Cost effectiveness of treatments for wet age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in people aged >= 50 years. Wet AMD in particular has a major impact on patient quality of life and imposes substantial burdens on healthcare systems. This systematic review examined the cost-effectiveness data for current therapeutic options for wet AMD. PubMed and EMBASE databases were searched for all articles reporting original cost-effectiveness analyses of wet AMD treatments. The Centre for Reviews and Dissemination and Cochrane Library databases were searched for all wet AMD health technology assessments (HTAs). Overall, 44 publications were evaluated in full and included in this review. A broad range of cost-effectiveness analyses were identified for the most commonly used therapies for wet AMD (pegaptanib, ranibizumab and photodynamic therapy [PDT] with verteporfin). Three studies evaluated the cost effectiveness of bevacizumab in wet AMD. A small number of analyses of other treatments, such as laser photocoagulation and antioxidant vitamins, were also found. Ranibizumab was consistently shown to be cost effective for wet AMD in comparison with all the approved wet AMD therapies (four of the five studies identified showed ranibizumab was cost effective vs usual care, PDT or pegaptanib); however, there was considerable variation in the methodology for cost-effectiveness modelling between studies. Findings from the HTAs supported those from the PubMed and EM BASE searches; of the seven HTAs that included ranibizumab, six (including HTAs for Australia, Canada and the UK) concluded that ranibizumab was cost effective for the treatment of wet AMD; most compared ranibizumab with PDT and/or pegaptanib. By contrast, HTAs at best generally recommended pegaptanib or PDT for restricted use in subsets of patients with wet AMD. In the literature analyses, pegaptanib was found to be cost effective versus usual/best supportive care (including PDT) or no treatment in one of five studies; the other four studies found pegaptanib was of borderline cost effectiveness depending on the stage of disease and time horizon. PDT was shown to be cost effective versus usual/best supportive care or no treatment in five of nine studies; two studies showed that PDT was of borderline cost effectiveness depending on baseline visual acuity, and two showed that PDT was not cost effective. We identified no robust studies that properly evaluated the cost effectiveness of bevacizumab in wet AMD

Cost-effectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment : evidence from the RESTORE trial

Background/aims To evaluate the cost-effectiveness of ranibizumab as either monotherapy or combined with laser therapy, compared with laser monotherapy, in the treatment of diabetic macular oedema (DME) causing visual impairment from a UK healthcare payer perspective. Methods A Markov model simulated long-term outcomes and costs of treating DME in one eye (BCVA <= 5 letters) based on data from the RESTORE Phase III trial. Outcomes measured in quality-adjusted life-years (QALYs) were simulated for a 15-year time horizon based on 12-month follow-up from RESTORE and published long-term data. Costs included treatment, disease monitoring, visual impairment and blindness (at 2010 price levels). Results Ranibizumab monotherapy resulted in a 0.17 QALY gain at an incremental cost of 4191 pound relative to laser monotherapy, yielding an incremental cost-effectiveness ratio (ICER) of 24 pound 028. Probabilistic sensitivity analysis showed a 64% probability of being cost-effective at a threshold of 30 pound 000 per QALY. Combined ranibizumab and laser therapy resulted in a 0.13 QALY gain at an incremental cost of 4695 pound relative to laser monotherapy (ICER 36 pound 106; 42% probability of ICER <30 pound 000). Conclusions Based on RESTORE 1-year follow-up data, ranibizumab monotherapy appears to be cost-effective relative to laser monotherapy, the current standard of care. Cost-effectiveness of combination therapy is less certain. Ongoing studies will further inform on disease progression and the need for additional ranibizumab treatment

Response-irrelevant number, duration and extent information triggers the SQARC effect: Evidence from an implicit paradigm

Spatial–Numerical Association Of Response Codes (SNARC) and Spatial–Quantity Association Of Response Codes (SQARC) effects are evident when people produce faster leftsided responses to smaller numbers, sizes and durations and faster right-sided responses to larger numbers, sizes and durations. SQARC effects have typically been demonstrated in paradigms where the explicit processing of quantity information is required for successful task completion. The current study tested whether the implicit presentation of task-irrelevant magnitude information could trigger a SQARC effect as has been demonstrated previously when task-irrelevant information triggers a SNARC effect (Mitchell, Bull & Cleland, 2012). In Experiment 1 participants (n = 20) made orientation judgments for triangles varying in numerosity and physical extent. In Experiment 2 participants (n = 20) made orientation judgments for triangles varying in numerosity and for a triangle preceded by a delay of varying duration. SNARC effects were observed for the numerosity conditions of Experiment 1 and 2 replicating Mitchell et al., (2012). SQARC effects were also demonstrated for physical extent and for duration. These findings demonstrate that SQARC effects can be implicitly triggered by the presentation of the task-irrelevant magnitude

The effect of face mask wearing on language processing and emotion recognition in young children

Face mask wearing was an important preventative strategy for the transmission of the COVID-19 virus. However, the effects that occluding the mouth and nose area with surgical masks could have on young children’s language processing and emotion recognition skills have received little investigation. To evaluate the possible effects, the current study recruited a sample of 74 children from the North West of England (aged 4–8 years). They completed two computer-based tasks with adults wearing or not wearing surgical face masks to assess (a) language processing skills and (b) emotion recognition ability. To control for individual differences, age, sex, receptive vocabulary, early reading skills, and parent-reported social–emotional competence were included in analyses. The findings from the study highlighted that although younger children were less accurate than older children, face masks did not significantly impair basic language processing ability. However, they had a significant effect on the children’s emotion recognition accuracy—with masked angry faces more easily recognized and masked happy and sad faces less easily recognized. Children’s age and social-emotional skills also played a role. The findings suggest that the effects of face masks should continue to be evaluated

Reliability and Confirmatory Factor Analysis (CFA) of a Paper- Versus App-Administered Resilience Scale in Scottish Youths: Comparative Study

Background: Adequately measuring resilience is important in order to support young people and children who may need to access resources through social work or educational settings. A widely accepted measure of youth resilience has been developed by Ungar and Liebenberg which has been shown to work within vulnerable youth [1]. While the measure is completed by the young person on paper, it has been designed to be worked through with a teacher or social worker in case further clarification is required. However, this method is time consuming and when faced with large groups of pupils who need assessing can be overwhelming for schools and practitioners. The current study assesses app software with a built-in avatar who can guide the young person through the assessment and its interpretation. Objective: The primary objective is to compare the reliability and psychometric properties of a mobile software app to a paper version of the Child and Youth Resilience measure (CYRM-28). Secondly, the study will assess the use of the CYRM-28 in a Scottish youth population (11-18 years). Methods: Following focus groups and discussion with teachers, social workers and young people, an avatar was developed by a software company and integrated into an android smartphone app designed to ask questions via the device’s inbuilt text-to-voice engine. Seven-hundred and fourteen students from two schools in North East Scotland completed either a paper version or app version of the CYRM-28. A cross-sectional design was used and students completed their allocated version twice, with a twoweek period in between each testing. All participants could request clarification either from a guidance teacher (paper version) or from the in-built software glossary (app version). Results: Test and retest correlations showed that the app version performed better than the paper version of the questionnaire. Paper (r(303)=.81, p<.001, 95%CI [.77, .85]); App (r(413)=.84, p <.001, 95%CI [.79, .89]). Fisher’s r to z transformation found the difference in the correlations to be statistically significant, Z=-2.97, p <.01. Similarly, Cronbach’s alpha in both conditions was very high (app: ?=.92; paper: ?=.87). Such a high Cronbach’s alpha indicates there may be item redundancy. Ordinarily this would lead to a possible removal of highly correlated items, however the primary aim of the current study is a comparison of app delivery method over a pen-and-paper mode and therefore outside the parameters of this paper. This will be considered in the discussion. Fisher’s r to z transformation found the difference in the correlations to be statistically significant [Z=-3.69, p <.01]. A confirmatory factor analysis [2] supported the three-factor solution (individual, relational and contextual) and reported a good model fit (?2 (15, N= 541) = 27.6, p=0.24). Conclusions: ALEX, an avatar with an integrated voice guide, increased reliability when measuring resilience compared to a paper versio

A longitudinal study looking at the impact of COVID-19 restrictions and transitions on psychological distress in caregivers of children with Intellectual Disabilities in the UK

Introduction: The current study explored longitudinally whether child behaviours that challenge and caregiver coping strategies was associated with psychological distress in caregivers of children with and without intellectual disability during and after lockdown. Method: An online survey was completed by caregivers who had children with and without intellectual disability during Time Period 1 (T1; August-December 2021, n = 171) and then again during Time Period 2 (T2; January-March 2022, n = 109). Results: Child behaviours that challenge and caregiver psychological distress reduced in T2 compared to T1. Child behaviours that challenge, emotion focused coping and avoidant coping was associated distress at both time points in caregivers of children with and without intellectual disabilities. Conclusions: The study shows that both child behaviours that challenge and caregiver psychological distress reduced as lockdown ended. However, caregiver coping strategies may have contributed to psychological distress, which has implications for interventions and support for caregivers

Optimizing drug therapy in patients with advanced dementia: A patient-centered approach

Background: Advanced dementia is a prevalent health problem in geriatric patients. These patients usually suffer from several chronic diseases, frequently leading to an end-of-life situation lasting months or years, generating complex and often inappropriate medication regimens. Objectives: Describe the re-orientation of drug therapy in patients with advanced dementia utilizing a systematic medication review process. Methods: This non-experimental pre-post analysis included all patients with advanced dementia admitted to acute geriatric unit (AGU) over one year. Medications were reviewed by a multidisciplinary team and together with the patient caregivers; new therapeutic objectives based on end-of-life care principles were established. Medications were classified as preventive, therapeutic, or symptomatic. The average number of medications per patient pre- and post-admission was compared. Results: We included 73 patients (mean age 86.1 years, mean Barthel Index: 14.5/100). At admission, patients had a mean of 7.27 drugs compared to 4.82 at discharge (66.85% reduction, P < 0.05). The main drugs withdrawn were cardiovascular and hematological (35.76%). Drugs for prevention decreased by 66.85% (from 1.8 to 0.6, P < 0.05) and those for symptomatic care decreased by 17,52% (from 2.34 to 1.93, P < 0.05). Conclusion: Medication therapy plans in patients with advanced dementia often do not meet their therapeutic goals. The proposed methodology is a useful tool to assess therapeutic appropriateness

A Francisella Mutant in Lipid A Carbohydrate Modification Elicits Protective Immunity

Francisella tularensis (Ft) is a highly infectious Gram-negative bacterium and the causative agent of the human disease tularemia. Ft is designated a class A select agent by the Centers for Disease Control and Prevention. Human clinical isolates of Ft produce lipid A of similar structure to Ft subspecies novicida (Fn), a pathogen of mice. We identified three enzymes required for Fn lipid A carbohydrate modifications, specifically the presence of mannose (flmF1), galactosamine (flmF2), or both carbohydrates (flmK). Mutants lacking either galactosamine (flmF2) or galactosamine/mannose (flmK) addition to their lipid A were attenuated in mice by both pulmonary and subcutaneous routes of infection. In addition, aerosolization of the mutants (flmF2 and flmK) provided protection against challenge with wild-type (WT) Fn, whereas subcutaneous administration of only the flmK mutant provided protection from challenge with WT Fn. Furthermore, infection of an alveolar macrophage cell line by the flmK mutant induced higher levels of tumor necrosis factor-α (TNF-α) and macrophage inhibitory protein-2 (MIP-2) when compared to infection with WT Fn. Bone marrow–derived macrophages (BMMø) from Toll-like receptor 4 (TLR4) and TLR2/4 knockout mice infected with the flmK mutant also produced significantly higher amounts of interleukin-6 (IL-6) and MIP-2 than BMMø infected with WT Fn. However, production of IL-6 and MIP-2 was undetectable in BMMø from MyD88−/− mice infected with either strain. MyD88−/− mice were also susceptible to flmK mutant infection. We hypothesize that the ability of the flmK mutant to activate pro-inflammatory cytokine/chemokine production and innate immune responses mediated by the MyD88 signaling pathway may be responsible for its attenuation, leading to the induction of protective immunity by this mutant

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21

Can human cardiovascular regulation during exercise be learnt from feedback from arterial baroreceptors?

During dynamic exercise, a large fall in systemic vascular resistance occurs. Arterial pressure (AP) is, however, maintained through a combination of central command and neural activity from muscle afferents that adjust the autonomic outflow to the circulation. How these signals are calibrated to provide accurate regulation of AP remains unclear. This study tests the hypothesis that the calibration can be ‘learnt’ through feedback from the arterial baroreceptors arising over multiple trials of exercise. Eight healthy subjects undertook three different protocols in random order. The test protocol consisted of 7 days' training, when subjects were exposed on 70 occasions to 4 min of exercise (50% of maximal oxygen uptake capacity) paired with neck suction (−40 mmHg) to mimic an excessive rise in AP at the carotid baroreceptors with exercise. Two control protocols involved training with either exercise or neck suction alone. No significant changes in mean AP, diastolic AP or heart rate during normal exercise were detected following training with any protocol. However, the rise in systolic AP with exercise was attenuated by an average of 7.3 ± 2.0 mmHg (mean ± s.e.m., P < 0.01) on the first and second days following training with the test protocol, but not with either control protocol (P < 0.05 for difference between protocols, ANOVA). In conclusion, this study failed to show that mean AP during normal exercise could be reduced through prior conditioning by overstimulation of the baroreceptors during exercise. However, a reduction in systolic AP was observed that suggests the presence of some plasticity within the autonomic response, consistent with our hypothesis