Emicizumab prophylaxis for people with hemophilia A: Waste estimation and the Brazilian perspective.

Costs of hemophilia A treatment are increasing. Waste of clotting products should be avoided. To estimate the first-year waste of emicizumab prophylaxis for people with hemophilia A and inhibitors (PwHAi) who failed immune tolerance induction (ITI), in Brazil. We evaluated the manufacturer and the Brazilian Ministry of Health (MoH) protocol-recommended regimens in a budget impact model. The loading dose consisted of 3.0 mg/kg/Q1W for 4 weeks, for both recommendations. The manufacturer maintenance regimens comprised 1.5 mg/kg/Q1W, 3.0 mg/kg/Q2W, and 6.0 mg/kg/Q4W. The MoH protocol maintenance regimen encompassed a hybrid Q1W/Q2W administration, depending on the body weight. The Q4W regimen was not recommended by the MoH protocol. Analyses were performed to estimate waste given its expense based on the World Health Organization body weight range (percentiles [P] 15, 50, and 85). The first-year emicizumab waste was estimated individually and for the disclosed PwHAi who failed ITI (n = 114). The highest emicizumab waste was estimated for the lowest body weights and the Q1W regimen. The Q4W regimen resulted in the lowest emicizumab waste, followed by the MoH protocol regimen. The total reconstituted costs estimated for the PwHAi who failed ITI according to the hybrid MoH protocol ranged from US$32,858,777 (P15) to US$47,186,858 (P85), with emicizumab waste ranging from 7.9 % (US$2,594,515) to 3.7 % (US$1,738,750), respectively. Lost resources due to current protocols for emicizumab prophylaxis for PwHAi who failed ITI in Brazil are considerable. Waste was more pronounced due to lower body weight and shorter administration intervals.

Examining patient and professional perspectives in the UK for gene therapy in haemophilia.

INTRODUCTION: With the development of gene therapy for people with haemophilia (PWH), it is important to understand how people impacted by haemophilia (PIH) and clinicians prioritise haemophilia treatment attributes to support informed treatment decisions. OBJECTIVE: To examine the treatment attribute preferences of PIH and clinical experts in the United Kingdom (UK) and to develop a profile of gene therapy characteristics fit for use in future discrete choice experiments (DCEs). METHODS: Semi-structured interviews were conducted with PIH (n = 14) and clinical experts (n = 6) who ranked pre-defined treatment attributes by importance. Framework analysis was conducted to identify key themes and treatment attributes; points were allocated based on the rankings. Synthesis of results by a multidisciplinary group informed development of a profile of gene therapy characteristics for use in future research. RESULTS: Key themes identified by PIH and clinical experts included patient relevant features and the importance of 'informed decision making'. The six top-ranked treatment attributes were 'effect on factor level' (79 points), 'uncertainty regarding long-term risks' (57 points), 'impact on daily life' (41 points), 'frequency of monitoring' (33 points), 'impact on ability to participate in physical activity' (29 points), and 'uncertainty regarding long-term benefits' (28 points). The final treatment characteristics were categorised as therapeutic option, treatment effectiveness, safety concerns, impact on self-management and quality of life (role limitations). CONCLUSION: We identified several gene therapy characteristics important to PIH and clinicians in the UK. These characteristics will be used in a future DCE to further investigate patient preferences for gene therapy.

Evidence of a disability paradox in patient-reported outcomes in haemophilia.

INTRODUCTION: People with inherited and long-term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox). AIM: To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population. METHODS: We conducted a discrete choice experiment including duration to capture valuations of health states based on patient-reported preferences. Participants indicated their preferences for hypothetical health states using the EQ-5D-5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional-logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ-5D-5L health states. RESULTS: After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ-5D-5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity. CONCLUSION: Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.

Déjà vu and the entorhinal cortex: dissociating recollective from familiarity disruptions in a single case patient.

Past research has demonstrated a relationship between déjà vu and the entorhinal cortex in patients with wider medial temporal lobe damage. The aim of the present research was to investigate this crucial link in a patient (MR) with a selective lesion to the left lateral entorhinal cortex to provide a more direct exploration of this relationship. Two experiments investigated the experiences of déjà vécu (using the IDEA questionnaire) and déjà vu (using an adapted DRM paradigm) in MR and a set of matched controls. The results demonstrated that MR had quantitatively more and qualitatively richer recollective experiences of déjà vécu. In addition, under laboratory-based déjà vu conditions designed to elicit both false recollection (critical lures) and false familiarity (weakly-associated lures), MR only revealed greater memory impairments for the latter. The present results are therefore the first to demonstrate a direct relationship between the entorhinal cortex and the experience of both déjà vu and déjà vécu. They furthermore suggest that the entorhinal cortex is involved in both weakly-associative false memory as well as strongly-associative memory under conditions that promote familiarity-based processing.

Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: An expert elicitation exercise.

INTRODUCTION: The benefits of physical activity (PA) for people with haemophilia (PWH) may include improvements in joint, bone and muscle health. However, the factor VIII activity level required to avoid a bleeding episode associated with PA is unknown. AIM: To elicit the opinion of clinical experts on the minimum level and ideal factor VIII activity ('level') required to avoid a bleeding episode during participation in different types of PA for PWH. METHODS: Based on the 2017 National Hemophilia Foundation PA descriptions, clinical experts estimated a minimally acceptable and an ideal factor level at which a bleed could be avoided. The uncertainty around estimates was quantified using an approach to construct a probability distribution to represent expert opinion. RESULTS: Minimum and ideal factor level increased with higher risk PA, whether or not joint morbidity was present, as did the experts' uncertainty in their estimates (ie the range between lowest and highest estimates for minimum and ideal levels). Mean minimum levels ranged from 4% to 48% for low to high risk for people without joint morbidity, and from 7% to 47% for those with joint morbidity. For ideal factor levels, corresponding figures were 9%-52% and 12%-64%, respectively. CONCLUSION: To support a patient-centric outcome, expert opinion indicates that the clinical norm of 0.01 IU/mL (1%) trough level is insufficient. It is anticipated that introducing a more targeted approach to meet the needs of patients who are increasingly physically active will benefit patients further in addition to recent treatment advances.

High étendue Fourier transform spectroscopy by quadratic off-axis path difference error cancellation.

Instrumentation design for Fourier transform spectroscopy has until now been hindered by a seemingly fundamental tradeoff between the étendue of the analyzed light source on one hand and the spectral resolution on the other. For example, if a freespace scanning Michelson interferometer is to achieve a spectral resolution of 4cm-1, it can have a maximum angular field of view of roughly 1° for wavelengths in the neighborhood of λ=800nm, where the general tradeoff for this instrument is that the quotient θm2/Δk of the square of the angular field of view θm and the minimum resolvable wavenumber difference Δk is a constant. This paper demonstrates a method to increase the angular field of view allowable for a given resolution by a full order of magnitude, and thus to increase the étendue and, with it, the potential power gathered from an extended source and potential measurement signal-to-noise ratio, by two orders of magnitude relative to the performance of a freespace Michelson interferometer. Generalizing this example, we argue that there may be no fundamental thermodynamic grounds for the tradeoff and that a scanning Fourier transform spectrometer can accept an arbitrarily high étendue field and still, in theory, achieve an arbitrarily narrow spectral resolution.

Avoiding Radical Surgery in Elderly Patients With Rectal Cancer Is Cost-Effective.

BACKGROUND: Radical surgery is associated with significant perioperative mortality in elderly and comorbid populations. Emerging data suggest for patients with a clinical complete response after neoadjuvant chemoradiotherapy that a watch-and-wait approach may provide equivalent survival and oncological outcomes. OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of watch and wait and radical surgery for patients with rectal cancer after a clinical complete response following chemoradiotherapy. DESIGN: Decision analytical modeling and a Markov simulation were used to model long-term costs, quality-adjusted life-years, and cost-effectiveness after watch and wait and radical surgery. Sensitivity analysis was used to investigate the effect of uncertainty in model parameters. SETTINGS: A third-party payer perspective was adopted. PATIENTS: Patients included in the study were a 60-year-old male cohort with no comorbidities, 80-year-old male cohorts with no comorbidities, and 80-year-old male cohorts with significant comorbidities. INTERVENTIONS: Radical surgery and watch-and-wait approaches were studied. MAIN OUTCOME MEASURES: Incremental cost, effectiveness, and cost-effectiveness ratio over the entire lifetime of the hypothetical patient cohorts were measured. RESULTS: Watch and wait was more effective (60-year-old male cohort with no comorbidities = 0.63 quality-adjusted life-years (95% CI, 2.48-3.65 quality-adjusted life-years); 80-year-old male cohort with no comorbidities = 0.56 quality-adjusted life-years (95% CI, 0.52-1.59 quality-adjusted life-years); 80-year-old male cohort with significant comorbidities = 0.72 quality-adjusted life-years (95% CI, 0.34-1.76 quality-adjusted life-years)) and less costly (60-year-old male cohort with no comorbidities = $11,332.35 (95% CI, $668.50-$23,970.20); 80-year-old male cohort with no comorbidities = $8783.93 (95% CI, $2504.26-$21,900.66); 80-year-old male cohort with significant comorbidities = $10,206.01 (95% CI, $2762.014-$24,135.31)) independent of patient cohort age and comorbidity. Consequently, watch and wait was more cost-effective with a high degree of certainty (range, 69.6%-89.2%) at a threshold of $50,000/quality-adjusted life-year. LIMITATIONS: Long-term outcomes were derived from modeled cohorts. Analysis was performed for a United Kingdom third-party payer perspective, limiting generalizability to other healthcare contexts. CONCLUSIONS: Watch and wait is likely to be cost-effective compared with radical surgery. These findings strongly support the discussion of organ-preserving strategies with suitable patients.

Evaluating the use of plerixafor in stem cell mobilisation - an economic analysis of the PHANTASTIC trial.

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc.

Acceptability and willingness to pay for a hypothetical HIV vaccine in Brazil and the implications: a cross-sectional study.

INTRODUCTION: The Human Immunodeficiency Virus (HIV) is one of the greatest public health challenges still facing communities worldwide, and until this moment, no vaccine is available for its prevention. In Brazil, the Rio de Janeiro State has stood out regarding the prevalence of this disease. As a result, an important state to consider the Willingness to Pay (WTP) for a hypothetical HIV vaccine to help with future pricing. METHODS: A cross-sectional study was conducted to assess the acceptability and WTP of individuals from Rio de Janeiro State for a hypothetical HIV vaccine with a 70% efficacy. RESULTS: 600 individuals were interviewed and the acceptability for this hypothetical vaccine was 77.2%. In addition, 452 participants were eligible for the WTP analysis and would accept a WTP US$79.37 (400 BRL) for this vaccine, a higher value than that found in another study (200 BRL) conducted in the Northern region of Brazil under the same methodological conditions. CONCLUSION: Economic studies such as WTP can contribute to discussions regarding the prices and specifications for future vaccines, particularly for a HIV vaccine in countries such as Brazil with over 5,000 municipalities spread across regions with diverse characteristics and challenges in terms of socioeconomic, epidemiological and cultural differences.

Health-Related Quality-of-Life Impacts Associated with Transfusion-Dependent ß-Thalassemia in the USA and UK: A Qualitative Assessment.

BACKGROUND: Individuals living with transfusion-dependent ß-thalassemia (TDT) experience reduced health-related quality of life due to fatigue and chronic pain, which cause disruptions to daily life. Currently, limited qualitative data exist that describe these impacts. OBJECTIVE: This study aimed to examine the ways in which symptoms and current treatments of TDT impact health-related quality of life, to holistically describe the humanistic burden of TDT, and to identify the unmet needs of individuals living with TDT. METHODS: Adults (aged ≥ 18 years) with TDT and caregivers of adolescents (aged 12‒17 years) with TDT participated in semi-structured one-on-one virtual interviews and focus group discussions. Interviews were conducted in the USA and UK and lasted approximately 60 minutes. After transcription, the interviews were analyzed thematically using a framework approach. RESULTS: A total of ten interviews/focus group discussions (six interviews and four focus group discussions) were conducted with 14 adults with TDT and two caregivers of adolescents with TDT. A framework analysis revealed five themes describing health-related quality of life (negative impacts on daily activities, social life, family life, work and education, and psychological well-being) and three themes describing the lived experience of TDT (impact of red blood cell transfusions and iron chelation therapy, treatment, and stigma). Physical, psychological, and treatment-related factors contributed to negative impacts on daily activities, social and family life, and work and education. Concerns about reduced lifespan, relationships and family planning, and financial independence were detrimental to participants' mental well-being. Participants reported having high resilience to the many physical and psychological challenges of living with TDT. A lack of TDT-specific knowledge among healthcare professionals, particularly regarding chronic pain associated with the disease, left some participants feeling ignored or undermined. Additionally, many participants experienced stigma and were reluctant to disclose their disease to others. CONCLUSIONS: Individuals living with TDT experience substantial negative impacts on health-related quality of life that disrupt their daily lives, disruptions that are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma. Our study highlights the unmet needs of individuals living with TDT, especially for alternative treatments that reduce or eliminate the need for red blood cell transfusions and iron chelation therapy.

Recommendations to address respondent burden associated with patient-reported outcome assessment.

Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.

Reliability of Long Vein Grafts for Reconstruction of Massive Wounds.

When handling large wounds, zone of injury is a key concept in reconstructive microsurgery, as it pertains to the selection of recipient vessels. Historically, surgeons have avoided placing microvascular anastomosis within widely traumatized, inflamed, or radiated fields. The harvest of vein grafts facilitates reconstruction in complex cases by extending arterial and/or venous pedicle length. To illustrate the utility and fidelity of these techniques, this paper reviews the indications and outcomes for vein grafting in ten consecutive patients at a single tertiary referral center hospital. The case series presented is unique in three aspects. First, there are two cases of successful coaptation of the flap artery to the side of the arterial limb of an arteriovenous loop. Second, there is a large proportion of cases where vein grafts were used to elongate the venous pedicle. In these 10 cases, the mean vein graft length was 37 cm. We observed zero flap failures and zero amputations. Although limited in sample size, these case data support the efficacy and reliability of long segment vein grafting in complex cases in referral centers.

Economic Evaluation of Immune Tolerance Induction in Children With Severe Hemophilia A and High-Responding Inhibitors: A Cost-Effectiveness Analysis of Prophylaxis With Emicizumab.

OBJECTIVE: This study aimed to measure the cost-effectiveness of prophylaxis with emicizumab in PsHAhri on ITI in Brazil. METHODS: A cost-effectiveness modeling analysis was used to estimate the costs per PsHAhri on ITI and the number of prevented bleedings from undertaking one intervention (prophylaxis with BpA) over another (prophylaxis with emicizumab), based on the Brazilian Ministry of Health perspective. Costs of ITI with recombinant FVIII, prophylaxis with BpA or emicizumab, and treated bleeding episodes with BpA costs were evaluated for PsHAhri who had ITI success or failure. This study was conducted with the perspective of the Brazilian Ministry of Health (payer). RESULTS: During ITI, prophylaxis with BpA cost US $924 666/PsHAhri/ITI, whereas prophylaxis with emicizumab cost US $488 785/PsHAhri/ITI. During ITI, there was an average of 9.32 bleeding episodes/PsHAhri/ITI when BpA were used as prophylaxis and 0.67 bleeding/PsHAhri/ITI when emicizumab was used. By univariate deterministic sensitivity analysis, emicizumab remained dominant whichever variable was modified. CONCLUSION: In this study, prophylaxis with emicizumab during ITI is a dominant option compared with prophylaxis with BpA during ITI.

Health state utilities for beta-thalassemia: a time trade-off study.

BACKGROUND: Beta-thalassemia (BT) is an inherited blood disorder characterized by reduced levels of functional hemoglobin resulting in phenotypes ranging from clinically asymptomatic to severely anemic. Patients with BT may require lifelong regular blood transfusions supported by appropriate iron chelation therapy (ICT). This study aimed to determine how the UK general population values BT health states associated with differing transfusion burden and ICT. METHODS: Composite time trade-off (cTTO) methodology was employed to elicit health state utilities in BT. Relevant BT literature related to symptom and quality-of-life impact, including physical, functional, and emotional well-being, and safety profiles of BT treatments were considered when drafting health state descriptions. Eleven health state descriptions were developed and validated by hematologists and patient advocates for clinical accuracy and completeness. 200 individuals from the UK general population participated in the cTTO interviews. RESULTS: The mean age of participants was 41.50 years (SD 16.01, range 18-81); 88 (46.8%) were female. Utility values ranged from 0.78 (SD 0.34) for non-transfusion dependent BT with oral ICT to 0.37 (SD 0.50) for high transfusion burden with subcutaneous ICT in transfusion-dependent BT. CONCLUSIONS: This study provides health utilities for a range of BT health states from the UK general population perspective. Importantly, lower transfusion burden and lower burden of anemia were associated with higher utilities. To a lesser extent, differential modes of ICT were found to impact utility valuations in patients with BT. The utilities obtained in this study can be employed as inputs in cost-effectiveness analyses of BT therapies.

High invertase activity in tomato reproductive organs correlates with enhanced sucrose import into, and heat tolerance of, young fruit.

Heat stress can cause severe crop yield losses by impairing reproductive development. However, the underlying mechanisms are poorly understood. We examined patterns of carbon allocation and activities of sucrose cleavage enzymes in heat-tolerant (HT) and -sensitive (HS) tomato (Solanum lycopersicum L.) lines subjected to normal (control) and heat stress temperatures. At the control temperature of 25/20 °C (day/night) the HT line exhibited higher cell wall invertase (CWIN) activity in flowers and young fruits and partitioned more sucrose to fruits but less to vegetative tissues as compared to the HS line, independent of leaf photosynthetic capacity. Upon 2-, 4-, or 24-h exposure to day or night temperatures of 5 °C or more above 25/20 °C, cell wall (CWIN) and vacuolar invertases (VIN), but not sucrose synthase (SuSy), activities in young fruit of the HT line were significantly higher than those of the HS line. The HT line had a higher level of transcript of a CWIN gene, Lin7, in 5-day fruit than the HS line under control and heat stress temperatures. Interestingly, heat induced transcription of an invertase inhibitor gene, INVINH1, but reduced its protein abundance. Transcript levels of LePLDa1, encoding phospholipase D, which degrades cell membranes, was less in the HT line than in the HS line after exposure to heat stress. The data indicate that high invertase activity of, and increased sucrose import into, young tomato fruit could contribute to their heat tolerance through increasing sink strength and sugar signalling activities, possibly regulating a programmed cell death pathway.

COMplex mental health PAThways (COMPAT) Study: A mixed methods study to inform an evidence-based service delivery model for people with complex needs: Study protocol.

BACKGROUND: Mental health services for adults, as they are currently configured, have been designed to provide predominantly community-based interventions. It has long been recognised that some patients have such significant clinical and/or risk needs that those needs cannot be adequately met within standard service delivery models, resulting in a pressing need to consider the best models for this group of people. This paper shares a protocol for a mixed methods study that aims to understand: the profile and history of service users described as having complex needs; the decision-making processes by clinicians that lead to complex needs categorisation; service users and carers experience of service use; and, associated economic impact. This protocol describes a comprehensive evaluation that aims to inform an evidence-based service delivery model for people with complex needs. METHODS: We will use a mixed methods design, combining quantitative and qualitative methods using in-depth descriptive and inferential analysis of patient records, written medical notes and in-depth interviews with service users, carers, and clinicians. The study will include five components: (1) a quantitative description and analysis of the demographic clinical characteristics of the patient group; (2) an economic evaluation of alternative patient pathways; (3) semi-structured interviews about service user and carer experiences; (4) using data from components 1-3 to co-produce vignettes jointly with relevant stakeholders involved in the care of service users with complex mental health needs; and, (5) semi-structured interviews about clinical decision-making by clinicians in relation to this patient group, using the vignettes as example case studies. DISCUSSION: The study's key outcomes will be to: examine the resource use and cost-impact associated with alternative care pathways to the NHS and other sectors of the economy (including social care); explore patient health and non-health outcomes associated with alternative care pathways; and, gain an understanding of a complex service user group and how treatment decisions are made to inform consistent and person-centred future service delivery.

Willingness to pay for a hypothetical malaria vaccine in Brazil: a cross-sectional study and the implications.

Aim: Malaria is an infection caused by protozoa of genus Plasmodium, considered the one associated with increasingly large outbreaks. Methods: A cross-sectional study was conducted with residents in the northern region of Brazil on the willingness to pay (WTP) for a hypothetical vaccine against malaria (effective protection of 80%). Results: Of 616 people interviewed, most interviewees were female (61%) and were employed (97%). The median individual maximum WTP for a hypothetical malaria vaccine was US$11.90 (BRL 50). Conclusion: The northern region of Brazil is one of the largest markets for a malaria vaccine due to its epidemiological relevance. Consequently, economic studies will be important to assist in the assessment of the potential price and value of new vaccines.

GIGANTEA is a component of a regulatory pathway determining wall ingrowth deposition in phloem parenchyma transfer cells of Arabidopsis thaliana.

Transfer cells are specialised transport cells containing invaginated wall ingrowths that generate an amplified plasma membrane surface area with high densities of transporter proteins. They trans-differentiate from differentiated cells at sites at which enhanced rates of nutrient transport occur across apo/symplasmic boundaries. Despite their physiological importance, little is known of the molecular mechanisms regulating construction of their intricate wall ingrowths. We investigated the genetic control of wall ingrowth formation in phloem parenchyma transfer cells of leaf minor veins in Arabidopsis thaliana. Wall ingrowth development in these cells is substantially enhanced upon exposing plants to high-light or cold treatments. A hierarchical bioinformatic analysis of public microarray datasets derived from the leaves of plants subjected to these treatments identified GIGANTEA (GI) as one of 46 genes that are commonly up-regulated twofold or more under both high-light and cold conditions. Histological analysis of the GI mutants gi-2 and gi-3 showed that the amount of phloem parenchyma containing wall ingrowths was reduced 15-fold compared with wild-type. Discrete papillate wall ingrowths were formed in gi-2 plants but failed to develop into branched networks. Wall ingrowth development in gi-2 was not rescued by exposing these plants to high-light or cold conditions. In contrast, over-expression of GI in the gi-2 background restored wall ingrowth deposition to wild-type levels. These results indicate that GI regulates the ongoing development of wall ingrowth networks at a point downstream of inputs from environmental signals.

Economic evaluation of different routes of surgery for the management of endometrial cancer: a retrospective cohort study.

OBJECTIVES: The benefits of minimally invasive surgery (MIS) for endometrial carcinoma (EC) are well established although the financial impact of robotic-assisted hysterectomy (RH) compared with laparoscopic hysterectomy (LH) is disputed. DESIGN: Retrospective cohort study. SETTING: English National Health Service hospitals 2011-2017/2018. PARTICIPANTS: 35 304 women having a hysterectomy for EC identified from Hospital Episode Statistics. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the association between route of surgery on cost at intervention, 30, 90 and 365 days for women undergoing an open hysterectomy (OH) or MIS (LH/RH) for EC in England. The average marginal effect was calculated to compare RH versus OH and RH versus LH which adjusted for any differences in the characteristics of the surgical approaches. Secondary outcomes were to analyse costing data for each surgical approach by age, Charlson Comorbidity Index (CCI) and hospital MIS rate classification. RESULTS: A total of 35 304 procedures were performed, 20 405 (57.8%) were MIS (LH: 18 604 and RH: 1801), 14 291 (40.5%) OH. Mean cost for LH was significantly less than RH, whereas RH was significantly less than OH at intervention, 30, 90 and 365 days (p<0.001). Over time, patients who underwent RH had increasing CCI scores and by the 2015/2016 year had a higher average CCI than LH. Comparing the cost of LH and RH against CCI score identified that the costs closely reflected the patients' CCI. Increasing disparity was also seen between the MIS and OH costs with rising age. When exploring the association between provider volume, MIS rate and surgical costs, there was an association with the higher the MIS rate the lower the average cost. CONCLUSIONS: Further research is needed to investigate costs in matched patient cohorts to determine the optimum surgical modality in different populations.