laboratory investigations, ocular fluorescein angiography, ocular ultrasonography, head CT, chest X-ray, abdominal ultrasonography, bone scan, and bilateral mammography., Diagnosis: Choroidal metastasis from breast carcinoma, with no other evidence of disease recurrence., Management: Radiation therapy to the left eye followed by ongoing hormonal therapy with oral letrozole 2.5 mg daily for the past 9.5 years.

Purpose: To characterize the macular anatomy of retinal dystrophy eyes using high-speed, high-resolution, Fourier-domain optical coherence tomography (FD-OCT)., Design: Case-control study., Methods: Retinal dystrophy patients and normal age- and gender-matched controls underwent FD-OCT imaging using the RTVue (Optovue Inc., Fremont, California, USA). Vertical and horizontal 8-mm scans of 1024 lines/cross-section were obtained. Based on boundaries manually drawn on computer displays of OCT cross-sections, the thicknesses of the retina, inner retinal layer (IRL), and outer retinal layer (ORL) were averaged over both 5-mm (macular) and 1.5-mm (foveal) regions centered at the fovea. The IRL was the sum of nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) thicknesses. Total retinal thickness (RT) was measured between the internal limiting membrane (ILM) and the retinal pigment epithelium. ORL thickness was calculated by subtracting IRL thickness from RT., Results: Fourteen patients (three retinitis pigmentosa, two cone-rod degeneration, two Stargardt disease, and seven normal controls) underwent FD-OCT imaging. Mean foveal RT was 271.3 +/- 23.3 microm for controls and 158.4 +/- 47.1 microm for retinal dystrophy patients (P < .001). Mean macular RT was 292.8 +/- 8.1 microm for controls and 199.1 +/- 32.6 microm for retinal dystrophy patients (P < .001). Mean macular ORL was 182.9 +/- 4.7 microm for controls and 101.3 +/- 18.7 microm for retinal dystrophy patients (P < .001); mean macular IRL was 109.9 +/- 6.4 microm for controls and 97.9 +/- 20.7 microm for retinal dystrophy patients (P = .06)., Conclusion: Eyes with retinal dystrophy had a small (11%) decrease in macular IRL and severe (45%) decrease in macular ORL compared to normal controls.

Background: The management of HIV-infected patients with cytomegalovirus (CMV) disease has changed significantly with the availability of highly active antiretroviral therapy (HAART)., Objectives: These updated guidelines are intended to provide practical help to physicians managing HIV-positive patients with or at risk for CMV disease., Methods: The 10 members of the Canadian CMV Disease in HIV/AIDS Consensus Group were infectious disease specialists, a primary care physician and ophthalmologists with expertise in HIV and CMV infection. Financial support by Hoffmann-La Roche Canada Ltd was unrestricted, and was limited to travel expenses and honoraria. The consensus group met in June and October 2002. Key areas to be considered were identified, and group members selected, reviewed and presented relevant recent literature for their assigned section for the group's consideration. Evidence was assessed based on established criteria, which were expert opinions of the members. Draft documents were circulated to the entire group and modified until consensus was reached. The final guidelines represent the group's consensus agreement. The guidelines were approved by the Canadian Infectious Disease Society., Results and Conclusions: The guidelines address symptom monitoring, screening for early detection and prevention, and treatment using oral, intravenous and intraocular anti-CMV therapies in conjunction with HAART.

Murine flank scarification with HSV-1 and -2 results in primary lesions at the site of inoculation within three days and lesions at secondary sites within four days. The severity of the infection can be given a numerical value or "score" which is derived from the number and size of these lesions. Using this model, we investigated the role of the epidermal basement membrane in HSV pathogenesis. We exposed murine epidermis to 5 x 10(4) plaque forming units of HSV-1 and -2, which by day 8 produced inoculation site (primary site) disease scores of 27 and 12.4 respectively, and secondary site disease scores of 29 and 30 respectively. In contrast, intradermal injection of HSV below the epidermal basement membrane did not cause disease. To determine if the basement membrane restricts HSV spread in vitro, Vero cells were cultured in the lower well of a dual well system. The upper well was separated from the lower well by a filter coated with the artificial basement membrane, matrigel. Addition of virus to the upper well failed to result in either viral accumulation in the lower well or infection of the cells in the lower well. These data suggest that the basement membrane is a barrier to the passage and spread of HSV.

Background and Objective: To determine the efficacy of combined phacoemulsification--trabeculectomy in preventing early postoperative increases in intraocular pressure (IOP)., Patients and Methods: Eighty patients were enrolled in a prospective cohort study. Thirty-six patients with cataracts and uncontrolled glaucoma underwent combined phacoemulsification--trabeculectomy, and 44 patients with cataracts underwent phacoemulsification alone. The operations were performed in a standardized manner by one surgeon. IOP was measured at 4 hours, 1 day, and 7 days after surgery. The need for intervention (digital massage, medications) and the presence of complications were documented., Results: Four hours after surgery, 5.5% of patients undergoing the combined procedure had IOPs greater than 30 mm Hg, compared with 22.7% of phacoemulsification patients (P < .05). No significant difference in IOP was found between the groups at postoperative day 1 or day 7., Conclusion: These results suggest that combined phacoemulsification-trabeculectomy protects against early postoperative elevations in IOP. This finding may influence the surgical management of cataracts in patients with poorly controlled glaucoma and significant compromise of visual field or optic nerve.

Water sorption which is not classically Fickian has been observed in a variety of polymers. Deviation from Fickian kinetics is widely assumed to be caused by rate-limiting polymer relaxation, despite minimal proof of this. To the contrary, the evidence accumulated in this work indicates that water transport in initially glassy poly(2-hydroxyethyl methacrylate) (PHEMA), an important water-swellable biomedical polymer, is controlled by Fickian diffusion. First of all, the fractional water uptake is initially linear and independent of sample thickness when plotted against the square root of time over initial thickness, as expected for a Fickian process. Furthermore, the moving solvent front also advanced with the square root of time. Temperature, polymer thermal history and initial solvent concentration all affected the sorption kinetics of PHEMA in manners consistent with a Fickian process. The invariably Fickian sorption mechanism is believed to be the consequence of the water molecule's small size and affinity for hydrophilic, swellable polymers.