DEFINING INNOVATION WITH RESPECT TO NEW MEDICINES: A SYSTEMATIC REVIEW FROM A PAYER PERSPECTIVE.

OBJECTIVES: The aim of this study was to investigate how innovation is defined with respect to new medicines. METHODS: MEDLINE, Embase, and EconLit databases were searched for articles published between January 1, 2010 and May 25, 2016 that described a relevant definition of innovation. Identified definitions were analyzed by mapping the concepts described onto a set of ten dimensions of innovation. RESULTS: In total, thirty-six articles were included, and described a total of twenty-five different definitions of innovation. The most commonly occurring dimension was therapeutic benefit, with novelty and the availability of existing treatments the second and third most common dimensions. Overall, there was little agreement in the published literature on what characteristics of new medicines constitute rewardable innovation. CONCLUSIONS: Alignment across countries and among regulators, health technology assessment bodies and payers would help manufacturers define research policies that can drive innovation, but may be challenging, as judgements about what aspects of innovation should be rewarded vary among stakeholders, and depend on political and societal factors.

Endometrial hyperplasia in pre-menopausal women: A systematic review of incidence, prevalence, and risk factors.

OBJECTIVES: Hormonal therapies have been associated with a range of effects on the endometrium, including endometrial hyperplasia (EH). With many medicinal products being developed for pre-menopausal women, epidemiological data regarding the population background risk could meaningfully supplement comparative risk data gathered in clinical trials. However, epidemiological studies on EH often focus on post-menopausal women. We aimed to assess the available observational evidence on the incidence and prevalence of EH among pre-menopausal women and to investigate the influence of specific risk factors. STUDY DESIGN: We conducted systematic literature searches on 27 August 2021, using the Embase and PubMed databases. Searches were designed to identify studies of EH epidemiology, published in English on or after 1 January 1995, in populations of predominantly pre-menopausal women. Studies were required to report diagnostic histopathology data for at least 500 women. Relevant outcomes were the prevalence and incidence of EH, and/or the impact of pre-specified risk factors including age, body mass index (BMI) and diabetes mellitus. RESULTS: In total, 3785 records were screened, and 31 references, describing 29 different studies, were included in the review. The incidence of EH among pre-menopausal women increased with age and was as high as 121 and 270 cases per 100,000 woman-years in South Korean women aged 46-50 years and US women aged 45-49 years, respectively. The prevalence of EH was highly dependent on the population studied. Estimates of EH prevalence in 14 studies of pre-menopausal women with abnormal uterine bleeding (AUB) ranged from 3.4% to 265%, higher than the reported prevalence in two studies of women with infertility (0.9% and 3.0%). Studies of risk factors found increasing age, BMI and diabetes to be associated with an increased prevalence of EH. CONCLUSIONS: Published data on the epidemiology of EH in pre-menopausal women are heterogeneous, with considerable variation in study methodology and populations, and in how EH subtypes are reported. The main factors affecting the reported prevalence and incidence of EH are the reason a biopsy was performed - particularly whether patients had AUB, a key symptom associated with EH - and the presence of known risk factors.

Pulmonary thromboembolic events in COVID-19-A systematic literature review.

Pulmonary thromboembolic events have been linked to coronavirus disease 2019 (COVID-19), but their incidence and long-term sequelae remain unclear. We performed a systematic literature review to investigate the incidence of pulmonary embolism (PE), microthrombi, thrombosis in situ (thromboinflammatory disease), and chronic thromboembolic pulmonary hypertension (CTEPH) during and after COVID-19. PubMed and the World Health Organization Global Research Database were searched on May 7, 2021. Hospital cohort and database studies reporting data for ≥1000 patients and autopsy studies reporting data for ≥20 patients were included. Results were summarized descriptively. We screened 1438 records and included 41 references (32 hospital/database studies and 9 autopsy studies). The hospital/database studies reported the incidence of PE but not CTEPH, microthrombi, or thromboinflammatory disease. PE incidence varied widely (0%-1.1% of outpatients, 0.9%-8.2% of hospitalized patients, and 1.8%-18.9% of patients in intensive care). One study reported PE events occurring within 45 days after hospital discharge (incidence in discharged patients: 0.2%). Segmental arteries were generally the most common location for PE. In autopsy studies, PE, thromboinflammatory disease, and microthrombi were reported in 6%-23%, 43%-100%, and 45%-84% of deceased patients, respectively. Overall, the included studies mostly focused on PE during the acute phase of COVID-19. The results demonstrate the challenges of identifying and characterizing vascular abnormalities using current protocols (e.g., visual computed tomography reads). Further research is needed to detect subtle pulmonary vascular abnormalities, distinguish thromboinflammatory disease from PE, optimize treatment, and assess the incidence of long-term sequelae after COVID-19.

Patient Preferences for Subcutaneous versus Intravenous Administration of Treatment for Chronic Immune System Disorders: A Systematic Review.

BACKGROUND: For many chronic immune system disorders, the available treatments provide several options for route of administration. The objective of this systematic literature review is to inform discussions about therapy choices for individual patients by summarizing the available evidence regarding the preferences of patients with chronic immune system disorders for intravenous (IV) or subcutaneous (SC) administration. METHODS: Searches of the MEDLINE, Embase and Cochrane Library databases were conducted using terms designed to capture studies reporting patient preferences between IV and SC therapy published in English. Relevant studies were limited to those in which mode of administration, including treatment frequency and setting, was the main difference between comparators. RESULTS: In total, 49 studies were included in the review. Among 18 studies that compared IV and SC immunoglobulin therapy, 16 found patients to prefer the SC administration route. The results of the 31 studies comparing IV infusion and SC injection of non-immunoglobulin therapies were mixed, with patients favoring SC administration in 20, IV infusion in seven, and having no overall preference in four. Patient experience had a strong effect on preferences, with treatment-experienced patients preferring their current administration route in most studies. Patients preferring SC administration tended also to prefer treatment at home, mainly due to the convenience and comfort of home treatment and the avoidance of having to attend hospital. By contrast, patients preferring IV infusion tended to cite the lower treatment frequency and a dislike of self-injecting, and preferred hospital treatment, mainly due to the presence of healthcare professionals and resulting feelings of safety. CONCLUSION: In general patients with chronic immune system disorders tend to be more likely to choose SC administration than IV infusion, but preferences may vary according among individuals. These findings may assist discussions around appropriate treatment choices for each patient.

Defining and Measuring the Affordability of New Medicines: A Systematic Review.

BACKGROUND: In many healthcare systems, affordability concerns can lead to restrictions on the use of expensive efficacious therapies. However, there does not appear to be any consensus as to the terminology used to describe affordability, or the thresholds used to determine whether new drugs are affordable. OBJECTIVES: The aim of this systematic review was to investigate how affordability is defined and measured in healthcare. METHODS: MEDLINE, EMBASE and EconLit databases (2005-July 2016) were searched using terms covering affordability and budget impact, combined with definitions, thresholds and restrictions, to identify articles describing a definition of affordability with respect to new medicines. Additional definitions were identified through citation searching, and through manual searches of European health technology assessment body websites. RESULTS: In total, 27 definitions were included in the review. Of these, five definitions described affordability in terms of the value of a product; seven considered affordability within the context of healthcare system budgets; and 15 addressed whether products are affordable in a given country based on economic factors. However, there was little in the literature to indicate that the price of medicines is considered alongside both their value to individual patients and their budget impact at a population level. CONCLUSIONS: Current methods of assessing affordability in healthcare may be limited by their focus on budget impact. A more effective approach may involve a broader perspective than is currently described in the literature, to consider the long-term benefits of a therapy and cost savings elsewhere in the healthcare system, as well as cooperation between healthcare payers and the pharmaceutical industry to develop financing models that support sustainability as well as innovation.

A mosaic genetic screen for novel mutations affecting Drosophila neuroblast divisions.

BACKGROUND: The asymmetric segregation of determinants during cell division is a fundamental mechanism for generating cell fate diversity during development. In Drosophila, neural precursors (neuroblasts) divide in a stem cell-like manner generating a larger apical neuroblast and a smaller basal ganglion mother cell. The cell fate determinant Prospero and its adapter protein Miranda are asymmetrically localized to the basal cortex of the dividing neuroblast and segregated into the GMC upon cytokinesis. Previous screens to identify components of the asymmetric division machinery have concentrated on embryonic phenotypes. However, such screens are reaching saturation and are limited in that the maternal contribution of many genes can mask the effects of zygotic loss of function, and other approaches will be necessary to identify further genes involved in neuroblast asymmetric division. RESULTS: We have performed a genetic screen in the third instar larval brain using the basal localization of Miranda as a marker for neuroblast asymmetry. In addition to the examination of pupal lethal mutations, we have employed the MARCM (Mosaic Analysis with a Repressible Cell Marker) system to generate postembryonic clones of mutations with an early lethal phase. We have screened a total of 2,300 mutagenized chromosomes and isolated alleles affecting cell fate, the localization of basal determinants or the orientation of the mitotic spindle. We have also identified a number of complementation groups exhibiting defects in cell cycle progression and cytokinesis, including both novel genes and new alleles of known components of these processes. CONCLUSION: We have identified four mutations which affect the process of neuroblast asymmetric division. One of these, mapping to the imaginal discs arrested locus, suggests a novel role for the anaphase promoting complex/cyclosome (APC/C) in the targeting of determinants to the basal cortex. The identification and analysis of the remaining mutations will further advance our understanding of the process of asymmetric cell division. We have also isolated a number of mutations affecting cell division which will complement the functional genomics approaches to this process being employed by other laboratories. Taken together, these results demonstrate the value of mosaic screens in the identification of genes involved in neuroblast division.

The Drosophila HMG-domain proteins SoxNeuro and Dichaete direct trichome formation via the activation of shavenbaby and the restriction of Wingless pathway activity.

Trichomes are cytoplasmic extrusions of epidermal cells. The molecular mechanisms that govern the differentiation of trichome-producing cells are conserved across species as distantly related as mice and flies. Several signaling pathways converge onto the regulation of a conserved target gene, shavenbaby (svb, ovo), which, in turn, stimulates trichome formation. The Drosophila ventral epidermis consists of the segmental alternation of two cell types that produce either naked cuticle or trichomes called denticles. The binary choice to produce naked cuticle or denticles is affected by the transcriptional regulation of svb, which is sufficient to cell-autonomously direct denticle formation. The expression of svb is regulated by the opposing gradients of two signaling molecules--the epidermal growth factor receptor (Egfr) ligand Spitz (Spi), which activates svb expression, and Wingless (Wg), which represses it. It has remained unclear how these opposing signals are integrated to establish a distinct domain of svb expression. We show that the expression of the high mobility group (HMG)-domain protein SoxNeuro (SoxN) is activated by Spi, and repressed by Wg, signaling. SoxN is necessary and sufficient to cell-autonomously direct the expression of svb. The closely related protein Dichaete is co-regulated with SoxN and has a partially redundant function in the activation of svb expression. In addition, we show that SoxN and Dichaete function upstream of Wg and antagonize Wg pathway activity. This suggests that the expression of svb in a discreet domain is resolved at the level of SoxN and Dichaete.

Asymmetric localisation of Miranda and its cargo proteins during neuroblast division requires the anaphase-promoting complex/cyclosome.

Asymmetric cell divisions generate cell fate diversity during both invertebrate and vertebrate development. Drosophila neural progenitors or neuroblasts (NBs) each divide asymmetrically to produce a larger neuroblast and a smaller ganglion mother cell (GMC). The asymmetric localisation of neural cell fate determinants and their adapter proteins to the neuroblast cortex during mitosis facilitates their preferential segregation to the GMC upon cytokinesis. In this study we report a novel role for the anaphase-promoting complex/cyclosome (APC/C) during this process. Attenuation of APC/C activity disrupts the asymmetric localisation of the adapter protein Miranda and its associated cargo proteins Staufen, Prospero and Brat, but not other components of the asymmetric division machinery. We demonstrate that Miranda is ubiquitylated via its C-terminal domain; removal of this domain disrupts Miranda localisation and replacement of this domain with a ubiquitin moiety restores normal asymmetric Miranda localisation. Our results demonstrate that APC/C activity and ubiquitylation of Miranda are required for the asymmetric localisation of Miranda and its cargo proteins to the NB cortex.

Functions of the segment polarity genes midline and H15 in Drosophila melanogaster neurogenesis.

The Drosophila melanogaster ventral nerve cord derives from neural progenitor cells called neuroblasts. Individual neuroblasts have unique gene expression profiles and give rise to distinct clones of neurons and glia. The specification of neuroblast identity provides a cell intrinsic mechanism which ultimately results in the generation of progeny which are different from each other. Segment polarity genes have a dual function in early neurogenesis: within distinct regions of the neuroectoderm, they are required both for neuroblast formation and for the specification of neuroblast identity. Previous studies of segment polarity gene function largely focused on neuroblasts that arise within the posterior part of the segment. Here we show that the segment polarity gene midline is required for neuroblast formation in the anterior-most part of the segment. Moreover, midline contributes to the specification of anterior neuroblast identity by negatively regulating the expression of Wingless and positively regulating the expression of Mirror. In the posterior-most part of the segment, midline and its paralog, H15, have partially redundant functions in the regulation of the NB marker Eagle. Hence, the segment polarity genes midline and H15 play an important role in the development of the ventral nerve cord in the anterior- and posterior-most part of the segment.

Evidence for differential and redundant function of the Sox genes Dichaete and SoxN during CNS development in Drosophila.

Group B Sox-domain proteins encompass a class of conserved DNA-binding proteins expressed from the earliest stages of metazoan CNS development. In all higher organisms studied to date, related Group B Sox proteins are co-expressed in the developing CNS; in vertebrates there are three (Sox1, Sox2 and Sox3) and in Drosophila there are two (SoxNeuro and Dichaete). It has been suggested there may be a degree of functional redundancy in Sox function during CNS development. We describe the CNS phenotype of a null mutation in the Drosophila SoxNeuro gene and provide the first direct evidence for both redundant and differential Sox function during CNS development in Drosophila. In the lateral neuroectoderm, where SoxNeuro is uniquely expressed, SoxNeuro mutants show a loss or reduction of achaete expression as well as a loss of many correctly specified lateral neuroblasts. By contrast, in the medial neuroectoderm, where the expression of SoxNeuro and Dichaete overlaps, the phenotypes of both single mutants are mild. In accordance with an at least partially redundant function in that region, SoxNeuro/Dichaete double mutant embryos show a severe neural hypoplasia throughout the central nervous system, as well as a dramatic loss of achaete expressing proneural clusters and medially derived neuroblasts. However, the finding that Dichaete and SoxN exhibit opposite effects on achaete expression within the intermediate neuroectoderm demonstrates that each protein also has region-specific unique functions during early CNS development in the Drosophila embryo.