The Effect of Macular Hole Duration on Surgical Outcomes: An Individual Participant Data Study of Randomized Controlled Trials

Topic: To define the effect of symptom duration on outcomes in people undergoing surgery for idiopathic full-thickness macular holes (iFTMHs) by means of an individual participant data (IPD) study of randomized controlled trials (RCTs). The outcomes assessed were primary iFTMH closure and postoperative best-corrected visual acuity (BCVA). Clinical Relevance: Idiopathic full-thickness macular holes are visually disabling with a prevalence of up to 0.5%. Untreated BCVA is typically reduced to 20/200. Surgery can close holes and improve vision. Symptom duration is thought to affect outcomes with surgery, but the effect is unclear. Methods: A systematic review identified eligible RCTs that included adults with iFTMH undergoing vitrectomy with gas tamponade in which symptom duration, primary iFTMH closure, and postoperative BCVA were recorded. Bibliographic databases were searched for articles published between 2000 and 2020. Individual participant data were requested from eligible studies. Results: Twenty eligible RCTs were identified. Data were requested from all studies and obtained from 12, representing 940 eyes in total. Median symptom duration was 6 months (interquartile range, 3–10). Primary closure was achieved in 81.5% of eyes. There was a linear relationship between predicted probability of closure and symptom duration. Multilevel logistic regression showed each additional month of duration was associated with 0.965 times lower odds of closure (95% confidence interval [CI], 0.935–0.996, P = 0.026). Internal limiting membrane (ILM) peeling, ILM flap use, better preoperative BCVA, face-down positioning, and smaller iFTMH size were associated with increased odds of primary closure. Median postoperative BCVA in eyes achieving primary closure was 0.48 logarithm of the minimum angle of resolution (logMAR) (20/60). Multilevel logistic regression showed for eyes achieving primary iFTMH closure, each additional month of symptom duration was associated with worsening BCVA by 0.008 logMAR units (95% CI, 0.005–0.011, P < 0.001) (i.e., ∼1 Early Treatment Diabetic Retinopathy Study letter loss per 2 months). ILM flaps, intraocular tamponade using long-acting gas, better preoperative BCVA, smaller iFTMH size, and phakic status were also associated with improved postoperative BCVA. Conclusions: Symptom duration was independently associated with both anatomic and visual outcomes in persons undergoing surgery for iFTMH. Time to surgery should be minimized and care pathways designed to enable this

Using virtual reality in criminological research

Since the pioneering early studies of the 1990s hinted at its promise as a research method, virtual reality (VR) technology has increasingly been used by social scientists. Given recent developments that have greatly enhanced realism, reduced costs, and increased possibilities for application, VR seems well on its way to become an established research tool in the social sciences. However, as with other ethodological innovations, the field of criminology hasbeen slow to catch on. To address this gap, this article explores the potential of VR as a tool for crime research. It provides readers with a brief and non-technical description of VR and its main elements and reviews severalapplications of VR in social scientific research that are potentially relevant for criminologists. By way of illustration, we identify and discuss in more detail different areas in which we think the field of criminology can particularly benefit from VR and offer suggestions for research. Some of the equipment available on the consumer market is also reviewed.In conjunction, the different sections should equip readers interested in applying VR in their own research with a fundamental understanding of what it entails and how it can be applied

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Bicistronic Lentiviruses Containing a Viral 2A Cleavage Sequence Reliably Co-Express Two Proteins and Restore Vision to an Animal Model of LCA1

The disease processes underlying inherited retinal disease are complex and are not completely understood. Many of the corrective gene therapies designed to treat diseases linked to mutations in genes specifically expressed in photoreceptor cells restore function to these cells but fail to stop progression of the disease. There is growing consensus that effective treatments for these diseases will require delivery of multiple therapeutic proteins that will be selected to treat specific aspects of the disease process. The purpose of this study was to design a lentiviral transgene that reliably expresses all of the proteins it encodes and does so in a consistent manner among infected cells. We show, using both in vitro and in vivo analyses, that bicistronic lentiviral transgenes encoding two fluorescent proteins fused to a viral 2A-like cleavage peptide meet these expression criteria. To determine if this transgene design is suitable for therapeutic applications, we replaced one of the fluorescent protein genes with the gene encoding guanylate cyclase -1 (GC1) and delivered lentivirus carrying this transgene to the retinas of the GUCY1*B avian model of Leber congenital amaurosis – 1 (LCA1). GUCY1*B chickens carry a null mutation in the GC1 gene that disrupts photoreceptor function and causes blindness at hatching, a phenotype that closely matches that observed in humans with LCA1. We found that treatment of these animals with the 2A lentivector encoding GC1 restored vision to these animals as evidenced by the presence of optokinetic reflexes. We conclude that 2A-like peptides, with proper optimization, can be successfully incorporated into therapeutic vectors designed to deliver multiple proteins to neural retinal. These results highlight the potential of this vector design to serve as a platform for the development of combination therapies designed to enhance or prolong the benefits of corrective gene therapies

Corneal Transduction by Intra-Stromal Injection of AAV Vectors In Vivo in the Mouse and Ex Vivo in Human Explants

The cornea is a transparent, avascular tissue that acts as the major refractive surface of the eye. Corneal transparency, assured by the inner stroma, is vital for this role. Disruption in stromal transparency can occur in some inherited or acquired diseases. As a consequence, light entering the eye is blocked or distorted, leading to decreased visual acuity. Possible treatment for restoring transparency could be via viral-based gene therapy. The stroma is particularly amenable to this strategy due to its immunoprivileged nature and low turnover rate. We assayed the potential of AAV vectors to transduce keratocytes following intra-stromal injection in vivo in the mouse cornea and ex vivo in human explants. In murine and human corneas, we transduced the entire stroma using a single injection, preferentially targeted keratocytes and achieved long-term gene transfer (up to 17 months in vivo in mice). Of the serotypes tested, AAV2/8 was the most promising for gene transfer in both mouse and man. Furthermore, transgene expression could be transiently increased following aggression to the cornea

A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations

Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (praw = 1.94×10−10, pgenome = 1.0×10−5), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans

Mechano-Electric Feedback in the Fish Heart

Mechanoelectric feedback (MEF) describes the modulation of electrical activity by mechanical activity. This may occur via the activation of mechanosensitive ion channels (MSCs). MEF has not previously been investigated in fish ventricular tissue even though fish can greatly increase ventricular end diastolic volume during exercise which should therefore provide a powerful mechanical stimulus for MEF.When the ventricles of extrinsically paced, isolated working trout hearts were dilated by increasing afterload, monophasic action potential (MAP) duration was significantly shortened at 25% repolarisation, unaltered at 50% repolarisation and significantly lengthened at 90% repolarisation. This observation is consistent with the activation of cationic non-selective MSCs (MSC(NS)s). We then cloned the trout ortholog of TRPC1, a candidate MSC(NS) and confirmed its presence in the trout heart.Our results have validated the use of MAP technology for the fish heart and suggest that, in common with amphibians and mammals, MEF operates in fish ventricular myocardium, possibly via the activation of mechanosensitive TRPC1 ion channels

Immune response of macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonas gingivalis

Periodontal disease is a chronic inflammatory gum disease that in severe cases leads to tooth loss. Porphyromonas gingivalis (Pg) is a bacterium closely associated with generalized forms of periodontal disease. Clinical onset of generalized periodontal disease commonly presents in individuals over the age of 40. Little is known regarding the effect of aging on inflammation associated with periodontal disease. In the present study we examined the immune response of bone marrow derived macrophages (BMM) from young (2-months) and aged (1-year and 2-years) mice to Pg strain 381. Pg induced robust expression of cytokines; tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10, chemokines; neutrophil chemoattractant protein (KC), macrophage colony stimulating factor (MCP)-1, macrophage inflammatory protein (MIP)-1α and regulated upon activation normal T cell expressed and secreted (RANTES), as well as nitric oxide (NO, measured as nitrite), and prostaglandin E2 (PGE2) from BMM of young mice. BMM from the 2-year age group produced significantly less TNF-α, IL-6 and NO in response to Pg as compared with BMM from 2-months and 1-year of age. We did not observe any difference in the levels of IL-1β, IL-10 and PGE2 produced by BMM in response to Pg. BMM from 2-months and 1-year of age produced similar levels of all chemokines measured with the exception of MCP-1, which was reduced in BMM from 1-year of age. BMM from the 2-year group produced significantly less MCP-1 and MIP-1α compared with 2-months and 1-year age groups. No difference in RANTES production was observed between age groups. Employing a Pg attenuated mutant, deficient in major fimbriae (Pg DPG3), we observed reduced ability of the mutant to stimulate inflammatory mediator expression from BMMs as compared to Pg 381, irrespective of age. Taken together these results support senescence as an important facet of the reduced immunological response observed by BMM of aged host to the periodontal pathogen Pg