The impact of the English national health inequalities strategy on inequalities in mortality at age 65: a time-trend analysis.

BACKGROUND: During the 1997-2010 Labour government, several policies were implemented to narrow health inequalities as part of a national health inequalities strategy. Many of these policies are likely to have had a disproportionately large impact on people aged 65 and over. We aimed to understand the association between the health inequalities strategy period and inequalities in mortality at age 65-69. METHODS: We use population at risk and mortality data covering 1991-2019 to calculate mortality rate at age 65-69 at the Local Authority level. We use the 2019 Index of Multiple Deprivation to examine geographical inequalities. We employ segmented linear regression models with marginal spline terms for the strategy period and interact these with an indicator of deprivation to understand how inequalities changed before, during and after the strategy. The reporting of this study adheres to STROBE guidelines. RESULTS: Mortality rates in each deprivation quintile improved continuously throughout the period of study. Prior to the programme (1991-9) there was no significant change in absolute inequalities. However, during the strategy (2000-10) there was a significant decrease in absolute inequalities of -9.66 (-17.48 to -1.84). The period following the strategy (2011-19) was associated with a significant increase in absolute inequalities of 12.84 (6.60 to 19.08). Our results were robust to a range of sensitivity tests. CONCLUSION: The English health inequalities strategy was associated with a significant reduction in absolute inequality in mortality age 65-69. Future strategies to address inequalities in ageing populations may benefit from adopting a similar approach.

Zika Virus Infection of Pregnant Ifnar1-/- Mice Triggers Strain-Specific Differences in Fetal Outcomes.

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed congenital Zika syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015 to 2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian-/American-lineage ZIKV strains in an established Ifnar1-/- pregnant mouse model. Here, we show significant differences in the rate of fetal demise following maternal inoculation with ZIKV strains from Puerto Rico, Panama, Mexico, Brazil, and Cambodia. Rates of fetal demise broadly correlated with maternal viremia but were independent of fetus and placenta virus titer, indicating that additional underlying factors contribute to fetal outcome. Our results, in concert with those from other studies, suggest that subtle differences in ZIKV strains may have important phenotypic impacts. With ZIKV now endemic in the Americas, greater emphasis needs to be placed on elucidating and understanding the underlying mechanisms that contribute to fetal outcome. IMPORTANCE Zika virus (ZIKV) transmission has been reported in 87 countries and territories around the globe. ZIKV infection during pregnancy is associated with adverse fetal outcomes, including birth defects, microcephaly, neurological complications, and even spontaneous abortion. Rates of adverse fetal outcomes vary between regions, and not every pregnancy exposed to ZIKV results in birth defects. Not much is known about how or if the infecting ZIKV strain is linked to fetal outcomes. Our research provides evidence of phenotypic heterogeneity between Asian-/American-lineage ZIKV strains and provides insight into the underlying causes of adverse fetal outcomes. Understanding ZIKV strain-dependent pathogenic potential during pregnancy and elucidating underlying causes of diverse clinical sequelae observed during human infections is critical to understanding ZIKV on a global scale.

Minority Participation in Randomized Controlled Trials for Prolonged Exposure Therapy: A Systematic Review of the Literature.

Per the most recent census, non-Latinx White individuals comprise the majority of the U.S. population (76.6%); Latinx individuals make up 18.3% of the total U.S. population, followed by African Americans (13.4%) and Asians (5.9%). Given the high prevalence rates of posttraumatic stress disorder (PTSD) observed across many ethnoracial minority groups in the United States, the fact that PTSD presentation may vary across culture, and the National Institute of Health's mandates for the inclusion of women and minorities in clinical outcome research, the aim of the present systematic review was to examine minority inclusion in clinical outcome research for PTSD. Our review focused exclusively on one empirically supported treatment: prolonged exposure therapy (PE); we identified 38 studies that met the inclusion criteria. Apart from African Americans, who were overrepresented in 21 studies (inclusion rate range: 13.5%-73.9%), ethnoracial minority inclusion in RCTs examining PE was low. More specifically, across included studies that reported ethnoracial minority data, 58.9% of participants were White, 31.1% were African American, 4.9% were Latinx, 0.6% were Asian American or Pacific Islander, and 4.7% reported race as "other." Inclusion rates for ethnoracial minorities appeared to increase across time, and recruitment strategies did not appear to be associated with increased ethnoracial minority participation in RCTs for PE.

Characterization of the Pro-Inflammatory Cytokine IL-1ß on Butyrate Oxidation in Colorectal Cancer Cells.

Cancer, in part, is driven, by alterations in cellular metabolism that promote cell survival and cell proliferation. Identifying factors that influence this shift in cellular metabolism in cancer cells is important. Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that has been reported to be elevated in colorectal cancer patients. While much is known toward the effect of dietary nutrients on regulating inflammation and the inflammatory response, which includes cytokines such as IL-1ß, far less is understood how cytokines impact nutrient fate to alter cancer cell metabolism. Butyrate, a nutrient derived from the fermentation of dietary fiber in the colon, is the preferential exogenous energetic substrate used by non-cancerous colonocytes, but is used less efficiently by colorectal cancer cells. To test whether IL-1ß alters colonocyte energy metabolism, we measured butyrate oxidation in HCT116 colorectal cancer cells with and without IL-1ß. We hypothesize that IL-1ß will push cancerous colonocytes away from the utilization and oxidation of butyrate. In this study, we demonstrate that pretreatment of colorectal cancer cells with IL-1ß diminished butyrate oxidation and NADH levels. This effect was blocked with the interleukin receptor antagonist A (IL-1RA). Moreover, IL-1ß suppressed basal mitochondrial respiration and lowered the mitochondrial spare capacity. By using inhibitors to block downstream targets of the interleukin-1 receptor pathway, we show that p38 is required for the IL-1ß-mediated decrease in butyrate oxidation. These data provide insight into the metabolic effects induced by IL-1ß in colorectal cancer, and identify relevant targets that may be exploited to block the effects of this cytokine. J. Cell. Biochem. 118: 1614-1621, 2017. © 2016 Wiley Periodicals, Inc.

Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc.

The construct of grooming in child sexual abuse: conceptual and measurement issues.

There have been claims that some child molesters engage in a "seduction stage" prior to committing abuse. These behaviors, commonly known as "grooming," are understood as methods child molesters use to gain access to and prepare future victims to be compliant with abuse. However, there is a lack of consensus regarding exactly what this process entails and how it is clearly distinguished from normal adult-child interactions. It is important to devise an accurate definition of grooming for scientific, clinical, and forensic purposes. We critically evaluate the various definitions and reveal problematic heterogeneity. Furthermore, there are no methods of known psychometrics to validly assess grooming. We review the empirical literature regarding the occurrence of grooming and propose future directions for research.

Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells.

The establishment and progression of bone metastatic breast cancer is supported by immunosuppressive myeloid populations that enable tumor growth by dampening the innate and adaptive immune response. Much work remains to understand how to target these tumor-myeloid interactions to improve treatment outcomes. Noncanonical Hedgehog signaling is an essential component of bone metastatic tumor progression, and prior literature suggests a potential role for Hedgehog signaling and its downstream effector Gli2 in modulating immune responses. In this work, we sought to identify if inhibition of noncanonical Hedgehog signaling alters the cytokine profile of osteolytic breast cancer cells and the subsequent communication between the tumor cells and myeloid cells. Examination of large patient databases revealed significant relationships between Gli2 expression and expression of markers of myeloid maturation and activation as well as cytokine expression. We found that treatment with HPI-1 reduced tumor cell expression of numerous cytokine genes, including CSF1, CSF2, and CSF3, as well as CCL2 and IL6. Secreted CSF-1 (M-CSF) was also reduced by treatment. Changes in tumor-secreted factors resulted in polarization of THP-1 monocytes toward a proinflammatory phenotype, characterized by increased CD14 and CD40 surface marker expression. We therefore propose M-CSF as a novel target of Hedgehog inhibition with potential future applications in altering the immune microenvironment in addition to its known roles in reducing tumor-induced bone disease.

Gli2 Overexpression Alters the Differentiation Status of Dedifferentiated Liposarcoma Cells and Results in an Immunosuppressive Myeloid Phenotype in Orthotopic Tumors.

Sarcomas are a rare classification of tumor derived from tissues of mesenchymal origin including bone, fat, muscle, cartilage, and blood vessels. These tumors often grow rapidly and have limited treatment options with few significant therapeutic advances in recent years. Liposarcomas (LPSs), the most common type of malignant soft tissue sarcoma, are derived from mesenchymal progenitors that have undergone an adipogenic lineage commitment compared to their multipotent counterparts. Interestingly, the grade of differentiation within LPS can vary highly, and the differentiation status of these tumors can drastically affect prognosis and likelihood of metastasis, making tumor differentiation a potential mechanism to target in liposarcoma development. Here, we show that overexpression of the Hedgehog transcription factor Gli2 in dedifferentiated liposarcoma (DDLPS) cells represses adipogenic differentiation while simultaneously activating markers of osteoblast differentiation in vitro . In addition, we observed marked differences in cytokine expression and secretion, prompting us to perform orthotopic fat pad injections of control and Gli2 overexpressing DDLPS cells. Using flow cytometry, we observed distinct changes in fat pad macrophage populations, with a particular increase in M2-like macrophages. Taken together, we find that overexpression of Gli2 in DDLPS cells alters their differentiation capacity and interactions between tumor cells and macrophages, highlighting a novel role for this developmental transcription factor in liposarcoma pathogenesis.

Targeting hedgehog-driven mechanisms of drug-resistant cancers.

Due to the cellular plasticity that is inherent to cancer, the acquisition of resistance to therapy remains one of the biggest obstacles to patient care. In many patients, the surviving cancer cell subpopulation goes on to proliferate or metastasize, often as the result of dramatically altered cell signaling and transcriptional pathways. A notable example is the Hedgehog (Hh) signaling pathway, which is a driver of several cancer subtypes and aberrantly activated in a wide range of malignancies in response to therapy. This review will summarize the field's current understanding of the many roles played by Hh signaling in drug resistance and will include topics such as non-canonical activation of Gli proteins, amplification of genes which promote tolerance to chemotherapy, the use of hedgehog-targeted drugs and tool compounds, and remaining gaps in our knowledge of the transcriptional mechanisms at play.

Bioinformatics Screen Reveals Gli-Mediated Hedgehog Signaling as an Associated Pathway to Poor Immune Infiltration of Dedifferentiated Liposarcoma.

Liposarcomas are the most diagnosed soft tissue sarcoma, with most cases consisting of well-differentiated (WDLPS) or dedifferentiated (DDLPS) histological subtypes. While both tumor subtypes can have clinical recurrence due to incomplete resections, DDLPS often has worse prognosis due to a higher likelihood of metastasis compared to its well-differentiated counterpart. Unfortunately, targeted therapeutic interventions have lagged in sarcoma oncology, making the need for molecular targeted therapies a promising future area of research for this family of malignancies. In this work, previously published data were analyzed to identify differential pathways that may contribute to the dedifferentiation process in liposarcoma. Interestingly, Gli-mediated Hedgehog signaling appeared to be enriched in dedifferentiated adipose progenitor cells and DDLPS tumors, and coincidentally Gli1 is often co-amplified with MDM2 and CDK4, given its genomic proximity along chromosome 12q13-12q15. However, we find that Gli2, but not Gli1, is differentially expressed between WDLPS and DDLPS, with a noticeable co-expression signature between Gli2 and genes involved in ECM remodeling. Additionally, Gli2 co-expression had a noticeable transcriptional signature that could suggest Gli-mediated Hedgehog signaling as an associated pathway contributing to poor immune infiltration in these tumors.

Socioeconomic inequalities in vaccine uptake: A global umbrella review.

This global umbrella review aimed to synthesise evidence of socioeconomic inequalities in the uptake of routine vaccinations and identify the mechanisms that may contribute to the association. To our knowledge, no attempt has been made to synthesise the global body of systematic reviews across a variety of vaccines, geographical locations, and measures of SES. The inclusion criteria were as follows: studies assessing vaccination uptake according to education, income, occupation/employment, and/or area-level deprivation; any country or universally recommended routine vaccination (according to the WHO); qualitative or quantitative reviews, published 2011-present. The searches were performed in eight databases. The screening process followed PRISMA-E guidelines, each stage was performed by one reviewer, and a 10% sample checked by a second for consistency. Included reviews underwent data extraction, quality appraisal (AMSTAR-2), and narrative synthesis according to country-context. After deduplication, 9,163 reports underwent title and abstract screening, leaving 119 full texts to be assessed for eligibility. Overall, 26 studies were included in the umbrella review. Evidence for lower uptake amongst disadvantaged SES individuals was found in all 26 reviews. However, 17 reviews showed mixed results, as inverse associations were also identified (lower uptake for advantaged SES, and/or higher uptake for disadvantaged SES). Those that explored high-income countries had a greater prevalence of mixed findings than those focusing on low/middle-income countries. The two most frequently cited mechanisms were vaccination knowledge, and confidence in vaccination or vaccination providers. These mechanisms were often understood by review authors as varying by level of education. We find socioeconomic differences in routine vaccination uptake, but the association did not always follow a gradient. Whilst education may be associated with uptake globally, our study indicates that its role varies by country-context. A limitation is the overlap of some primary studies across the included systematic reviews.

The impact of integrating bioscience and nursing subjects in a first-year nursing curriculum: A retrospective study.

AIM: The aim of this study is to explore the effects of integrating bioscience and nursing units on academic achievement and perception in the first-year nursing curriculum. BACKGROUND: Nursing students have historically found biosciences difficult and struggle to relate it to nursing practice. In response, nursing and non-nursing academics have employed different teaching modes and integration strategies to enhance learning. Despite these efforts, substantial gaps still persist concerning the integration of biosciences within nursing curriculum and the effect of integration on student academic achievement and student perception. DESIGN: Retrospective descriptive. The setting was a large University in Victoria Australia with two undergraduate nursing campuses (metropolitan and non-metropolitan). METHOD: Student academic records and online evaluation surveys that were completed from 2014 to 2019 were examined. Students self-reported their experiences of the unit using a five-point Likert scale and two open-ended questions. Descriptive and inferential statistics were used to analyse the data. Content analysis was used to analyse the two open-response survey items. RESULTS: First-year student records from 2014 to 2016 (pre-integration) and 2017-2019 (post-integration) were examined. Student mean age was 24.5 years (SD 7.2) and 20.9 years (SD 4.8) pre-integration and post-integration respectively. There was a statistically significant decrease in student attrition from pre-integration (n=536, 29.9%) to post-integration (n=358, 20.2%) (p <0.001), and a significant improvement in students' mean academic scores post-integration in the first semester 61.9 (SD 15.9) and 67.0 (SD 14.9) respectively, confidence interval 3.9-6.2 (p <0.001). Student satisfaction with the units improved post-integration, from 77.8% to 85.8% (χ2 = 10.1076) (p=0.001). However, there was no significant difference in students' perception of feeling overwhelmed, and their self-reported ability to link theory to practice. CONCLUSION: Integrating bioscience and clinical nursing practice units in the first-year curriculum can help decrease student attrition rates, improve student academic results and increase student satisfaction which may lead to an overall improvement in student learning experiences.

Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction.

When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 hours, enhancing antitumor immunity through proinflammatory cytokine production and early T-cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after 2 weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction. Significance: Bone metastases are difficult to treat due to the inaccessibility of the bone marrow compartment and the immunosuppressive microenvironment that protects resident stem cells. Packaging a STING agonist into a nanoparticle that enables systemic administration and drug accumulation at tumor sites overcomes both barriers to stymie metastatic breast cancer growth.

Octopus bimaculoides' arm recruitment and use during visually evoked prey capture.

Octopus' limb hyper-redundancy complicates traditional motor control system theory due to its extensive sensory inputs, subsequent decision-making, and arm coordination. Octopuses are thought to reduce flexibility control complexity by relying on highly stereotypical motor primitives (e.g., reaching1,2,3,4 and crawling5) and multi-level processes to coordinate movement,6,7 utilizing extensive peripheral nervous system (PNS) processing.2,8,9 Division of labor along the anterior-posterior axis10 and limb specialization of the four anterior arms in T-maze food retrieval11 further simplify control. However, specific arm recruitment and coordination during visually guided reaching behavior remains poorly understood. Here, we investigated visually evoked Octopus bimaculoides' prey capture capabilities12,13 by eliciting and examining prey-specific arm recruitment. When striking crabs, octopuses preferred synchronous arm recruitment, while sequential arm recruitment with a characteristic swaying movement is employed for shrimp. Such behavioral selection aligns with specific prey escape strategies and the octopus' flexible arm biomechanical constraints. Although side bias existed, we found significant bilateral symmetry, with one side being functionally a mirror of the other rather than anterior arm use being functionally equal and differing to posterior arm use. Among arms, the second limb is unequivocally dominant for goal-directed monocularly driven prey capture. Although the eight arms share gross anatomy and are considered equipotential,10,14 such arm use for specific actions could reflect subtle evolutionary adaptations. Finally, we quantitatively show, corroborating earlier observations,10,15 that octopuses employ a dimension reduction strategy by actively deciding to recruit adjacent arms over other available arms during either sequential or synchronous visually evoked prey attack.

Distress Tolerance and Emotion Regulation as Potential Mediators Between Secondary Traumatic Stress and Maladaptive Coping.

The extant literature has illustrated that protective service workers experience negative repercussions associated with their job (including the development of secondary traumatic stress; STS) and may utilize maladaptive coping mechanisms. Developing an improved understanding of factors that might explain the relationship between STS and the utilization of maladaptive coping mechanisms is warranted. This study sought to examine emotion regulation and distress tolerance as potential mediators between STS and the utilization of maladaptive coping mechanisms. Participants were 152 elder protective service workers and 105 child protective service workers who completed an online survey of self-report measures of emotion regulation, distress tolerance, STS, and coping behaviors. A parallel multiple mediator model was analyzed using structural equation modeling (SEM) to examine the hypothesis that distress tolerance and emotion regulation would mediate the relationship between STS and the utilization of maladaptive coping. Our hypothesis was partially supported as the effect of STS on maladaptive coping was mediated by emotion regulation but not by distress tolerance. The results from this study have both prevention and intervention implications. From a prevention perspective, efforts could be directed at teaching emotion regulation skills to those at risk for developing STS as a mechanism for decreasing the probability of denial, substance use, behavioral disengagement, and self-blame that may occur as a consequence of STS. From an intervention perspective, some of the negative sequelae of exposure to STS may be averted by teaching EPS and CPS workers who present with STS symptoms, emotion regulation skills.

Horizontal integration of bioscience and nursing in first-year nursing curricula: A systematic review.

OBJECTIVES: To systematically identify, appraise and summarise available evidence related to the horizontal integration of bioscience and nursing in first-year nursing curricula; to examine students', nurses' and academics' perceptions of the integration and provide recommendations for future curriculum development, practice and research priorities. DESIGN: A systematic review. DATA SOURCES: An online search of Ovid Medline, Ovid Emcare, CINAHL, Embase Classic + and Embase, ERIC, A+Education, Scopus (Elsevier) and Google Scholar was conducted between July and September 2021. A manual search of the reference list of included articles was also undertaken. REVIEW METHODS: This systematic review followed The PRISMA Statement. The study selection process was managed using the Covidence software platform and quality was assessed using JBI Critical appraisal tools and Mixed Methods Appraisal tools. A narrative synthesis of included studies was undertaken. RESULTS: Six articles were identified which met the inclusion criteria. The study population included students, academics and registered nurses. Four studies used clinical scenarios as a method of horizontally integrating bioscience and nursing content. The integration outcomes were measured by student understanding and learning, satisfaction and motivation. Students', nurses' and academics' perceptions of integration challenges were: i) depth of bioscience content; ii) structure of bioscience content; and iii) knowledge and experience. CONCLUSIONS: This systematic review did not identify a wide range of methods to integrate bioscience in first year nursing curricula. The use of clinical scenarios increased student understanding and learning. However, teaching academics needed to be cognizant of both nursing and bioscience to achieve the required depth of bioscience content and demonstrate integration of bioscience in nursing practice. There is a need for further investigations of methods of horizontal integration of bioscience and nursing in the first-year nursing curricula.

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK.

INTRODUCTION: Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) process recommended VN for patients in England and Wales. We assessed the cost-effectiveness of VN compared with best supportive care (BSC) in individuals with biallelic RPE65-mediated IRD in the UK. METHODS: A Markov model was developed to estimate the incremental cost per quality-adjusted life-year (QALY) gained for VN compared with BSC, from the perspective of the UK National Health Service and Personal Social Services. Phase III trial data were used to inform transition probabilities up to year 1, after which the treatment effect was assumed to be maintained for 40 years, followed by a decline in vision. A bespoke elicitation exercise involving clinical experts, patients and carers was conducted to estimate utility values for each model health state. RESULTS: At list price, VN is associated with incremental costs of £612,404 and incremental QALYs of 6.4, resulting in an incremental cost-effectiveness ratio (ICER) of £95,072 per QALY gained. Voretigene neparvovec is associated with a significant undiscounted QALY gain (20.5) and is therefore eligible for additional QALY weighting under the NICE HST process; an ICER of up to £205,000 per QALY gained could be considered cost-effective under this framework. CONCLUSION: The results of the model show VN to be a cost-effective use of healthcare resources in the UK at list price. The availability of a commercial discount in the UK (as considered in the NICE appraisal) means that in reality the ICER will be even lower. Plain language summary available for this article.

CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina.

Ciliary neurotrophic factor (CNTF) acts in several processes in the vertebrate retina, including neuroprotection of photoreceptors in the stressed adult retina and regulation of neuronal progenitor cell proliferation during retinal development. However, the signaling pathway it utilizes (Jak/Stat, MAPK, or Akt) in these processes is ambiguous. Because dark-adapted albino zebrafish exhibit light-induced rod and cone cell death and subsequently regenerate the lost photoreceptor cells, zebrafish should be a useful model to study the role of CNTF in both neuroprotection and neuronal progenitor cell proliferation. We therefore investigated the potential roles of CNTF in both the undamaged and light-damaged adult zebrafish retinas. Intraocular injection of CNTF suppressed light-induced photoreceptor cell death, which then failed to exhibit the regeneration response that is marked by proliferating Müller glia and neuronal progenitor cells. Inhibiting the MAPK signaling pathway, but neither the Stat3 nor Akt pathways, significantly reduced the CNTF-mediated neuroprotection of light-induced photoreceptor cell death. Intraocular injection of CNTF into non-light-treated (undamaged) eyes mimicked constant intense light treatment by increasing Stat3 expression in Müller glia followed by increasing the number of proliferating Müller glia and neuronal progenitors. Knockdown of Stat3 expression in the CNTF-injected non-light-treated retinas significantly reduced the number of proliferating Müller glia, while coinjection of CNTF with either MAPK or Akt inhibitors did not inhibit the CNTF-induced Müller glia proliferation. Thus, CNTF utilizes a MAPK-dependant signaling pathway in neuroprotection of light-induced photoreceptor cell death and a Stat3-dependant signaling pathway to stimulate Müller glia proliferation.

Intravitreal Ranibizumab for the Treatment of Visual Impairment Due to Choroidal Neovascularization Associated with Rare Diseases: Cost-Effectiveness in the UK.

INTRODUCTION: This study sought to determine the cost-effectiveness of intravitreal ranibizumab compared with best supportive care (BSC; considered to be no active treatment) for the treatment of visual impairment due to choroidal neovascularization (CNV) associated with causes other than neovascular age-related macular degeneration (nAMD) and pathologic myopia (PM) in a UK setting. METHODS: An individual patient-level simulation model was developed to estimate the lifetime costs and quality-adjusted life years (QALYs) of ranibizumab vs. BSC. Regression analyses, performed on patient-level data collected within the pivotal phase III MINERVA trial, modelled visual acuity (VA) progression while patients remained on treatment. Patient utilities were modelled as a function of VA in both eyes and resource use estimates were based on trial data or the literature. Costs were evaluated from the perspective of the UK National Health Service and personal social services, with future costs and health outcomes discounted at 3.5% per annum. Sensitivity and scenario analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for intravitreal ranibizumab was £1363 per QALY compared to BSC and was associated with an incremental benefit of 1.06 QALYs and an incremental cost of £1444 per patient. Drug and administration costs of intravitreal ranibizumab were offset by the prevention of the development of blindness and its associated costs, while the increase in benefits was driven by a reduction in mortality risk and an improved health-related quality of life attributed to an improvement in VA. The findings were robust to a range of sensitivity analyses and ranibizumab consistently remained cost-effective at a willingness-to-pay threshold of £20,000-30,000 per QALY gained for all sensitivity analyses. CONCLUSION: Intravitreal ranibizumab is a highly cost-effective intervention for the treatment of CNV due to causes other than nAMD and PM as it delivers substantial QALY gains to patients while making cost savings vs. BSC. FUNDING: Novartis Pharmaceuticals UK Ltd.