Metapopulation dynamics of SARS-CoV-2 transmission in a small-scale Amazonian society.

The severity of infectious disease outbreaks is governed by patterns of human contact, which vary by geography, social organization, mobility, access to technology and healthcare, economic development, and culture. Whereas globalized societies and urban centers exhibit characteristics that can heighten vulnerability to pandemics, small-scale subsistence societies occupying remote, rural areas may be buffered. Accordingly, voluntary collective isolation has been proposed as one strategy to mitigate the impacts of COVID-19 and other pandemics on small-scale Indigenous populations with minimal access to healthcare infrastructure. To assess the vulnerability of such populations and the viability of interventions such as voluntary collective isolation, we simulate and analyze the dynamics of SARS-CoV-2 infection among Amazonian forager-horticulturalists in Bolivia using a stochastic network metapopulation model parameterized with high-resolution empirical data on population structure, mobility, and contact networks. Our model suggests that relative isolation offers little protection at the population level (expected approximately 80% cumulative incidence), and more remote communities are not conferred protection via greater distance from outside sources of infection, due to common features of small-scale societies that promote rapid disease transmission such as high rates of travel and dense social networks. Neighborhood density, central household location in villages, and household size greatly increase the individual risk of infection. Simulated interventions further demonstrate that without implausibly high levels of centralized control, collective isolation is unlikely to be effective, especially if it is difficult to restrict visitation between communities as well as travel to outside areas. Finally, comparison of model results to empirical COVID-19 outcomes measured via seroassay suggest that our theoretical model is successful at predicting outbreak severity at both the population and community levels. Taken together, these findings suggest that the social organization and relative isolation from urban centers of many rural Indigenous communities offer little protection from pandemics and that standard control measures, including vaccination, are required to counteract effects of tight-knit social structures characteristic of small-scale populations.

Effects of family planning on fertility behaviour across the demographic transition.

The adoption of contraception often coincides with market integration and has transformative effects on fertility behavior. Yet many parents in small-scale societies make decisions about whether and when to adopt family planning in an environment where the payoffs to  have smaller families are uncertain. Here we track the fertility of Maya women across 90 years, spanning the transition from natural to contracepting fertility. We first situate the uncertainty in which fertility decisions are made and model how childbearing behaviors respond. We find that contraception, a key factor in cultural transmission models of fertility decline, initially has little effect on family size as women appear to hedge their bets and adopt fertility control only at the end of their reproductive careers. Family planning is, however, associated with the spread of lower fertility in later cohorts. Distinguishing influences on the origin versus spread of a behaviour provides valuable insight into causal factors shaping individual and normative changes in fertility.

Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited GlaxoSmithKline, the manufacturer of dabrafenib, to submit evidence for the clinical and cost effectiveness of dabrafenib for the treatment of unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the company and provides a summary of the Appraisal Committee's (AC) final decision in October 2014. The clinical evidence for dabrafenib was derived from an ongoing phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BREAK-3) involving 230 patients randomized 2:1 to receive either dabrafenib or dacarbazine. A significant improvement in median progression-free survival (PFS) but not overall survival (OS) was reported in the dabrafenib arm compared with dacarbazine. Vemurafenib is considered a more appropriate comparator than is dacarbazine. The clinical evidence for vemurafenib was derived from a completed phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BRIM-3) involving 675 patients randomized 1:1 to receive either vemurafenib or dacarbazine. A significant improvement in median PFS and OS was reported in the vemurafenib arm compared with dacarbazine. As there is no direct evidence comparing dabrafenib versus vemurafenib, the company presented an indirect treatment comparison (ITC) that demonstrated no statistical differences between dabrafenib and vemurafenib for PFS or OS. The ERG expressed concerns with the ITC, mainly in relation to the validity of the assumptions underpinning the methodology; the ERG concluded this resulted in findings that are unlikely to be robust or reliable. Dabrafenib and vemurafenib are both available to patients treated by the National Health Service (NHS) in England via a Patient Access Scheme (PAS) in which the costs of the drugs are discounted. Using these discounted costs, the incremental cost-effectiveness ratios (ICERs) generated by the company were £60,980 per quality-adjusted life-year (QALY) for dabrafenib versus dacarbazine and £11,046 per QALY gained for dabrafenib versus vemurafenib. The ERG considered the economic model structure developed by the company to derive the ICERs to be overly complex and based on unsubstantiated assumptions, most importantly in relation to the projection of OS. Applying the latest OS data from BREAK-3 to a less complex model structure increased the estimated ICER for dabrafenib compared with dacarbazine from £60,980 to £112,727 per QALY gained. Since the results from the ITC were considered by the ERG to be neither reliable nor robust, the ERG also considered a cost-effectiveness comparison to be inappropriate due to a lack of meaningful or reliable data. In spite of limitations in the data, the AC took the view that dabrafenib and vemurafenib were "likely" of similar clinical effectiveness. Since the overall costs of these two drugs were similar, the AC recommended the use of dabrafenib in patients with unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma.

Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy: a NICE single technology appraisal.

The UK National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of erlotinib (Roche) to submit evidence for the clinical and cost effectiveness of erlotinib as monotherapy for the maintenance treatment of patients with non-small cell lung cancer (NSCLC) and stable disease following previous treatment with four cycles of platinum-containing therapy. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG) for this appraisal. The ERG reviewed the clinical- and cost-effectiveness evidence in two stages and in accordance with the decision problem defined by NICE. The analysis of the submitted models assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem. Analysis also included reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to have substantial impact on the base-case cost-effectiveness results. Clinical evidence was derived from a multi-centre, double-blind, randomized, phase III study designed to address the overall population of NSCLC patients. Outcomes included progression-free survival (PFS) and overall survival (OS). The recruited population was mainly from outside of Western Europe and no patients in the pivotal trial had received pemetrexed as a first-line therapy, which is now accepted clinical practice in the UK. The evidence considered in this article includes only the population for whom marketing authorizations has been received--that is, patients with stable disease following first-line therapy. The trial reported a small but statistically significant increase in both PFS and OS in patients with stable disease receiving erlotinib compared with placebo. However, no significant difference was identified in OS when patients with non-squamous disease and stable disease were considered as a subgroup. The economic evidence was focussed on the ERG's assessment of three economic models that related to patients with stable disease and compared erlotinib with placebo in the squamous and non-squamous populations and erlotinib with pemetrexed in the non-squamous population. The incremental cost-effectiveness ratios (ICERs) reported by the manufacturer were £39,936 per QALY gained (stable disease, all); £35,491 per QALY gained (stable disease, squamous); and £40,020 per QALY gained (stable disease, non-squamous). In comparison with pemetrexed, in the cases where erlotinib was considered to be superior or equivalent, erlotinib dominated. In the cases where erlotinib was considered to be slightly inferior, then the ICERs ranged between £91,789 and £511,351 per QALY gained; these ICERs appear in the south-west corner of a cost-effectiveness plane, i.e. erlotinib is cheaper but less effective than pemetrexed. The ERG recalculated the base-case cost-effectiveness results in the manufacturer's submission, considering nine key areas where corrections and/or adjustments were required, related to time horizon, discounting logic, costs of erlotinib and pemetrexed, cost of second-line chemotherapy, unit costs, utility values, PFS and OS. This resulted in ERG-revised ICERs for the stable disease squamous population of £44,812 per QALY gained, in the stable disease non-squamous population of £68,120 per QALY gained, and, when erlotinib was compared with pemetrexed, the result was £84,029 per QALY gained. All values were above NICE's perceived willingness-to-pay threshold. After the second Appraisal Committee meeting, the Committee did not recommend the use of erlotinib in this patient population.

Utility and value of a medicines information service provided by pharmacists: a survey of health professionals.

OBJECTIVES: many health professionals lack the time and skills to search for and appraise information on medicines. A solution might be to use others skilled in evidence appraisal, who make recommendations or provide information tailored to patients' needs. The objectives of this study were to assess how advice provided to health professionals by the northwest of England regional medicines information centre is used, whether it is useful for patient care and to measure satisfaction with the service. METHODS: a questionnaire was designed and sent to health professionals who contacted the centre between September 2008 and March 2009. Enquirers contacting the centre more than once were sent a questionnaire only in response to their first enquiry during the study period. Non-responders were sent a reminder. KEY FINDINGS: questionnaires were sent to 672 enquirers; 68% were returned. Nearly all respondents used the advice provided. Of the 430 respondents who provided data on how they used the information, 81% used it to manage a current patient and 29% to plan the care of future patients; nearly all considered it useful. Where data were given (n = 366), half used it to check if current or proposed management was appropriate, 45% to make changes to therapy and 35% to advise another health professional. In addition to patient care, one-quarter (n = 105/430) of respondents used the information for continuing professional development and 16% (n = 69/430) for training or teaching. CONCLUSIONS: health professionals value the enquiry-answering service and use the advice provided for patient care, continuing professional development and educating patients and other health professionals. The service is responsive, supporting the care of patients needing immediate and future management.

Accommodation to large disparity stereograms.

PURPOSE: The purpose of this study was to test whether observers would show accommodation changes to depth depicted in large disparity stereograms and whether the amount of accommodation was related to the amount of depth seen in the stereograms. Previous studies have shown small accommodation changes to depth depicted in stereograms. We tested a larger range of depths than previously investigated and also asked observers to judge the depth depicted in the stereogram, because a previous study had suggested that this might be an important factor. METHODS: All our observers had emmetropia. Accommodation was measured with a Canon Autoref R-1autorefractor as an observer viewed a depthful 4-by-4 cm planar target set against a 20-by-20 cm planar background 57 cm from the observer. The target was presented at a range of depths, -8 to +8 cm, either in stereogram stimuli or real stimuli. Each observer also made depth judgments of stereogram targets, after training with real targets. We also recorded the time taken for each observer to discern the depicted depths in stereograms. RESULTS: The accommodation shown by all observers (n = 9) to stereogram targets was significant but was on average about 60% of that predicted. There were individual differences in the accommodation an observer showed to stereogram targets, but this was not related to the amount of depth the observer saw in the stereogram. CONCLUSIONS: Accommodation changes did occur to stereogram targets, but these were generally less than predicted and also less than those shown for real targets. Possible reasons for these findings and the implications for the use of stereograms in clinical tests are discussed.