Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

Distributional Cost-Effectiveness Analysis of Health Technologies: Data Requirements and Challenges.

Governments and health technology assessment agencies are putting greater focus on and efforts in understanding and addressing health inequities. Cost-effectiveness analyses are used to evaluate the costs and health gains of different interventions to inform the decision-making process on funding of new treatments. Distributional cost-effectiveness analysis (DCEA) is an extension of cost-effectiveness analysis that quantifies the equity impact of funding new treatments. Key challenges for the routine and consistent implementation of DCEA are the lack of clearly defined equity concerns from decision makers and endorsed measures to define equity subgroups and the availability of evidence that allows analysis of differences in data inputs associated with the equity characteristics of interest. In this article, we detail the data gaps and challenges to build robust DCEA analysis routinely in health technology assessment and suggest actions to overcome these hurdles.

Quality-Adjusted Life Expectancy Norms for the English Population.

OBJECTIVES: The National Institute for Health and Care Excellence in England has implemented severity-of-disease modifiers that give greater weight to health benefits accruing to patients who experience a larger shortfall in quality-adjusted life-years (QALYs) under current standard of care than healthy individuals. This requires an estimate of quality-adjusted life expectancy (QALE) of the general population based on age and sex. Previous QALE population norms are based on nearly 30-year-old assessments of health-related quality of life in the general population. This study provides updated QALE estimates for the English population based on age and sex. METHODS: 5-level version of EQ-5D data for 14 412 participants from the Health Survey for England (waves 2017 and 2018) were pooled, and health-related quality of life population norms were calculated. These norms were combined with official life tables from the Office for National Statistics for 2017 to 2019 using the Sullivan method to derive QALE estimates based on age and sex. Values were discounted using 0%, 1.5%, and 3.5% discount rates. RESULTS: QALE at birth is 68.24 QALYs for men and 68.21 QALYs for women. These values are significantly lower than previously published QALE population norms based on the older 3-level version of EQ-5D data. CONCLUSION: This study provides new QALE population norms for England that serve to establish absolute and relative QALY shortfalls for the purpose of health technology assessments.

Is primary health care worth it in the long run? Evidence from Brazil.

This paper assesses whether Brazilian primary health care is worth it in the long-run by estimating the accumulated costs and benefits of its flagship, the Family Health Strategy program (ESF). We employ an alternative strategy centered on years of exposure to the program to incorporate its dynamics. We also account for the program's heterogeneity with respect to the remuneration of ESF health teams and the intensity of coverage across Brazilian municipalities, measure by the number of people assisted by each ESF team, on average. To address heterogeneity in professional earnings, this paper employs, for the first time, a dataset containing the remuneration of professionals allocated to all ESF teams nationwide. The benefits are measured by the avoided deaths and hospitalizations due to causes sensitive to primary care. Results suggest that the net monetary benefit of the program is positive on average, with an optimum time of exposure of approximately 16 years. Significant heterogeneities in cost-benefit results were found since costs outweigh benefits in localities where the coverage is low intensive. On the other hand, the benefits outweigh the costs by 22.5% on average in municipalities with high intensive coverage.

Effects of Multi-stage Procurement on the Viability and Function of Human Donor Parathyroid Glands.

INTRODUCTION: Parathyroid allotransplantation is an emerging treatment for severe hypoparathyroidism. Ensuring the viability and functional integrity of donor parathyroid glands following procurement is essential for optimal transplantation outcomes. METHODS: Cellular viability, calcium-responsive hormone secretion, and gland xenograft survival were assessed in a series of deceased donor parathyroid glands following a two-stage procurement procedure recently developed by our group (en bloc cadaveric dissection with subsequent gland isolation after transport to the laboratory). RESULTS: Parathyroid glands resected in this manner and stored up to 48 h in 4°C University of Wisconsin (UW) media retained in vitro viability with no induction of hypoxic stress (HIF-1α) or apoptotic (caspase-3) markers. Ex vivo storage did not significantly affect parathyroid gland calcium sensing capacity, with comparable calcium EC50 values and suppression of parathyroid hormone secretion at high ambient calcium concentrations. The isolated glands engrafted readily, vascularizing rapidly in vivo following transplantation into mice. CONCLUSIONS: Parathyroid tissue retains viability, calcium-sensing capacity, and in vivo engraftment capability after en bloc cadaveric resection, ex vivo dissection, and extended cold storage.

Socioeconomic inequalities in HRQoL in England: an age-sex stratified analysis.

BACKGROUND: Socioeconomic status is a key predictor of lifetime health: poorer people can expect to live shorter lives with lower average health-related quality-of-life (HRQoL) than richer people. In this study, we aimed to improve understanding of the socioeconomic gradient in HRQoL by exploring how inequalities in different dimensions of HRQoL differ by age. METHODS: Data were derived from the Health Survey for England for 2017 and 2018 (14,412 participants). HRQoL was measured using the EQ-5D-5L instrument. We estimated mean EQ-5D utility scores and reported problems on five HRQoL dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for ages 16 to 90+ and stratified by neighbourhood deprivation quintiles. Relative and absolute measures of inequality were assessed. RESULTS: Mean EQ-5D utility scores declined with age and followed a socioeconomic gradient, with the lowest scores in the most deprived areas. Gaps between the most and least deprived quintiles emerged around the age of 35, reached their greatest extent at age 60 to 64 (relative HRQoL of most deprived compared to least deprived quintile: females = 0.77 (95% CI: 0.68-0.85); males = 0.78 (95% CI: 0.69-0.87)) before closing again in older age groups. Gaps were apparent for all five EQ-5D dimensions but were greatest for mobility and self-care. CONCLUSION: There are stark socioeconomic inequalities in all dimensions of HRQoL in England. These inequalities start to develop from early adulthood and increase with age but reduce again around retirement age.

Methods to promote equity in health resource allocation in low- and middle-income countries: an overview.

Unfair differences in healthcare access, utilisation, quality or health outcomes exist between and within countries around the world. Improving health equity is a stated objective for many governments and international organizations. We provide an overview of the major tools that have been developed to measure, evaluate and promote health equity, along with the data required to operationalise them.Methods are organised into four key policy questions facing decision-makers: (i) what is the current level of inequity in health; (ii) does government health expenditure benefit the worst-off; (iii) can government health expenditure more effectively promote equity; and (iv) which interventions provide the best value for money in reducing inequity.Benefit incidence analysis can be used to estimate the distribution of current public health sector expenditure, with geographical resource allocation formulae and health system reform being the main government policy levers for improving equity. Techniques from the economic evaluation literature, such as extended and distributional cost-effectiveness analysis can be used to identify 'best buy' interventions from a health equity perspective. A range of inequality metrics, from gap measures and slope indices to concentration indices and regression analysis, can be applied to these approaches to evaluate changes in equity.Methods from the economics literature can provide policymakers with a toolkit for addressing multiple aspects of health equity, from outcomes to financial protection, and can be adapted to accommodate data commonly available in low- and middle-income settings.

Aggregate Distributional Cost-Effectiveness Analysis of Health Technologies.

BACKGROUND: Health inequalities can be partially addressed through the range of treatments funded by health systems. Nevertheless, although health technology assessment agencies assess the overall balance of health benefits and costs, no quantitative assessment of health inequality impact is consistently undertaken. OBJECTIVES: To assess the inequality impact of technologies recommended under the NICE single technology appraisal process from 2012 to 2014 using an aggregate distributional cost-effectiveness framework. METHODS: Data on health benefits, costs, and patient populations were extracted from the NICE website. Benefits for each technology were distributed to social groups using the observed socioeconomic distribution of hospital utilization for the targeted disease. Inequality measures and estimates of cost-effectiveness were compared using the health inequality impact plane and combined using social welfare indices. RESULTS: Twenty-seven interventions were evaluated. Fourteen interventions were estimated to increase population health and reduce health inequality, 8 to reduce population health and increase health inequality, and 5 to increase health and increase health inequality. Among the latter 5, social welfare analysis, using inequality aversion parameters reflecting high concern for inequality, indicated that the health gain outweighs the negative health inequality impact. CONCLUSIONS: The methods proposed offer a way of estimating the health inequality impacts of new health technologies. The methods do not allow for differences in technology-specific utilization and health benefits, but require less resources and data than conducting full distributional cost-effectiveness analysis. They can provide useful quantitative information to help policy makers consider how far new technologies are likely to reduce or increase health inequalities.

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia.

Parathyroid adenomas (PAs) causing primary hyperparathyroidism (PHPT) are histologically heterogeneous yet have been historically viewed as largely monotypic entities arising from clonal expansion of a single transformed progenitor. Using flow cytometric analysis of resected adenomatous parathyroid glands, we have isolated and characterized chief cells, oxyphil cells, and tumor-infiltrating lymphocytes. The parathyroid chief and oxyphil cells produce parathyroid hormone (PTH), express the calcium-sensing receptor (CASR), and mobilize intracellular calcium in response to CASR activation. Parathyroid tumor infiltrating lymphocytes are T cells by immunophenotyping. Under normocalcemic conditions, oxyphil cells produce ∼50% more PTH than do chief cells, yet display significantly greater PTH suppression and calcium flux response to elevated calcium. In contrast, CASR expression and localization are equivalent in the respective parathyroid cell populations. Analysis of tumor clonality using X-linked inactivation assays in a patient-matched series of intact tumors, preparatively isolated oxyphil and chief cells, and laser-captured microdissected PA specimens demonstrate polyclonality in 5 of 14 cases. These data demonstrate the presence of functionally distinct oxyphil and chief cells within parathyroid primary adenomas and provide evidence that primary PA can arise by both clonal and polyclonal mechanisms. The clonal differences, biochemical activity, and relative abundance of these parathyroid adenoma subpopulations likely reflect distinct mechanisms of disease in PHPT.

Single-cell functional analysis of parathyroid adenomas reveals distinct classes of calcium sensing behaviour in primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused by a failure of calcium sensing secondary to tumour development in one or more of the parathyroid glands. Parathyroid adenomas are comprised of distinct cellular subpopulations of variable clonal status that exhibit differing degrees of calcium responsiveness. To gain a clearer understanding of the relationship among cellular identity, tumour composition and clinical biochemistry in PHPT, we developed a novel single cell platform for quantitative evaluation of calcium sensing behaviour in freshly resected human parathyroid tumour cells. Live-cell intracellular calcium flux was visualized through Fluo-4-AM epifluorescence, followed by in situ immunofluorescence detection of the calcium sensing receptor (CASR), a central component in the extracellular calcium signalling pathway. The reactivity of individual parathyroid tumour cells to extracellular calcium stimulus was highly variable, with discrete kinetic response patterns observed both between and among parathyroid tumour samples. CASR abundance was not an obligate determinant of calcium responsiveness. Calcium EC50 values from a series of parathyroid adenomas revealed that the tumours segregated into two distinct categories. One group manifested a mean EC50 of 2.40 mM (95% CI: 2.37-2.41), closely aligned to the established normal range. The second group was less responsive to calcium stimulus, with a mean EC50 of 3.61 mM (95% CI: 3.45-3.95). This binary distribution indicates the existence of a previously unappreciated biochemical sub-classification of PHPT tumours, possibly reflecting distinct etiological mechanisms. Recognition of quantitative differences in calcium sensing could have important implications for the clinical management of PHPT.

Single-cell approaches for molecular classification of endocrine tumors.

PURPOSE OF REVIEW: In this review, we summarize recent developments in single-cell technologies that can be employed for the functional and molecular classification of endocrine cells in normal and neoplastic tissue. RECENT FINDINGS: The emergence of new platforms for the isolation, analysis, and dynamic assessment of individual cell identity and reactive behavior enables experimental deconstruction of intratumoral heterogeneity and other contexts where variability in cell signaling and biochemical responsiveness inform biological function and clinical presentation. These tools are particularly appropriate for examining and classifying endocrine neoplasias, as the clinical sequelae of these tumors are often driven by disrupted hormonal responsiveness secondary to compromised cell signaling. Single-cell methods allow for multidimensional experimental designs incorporating both spatial and temporal parameters with the capacity to probe dynamic cell signaling behaviors and kinetic response patterns dependent upon sequential agonist challenge. SUMMARY: Intratumoral heterogeneity in the provenance, composition, and biological activity of different forms of endocrine neoplasia presents a significant challenge for prognostic assessment. Single-cell technologies provide an array of powerful new approaches uniquely well suited for dissecting complex endocrine tumors. Studies examining the relationship between clinical behavior and tumor compositional variations in cellular activity are now possible, providing new opportunities to deconstruct the underlying mechanisms of endocrine neoplasia.

Cellular senescence mediated by p16INK4A-coupled miRNA pathways.

p16 is a key regulator of cellular senescence, yet the drivers of this stable state of proliferative arrest are not well understood. Here, we identify 22 senescence-associated microRNAs (SA-miRNAs) in normal human mammary epithelial cells. We show that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (Suz12), thereby activating p16. We demonstrate the existence of a tight positive feedback loop in which SA-miRNAs activate and re-enforce the expression of other SA-miRNA members. In contrast, PcG members restrain senescence by epigenetically repressing the expression of these SA-miRNAs. Importantly, loss of p16 leads to repression of SA-miRNA expression, intimately coupling this effector of senescence to the SA-miRNA/PcG self-regulatory loop. Taken together, our findings illuminate an important regulatory axis that underpins the transition from proliferation to cellular senescence.

Dielectrophoresis of spermatozoa in viscoelastic medium.

Knowledge of spermatozoa motility is important in selecting suitable spermatozoa for assisted reproduction procedures. By considering the internal sliding force within an active filament, its shape in a viscoelastic Oldroyd-B fluid subjected to nonuniform electric field is presented. The resulting velocity is a function of the beating pattern and DEP force, which is dependent on the spermatozoon's morphology as well as the gradient of the mean square electric field. Finally, the velocities of the X- and Y-spermatozoa are compared under various conditions of nonuniform electric field and viscoelasticity of the medium. The presence of DEP force alters their velocities to different extents, giving an 84% level of confidence for selecting spermatozoon that contains the chromosome leading to a female. Therefore, a nonuniform electric field can be used not only to sort and select spermatozoa of desired morphology, but also for gender selection. Moreover, we found that sorting in a viscoelastic fluid medium is more effective as the effect of DEP on the spermatozoa velocity is enhanced by an order of magnitude.

The Social Distribution of Health: Estimating Quality-Adjusted Life Expectancy in England.

OBJECTIVE: To model the social distribution of quality-adjusted life expectancy (QALE) in England by combining survey data on health-related quality of life with administrative data on mortality. METHODS: Health Survey for England data sets for 2010, 2011, and 2012 were pooled (n = 35,062) and used to model health-related quality of life as a function of sex, age, and socioeconomic status (SES). Office for National Statistics mortality rates were used to construct life tables for age-sex-SES groups. These quality-of-life and length-of-life estimates were then combined to predict QALE as a function of these characteristics. Missing data were imputed, and Monte-Carlo simulation was used to estimate standard errors. Sensitivity analysis was conducted to explore alternative regression models and measures of SES. RESULTS: Socioeconomic inequality in QALE at birth was estimated at 11.87 quality-adjusted life-years (QALYs), with a sex difference of 1 QALY. When the socioeconomic-sex subgroups are ranked by QALE, a differential of 10.97 QALYs is found between the most and least healthy quintile groups. This differential can be broken down into a life expectancy difference of 7.28 years and a quality-of-life adjustment of 3.69 years. CONCLUSIONS: The methods proposed in this article refine simple binary quality-adjustment measures such as the widely used disability-free life expectancy, providing a more accurate picture of overall health inequality in society than has hitherto been available. The predictions also lend themselves well to the task of evaluating the health inequality impact of interventions in the context of cost-effectiveness analysis.

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency.

Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population (1-3), but the basis for this association remains unclear. We employed a spatially defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from vitamin D-deficient or vitamin D-replete PHPT patients. A cross-sectional panel of eucalcemic cadaveric donor parathyroid glands was examined in parallel as normal tissue controls. Here, we report that parathyroid tumors from vitamin D-deficient PHPT patients (Def-Ts) are intrinsically different from those of vitamin D-replete patients (Rep-Ts) of similar age and preoperative clinical presentation. The parathyroid oxyphil cell content is markedly higher in Def-Ts (47.8%) relative to Rep-Ts (17.8%) and normal donor glands (7.7%). Vitamin D deficiency is associated with increased expression of electron transport chain and oxidative phosphorylation pathway components. Parathyroid oxyphil cells, while morphologically distinct, are comparable to chief cells at the transcriptional level, and vitamin D deficiency affects the transcriptional profiles of both cell types in a similar manner. These data suggest that oxyphil cells are derived from chief cells and imply that their increased abundance may be induced by low vitamin D status. Gene set enrichment analysis reveals that pathways altered in Def-Ts are distinct from Rep-Ts, suggesting alternative tumor etiologies in these groups. Increased oxyphil content may thus be a morphological indicator of tumor-predisposing cellular stress.

Applications of Genomics and Transcriptomics in Precision Medicine for Myopia Control or Prevention.

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for the design of precise and effective therapeutics. A strong understanding of altered biochemical pathways and underlying pathogenesis leading to myopia may facilitate early diagnosis and treatment of myopia, ultimately leading to the development of more effective preventive and therapeutic measures. In this review, we summarize current data about the genomics and transcriptomics of myopia in human and animal models. We also discuss the potential applicability of these findings to precision medicine for myopia treatment.

Decomposition of Quality-Adjusted Life Expectancy Inequalities by Mortality and Health-Related Quality of Life Dimensions.

BACKGROUND: Quality-adjusted life expectancy (QALE) combines mortality risk and multidimensional health-related quality of life (HRQoL) information to measure healthy life expectancy in terms of quality-adjusted life years (QALYs). This paper estimates the relative importance of individual quality of life dimensions in explaining inequalities in QALE. METHODS: We combined EQ-5D-5L data from the Health Survey for England for 2017 and 2018 (N = 14,412) with full population mortality data from the Office for National Statistics to calculate QALE by age, sex and deprivation quintile. The effect of HRQoL dimensions on the socioeconomic gradient in QALE was decomposed using an iterative imputation approach, in which inequalities associated with socioeconomic status in each domain were removed by imputing the response distribution of the richest quintile for all participants. Sampling uncertainty in the HRQoL data was evaluated using bootstrapping. RESULTS: People in the least deprived fifth of neighbourhoods in England can expect to live 7.0 years longer and experience 11.1 more QALYs than those in the most deprived fifth. Inequalities in HRQoL accounted for 28.0% and 45.7% of QALE inequalities for males and females, respectively. Pain/discomfort, anxiety/depression and mobility were the most influential HRQoL domains. DISCUSSION: Our results identify the extent of inequalities associated with socioeconomic status in lifetime health and the relative importance of inequalities by mortality and HRQoL. The contributions of the individual dimensions of HRQoL towards lifetime inequalities vary substantially by sex. Our findings can help to identify the types of interventions most likely to alleviate health inequalities, which may be different for males and females.

Equity and economic evaluation of system-level health interventions: A case study of Brazil's Family Health Program.

Distributional economic evaluation estimates the value for money of health interventions in terms of population health and health equity impacts. When applied to interventions delivered at the population and health system-level interventions (PSIs) instead of clinical interventions, additional practical and methodological challenges arise. Using the example of the Programme Saúde da Familia (PSF) in Brazil, a community-level primary care system intervention, we seek to illustrate these challenges and provide potential solutions. We use a distributional cost-effectiveness analysis (DCEA) approach to evaluate the impact of the PSF on population health and between-state health inequalities in Brazil. Data on baseline health status, disease prevalence and PSF effectiveness are extracted from the literature and incorporated into a Markov model to estimate the long-term impacts in terms of disability-adjusted life years. The inequality and average health impacts are analysed simultaneously using health-related social welfare functions. Uncertainty is computed using Monte Carlo simulation. The DCEA encountered several challenges in the context of PSIs. Non-randomized, quasi-experimental methods may not be powered to identify treatment effect heterogeneity estimates to inform a decision model. PSIs are more likely to be funded from multiple public sector budgets, complicating the calculation of health opportunity costs. We estimate a cost-per-disability-adjusted life years of funding the PSF of $2640. Net benefits were positive across the likely range of intervention cost. Social welfare analysis indicates that, compared to gains in average health, changes in health inequalities accounted for a small proportion of the total welfare improvement, even at high levels of social inequality aversion. Evidence on the population health and health equity impacts of PSIs can be incorporated into economic evaluation methods, although with additional complexity and assumptions. The case study results indicate that the PSF is likely to be cost-effective but that the inequality impacts are small and highly uncertain.

Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas.

CONTEXT: The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood. OBJECTIVE: This study aimed to define parathyroid tumor biochemical properties associated with calcium-sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation. METHODS: Preoperative clinical data from a sequential series of 39 patients undergoing surgery for PHPT at an endocrine surgery referral center in a large, public university hospital were evaluated for correlation to parathyroid tumor biochemical behavior. An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of 3 key components in the calcium/parathyroid hormone (PTH) signaling axis-CASR, RGS5, and RCAN1-were evaluated as potential mechanisms for calcium-sensing failure. RESULTS: Parathyroid adenomas grouped into 3 distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (P = 0.0009). Tumors with no calcium-sensing deficit (11 of 39) were associated with higher preoperative PTH (P = 0.036). A third group (6/39) displayed a nonsigmoid calcium/PTH response curve; 4 of these 6 tumors expressed elevated RCAN1. CONCLUSION: Calcium-sensing capacity varies among parathyroid tumors but downregulation of the calcium-sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.

How Useful Are Early Economic Models? Comment on "Problems and Promises of Health Technologies: The Role of Early Health Economic Modelling".

Early economic modelling has long been recommended to aid research and development (R&D) decisions in medical innovation, although they are less frequently published and critically appraised. A review of 30 innovations by Grutters et al provides an opportunity to evaluate how early models are used in practice. The evidence of early models can be used to inform two types of decision: to continue development ("stop or go") or to alter future R&D activities. I argue that early models have limited use in stop or go decisions, as less resource and data undermine the reliability of the models' indicative estimates of cost-effectiveness. Whilst they are far more useful for informing future R&D directions, the best techniques available from statistical decision science, such as value of information analysis, are not regularly used. It is highly recommended that early models adopt these methods to best deal with uncertainty, quantify the potential value of further research, identify areas of study with the greatest potential benefit and generate recommendations on study design and sample size.