Diagnostic Pathway Outcomes for Bi-parametric MRI Targeted Lesions Using Cognitive Registration and Freehand Transperineal Prostate Biopsy in Biopsy Naïve Men (CRAFT Single Centre Study).

PURPOSE: Enhanced histological detection of clinically significant prostate cancer is the goal of the pre-biopsy imaging pathway. Risk stratification at a pre-biopsy meeting can facilitate optimisation of lesion targeting. We aimed to evaluate the feasibility of cognitive registration, freehand transperineal prostate biopsy in a biopsy naïve population following bi-parametric magnetic resonance imaging for the detection of clinically significant disease (International Society of Urological Pathology Grade Group ≥2). MATERIALS AND METHODS: A consecutive series of biopsy naïve men, prospectively recorded between July 2018 and March 2023, were risk stratified at our pre-biopsy meeting following bi-parametric magnetic resonance imaging to undergo either target only biopsy or target with systematic biopsy. Biopsies were routinely performed under local anaesthesia and without antibiotic prophylaxis in the outpatient setting. Overall prostate cancer and clinically significant prostate cancer detection were primary outcomes. RESULTS: Of 1251 biopsies, prostate cancer was detected in 84% and clinically significant disease detected in 70.6%. Prostate cancer and clinically significant disease were detected in 86.2% and 76.5% of target only biopsies and in 78.7% and 56.3% of target with systematic biopsies. Post-biopsy complication rate was 0.7%. CONCLUSIONS: Pre-biopsy bi-parametric magnetic resonance imaging with risk stratification at a pre-biopsy meeting in the setting of cognitive targeting and freehand transperineal prostate biopsy yielded a high detection of prostate cancer that is comparable to other studies. This data supports the use of cognitive registration, freehand transperineal prostate biopsy as safe, feasible and cost-effective.

Agent-based simulation and child protection systems: Rationale, implementation, and verification.

BACKGROUND AND OBJECTIVE: Simulation models are an important tool used in health care and other disciplines to support operational research and decision-making. In the child protection literature, simulation models are an under-utilized source of research evidence. PARTICIPANTS AND SETTING: In this paper, we describe the rationale for and the development of an agent-based simulation of a child protection system in the US. Using the investigation, prevention service, and placement histories of 600,000 children served in an urban child welfare system, we walk the reader through the development of a prototype known as OSPEDALE. METHODS: The governing equations built into OSPEDALE probabilistically simulate the onset of investigations. Then, drawing from empirical survival distributions, the governing equations trace the probability of subsequent interactions with the system (recurrence of maltreatment, service referrals, and placement) conditional on the characteristics of children, their assessed risk level, and prior child protection system involvement. RESULTS: As an initial test of OSPEDALE's utility, we compare empirical admission counts with counts generated from OSPEDALE. Though the verification step is admittedly simple, the comparison shows that OSPEDALE replicates the empirical count of new admissions closely enough to justify further investment in OSPEDALE. CONCLUSIONS: Management of public child protection systems is increasingly research evidence-dependent. The emphasis on research evidence as a decision-support tool has elevated evidence acquired through randomized clinical trials. Though important, the evidence from clinical trials represents only one type of research evidence. Properly specified, simulation models are another source of evidence with real-world relevance.

Trabeculectomy in the 21st century: a multicenter analysis.

OBJECTIVE: To evaluate the efficacy and safety of current trabeculectomy surgery in the United Kingdom. DESIGN: Cross-sectional, multicenter, retrospective follow-up. PARTICIPANTS: A total of 428 eyes of 395 patients. METHODS: Consecutive trabeculectomy cases with open-angle glaucoma and no previous incisional glaucoma surgery from 9 glaucoma units were evaluated retrospectively. Follow-up was a minimum of 2 years. MAIN OUTCOME MEASURES: Surgical success, intraocular pressure (IOP), visual acuity, complications, and interventions. Success was stratified according to IOP, use of hypotensive medications, bleb needling, and resuturing/revision for hypotony. Reoperation for glaucoma and loss of perception of light were classified as failures. RESULTS: Antifibrotics were used in 400 cases (93%): mitomycin C (MMC) in 271 (63%), 5-fluorouracil (5-FU) in 129 (30%), and no antifibrotic in 28 (7%). At 2 years, IOP (mean ± standard deviation) was 12.4 ± 4 mmHg, and 342 patients (80%) achieved an IOP ≤ 21 mmHg and 20% reduction of preoperative IOP without IOP-lowering medication, whereas 374 patients (87%) achieved an IOP ≤ 21 mmHg and 20% reduction of preoperative IOP overall. An IOP ≤18 mmHg and 20% reduction of preoperative IOP were achieved by 337 trabeculectomies (78%) without IOP-lowering treatment and by 367 trabeculectomies (86%) including hypotensive medication. Postoperative treatments included suture manipulation in 184 patients (43%), resuturing or revision for hypotony in 30 patients (7%), bleb needling in 71 patients (17%), and cataract extraction in 111 of 363 patients (31%). Subconjunctival 5-FU injection was performed postoperatively in 119 patients (28%). Visual loss of >2 Snellen lines occurred in 24 of 428 patients (5.6%). A total of 31 of the 428 patients (7.2%) had late-onset hypotony (IOP <6 mmHg after 6 months). In 3 of these, visual acuity decreased by >2 Snellen lines. Bleb leaks were observed in 59 cases (14%), 56 (95%) of which occurred within 3 months. Two patients developed blebitis. Bleb-related endophthalmitis developed in 1 patient within 1 month postoperatively and in 1 patient at 3 years. There was an endophthalmitis associated with subsequent cataract surgery. CONCLUSIONS: This survey shows that good trabeculectomy outcomes with low rates of surgical complications can be achieved, but intensive proactive postoperative care is required.

Genome-wide association study of primary open angle glaucoma risk and quantitative traits.

PURPOSE: Primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss. Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved. We analyzed carefully characterized POAG cases in a genome-wide association study (GWAS). METHODS: We performed a GWAS in 387 POAG cases using public control data (WTCCC2). We also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP). Promising single nucleotide polymorphisms (SNPs), based on various prioritisation criteria, were genotyped in a cohort of 294 further POAG cases and controls. RESULTS: We found 2 GWAS significant results in the discovery stage for association, one of which which had multiple evidence in the gene 'neural precursor cell expressed, developmentally down-regulated 9' (NEDD9; rs11961171, p=8.55E-13) and the second on chromosome 16 with no supporting evidence. Taking into account all the evidence from risk and quantitative trait ocular phenotypes we chose 86 SNPs for replication in an independent sample. Our most significant SNP was not replicated (p=0.59). We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing. Two of these, for phenotypes CDR (rs4385494, discovery p=4.51x10-5, replication p=0.029) and CCT (rs17128941, discovery p=5.52x10-6, replication=0.027), show the consistent direction of effects between the discovery and replication data. We also assess evidence for previously associated known genes and find evidence for the genes 'transmembrane and coiled-coil domains 1' (TMCO1) and 'cyclin-dependent kinase inhibitor 2B' (CDKN2B). CONCLUSIONS: Although we were unable to replicate any novel results for POAG risk, we did replicate two SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing. There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits. We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study. Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.

Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study.

BACKGROUND: Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H (CFH) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 (C3) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease. METHODS: We used a case-control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals. FINDINGS: The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4.0x10(-5), corrected p=0.00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0.63 (95% CI 0.47-0.84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0.44 (0.31-0.64). We replicated the observed genotypic association in a US cohort (p=0.008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988). INTERPRETATION: Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 (C1) and might implicate the classic pathway of complement activation in this disease.

Deep sclerectomy versus trabeculectomy: a morphological study with anterior segment optical coherence tomography.

PURPOSE: To investigate the intraocular pressure (IOP) lowering mechanisms of deep sclerectomy (DS) with anterior segment optical coherence tomography (AS-OCT). METHODS: In a prospective cross-sectional study, AS-OCT parameters were compared between DS, trabeculectomy and control cases. Association with IOP and success (IOP≤16 mm Hg without medication) was investigated. RESULTS: 18 DS (15 patients), 17 trabeculectomy (16 patients) and 15 controls (15 patients) were examined. Successful had a taller intrascleral lake (IL) and thicker conjunctival/Tenon's layer (CTL) than non-successful cases (513.3 vs 361.1 µm, p=0.027 and 586.7 vs 251.1 µm, p<0.001, respectively). CTL thickness correlated with IOP (r=-0.6407, p=0.004). CTL thickness was significantly different between controls, DS and trabeculectomy (mean (SD): 203.3 (62.6) vs 418.9 (261.9) vs 604.1 (220.7) µm, p<0.0001). Successful trabeculectomy cases had a taller bleb cavity (BC) than non-successful cases (607.5 vs 176.7 µm, p=0.041). CTL microcysts were detected in 50% of DS and 52.9% of trabeculectomy cases (p=1). CONCLUSIONS: Trans-conjunctival aqueous percolation was identified as a novel DS drainage route. DS had a fluid reservoir below the scleral flap, the IL, in analogy to the trabeculectomy BC. A postoperative tall IL and a thick CTL were associated with good outcome.

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma.

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10⁻¹°). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Design of a UV-C irradiation process for the inactivation of viruses in protein solutions.

The ability of ultraviolet (UV) light to inactivate viruses is well established. However, attempts to apply this to the manufacture of pharmaceutical proteins have been limited by incomplete treatment, low capacity or excessive dilution. Effective processing of large-scale batches of UV-opaque protein solutions has been achieved using a continuous-flow device. The operation of this device has been modelled and a design equation derived to relate the processing conditions and product characteristics to the degree of virus inactivation obtained. Variables included in the model are UV-absorbance at 254 nm (A(254)), hydrodynamic properties of the protein solution, residence time, intensity of UV light and diameter and length of irradiation tube. With this information a specific constant was calculated for each virus which denotes its relative sensitivity to UV and from which the degree of virus inactivation expected can be estimated.