A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

OBJECTIVES: To clarify the role of growth monitoring in primary school children, including obesity, and to examine issues that might impact on the effectiveness and cost-effectiveness of such programmes. DATA SOURCES: Electronic databases were searched up to July 2005. Experts in the field were also consulted. REVIEW METHODS: Data extraction and quality assessment were performed on studies meeting the review's inclusion criteria. The performance of growth monitoring to detect disorders of stature and obesity was evaluated against National Screening Committee (NSC) criteria. RESULTS: In the 31 studies that were included in the review, there were no controlled trials of the impact of growth monitoring and no studies of the diagnostic accuracy of different methods for growth monitoring. Analysis of the studies that presented a 'diagnostic yield' of growth monitoring suggested that one-off screening might identify between 1:545 and 1:1793 new cases of potentially treatable conditions. Economic modelling suggested that growth monitoring is associated with health improvements [incremental cost per quality-adjusted life-year (QALY) of 9500 pounds] and indicated that monitoring was cost-effective 100% of the time over the given probability distributions for a willingness to pay threshold of 30,000 pounds per QALY. Studies of obesity focused on the performance of body mass index against measures of body fat. A number of issues relating to human resources required for growth monitoring were identified, but data on attitudes to growth monitoring were extremely sparse. Preliminary findings from economic modelling suggested that primary prevention may be the most cost-effective approach to obesity management, but the model incorporated a great deal of uncertainty. CONCLUSIONS: This review has indicated the potential utility and cost-effectiveness of growth monitoring in terms of increased detection of stature-related disorders. It has also pointed strongly to the need for further research. Growth monitoring does not currently meet all NSC criteria. However, it is questionable whether some of these criteria can be meaningfully applied to growth monitoring given that short stature is not a disease in itself, but is used as a marker for a range of pathologies and as an indicator of general health status. Identification of effective interventions for the treatment of obesity is likely to be considered a prerequisite to any move from monitoring to a screening programme designed to identify individual overweight and obese children. Similarly, further long-term studies of the predictors of obesity-related co-morbidities in adulthood are warranted. A cluster randomised trial comparing growth monitoring strategies with no growth monitoring in the general population would most reliably determine the clinical effectiveness of growth monitoring. Studies of diagnostic accuracy, alongside evidence of effective treatment strategies, could provide an alternative approach. In this context, careful consideration would need to be given to target conditions and intervention thresholds. Diagnostic accuracy studies would require long-term follow-up of both short and normal children to determine sensitivity and specificity of growth monitoring.

Changing osteocalcin concentrations during pregnancy and lactation: implications for maternal mineral metabolism.

We measured serum osteocalcin concentrations in 82 pregnant and 21 nonpregnant women. Osteocalcin values declined in the second trimester, but returned to nonpregnant levels late in the third trimester. The mean serum osteocalcin concentration in 36 women during pregnancy (mean gestation, 26 weeks) of 2.8 ng/mL was significantly lower than that in nonpregnant women (6.4 ng/mL; P less than 0.001) or term pregnant women at delivery (6.1 ng/mL; n = 46). Serum immunoreactive PTH (iPTH) levels were significantly higher during pregnancy than in nonpregnant women [97 +/- 5 vs. 56 +/- 4 ng/L (mean +/- SE); P less than 0.001]. No significant correlations were found between maternal osteocalcin concentrations and serum phosphorus, alkaline phosphatase, or iPTH, but significant negative correlations were found between osteocalcin and total calcium or total protein. Osteocalcin concentrations in midtrimester amniotic fluid were very low (mean, 0.3 +/- 0.1 ng/mL; n = 11). In 29 lactating mothers, the mean serum osteocalcin level was 9.5 +/- 1.5 ng/mL, significantly higher than in any of the other groups (P less than 0.05), but their serum calcium and iPTH levels were normal. There was no correlation between serum osteocalcin and calcium or iPTH concentrations in lactating women. These changes are compatible with a sequence in which bone turnover is reduced during early pregnancy, rebounds in the third trimester, and increases in postpartum lactating women.

Increased renal reabsorption of inorganic sulfate in third-trimester high-risk pregnancies.

Inorganic sulfate (SO4) is an essential metabolite for the synthesis of sulfated mucopolysaccharides and steroid sulfates in the fetus and placenta. The authors' previous study of pregnant women at delivery revealed a substantial increase in serum SO4 compared with nonpregnant adults. To determine whether or not this difference was related to altered renal handling, creatinine clearance and SO4 reabsorption was measured in 43 women in the third trimester of pregnancy and in 22 nonpregnant control subjects. Serum SO4 was 32% higher in the pregnant women than in control subjects. Urinary excretion of SO4 was unchanged, but absolute reabsorption of SO4 was significantly higher. Blood pressure, serum creatinine, and serum chloride were significant predictors of serum SO4. As a group, women with hypertension (diastolic blood pressure greater than 80 mmHg) had a significantly higher serum SO4 than those with normal blood pressure. One result of the increased SO4 reabsorption by maternal kidney is that it generates a larger maternal reservoir on which the fetoplacental unit can draw for its biosynthetic needs.

EOS 2D/3D X-ray imaging system: a systematic review and economic evaluation.

BACKGROUND: EOS is a biplane X-ray imaging system manufactured by EOS Imaging (formerly Biospace Med, Paris, France). It uses slot-scanning technology to produce a high-quality image with less irradiation than standard imaging techniques. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of EOS two-dimensional (2D)/three-dimensional (3D) X-ray imaging system for the evaluation and monitoring of scoliosis and other relevant orthopaedic conditions. DATA SOURCES: For the systematic review of EOS, electronic databases (MEDLINE, Allied and Complementary Medicine Database, BIOSIS Previews, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, EMBASE, Health Management Information Consortium, Inspec, ISI Science Citation Index and PASCAL), clinical trials registries and the manufacturer's website were searched from 1993 to November 2010. REVIEW METHODS: A systematic review of studies comparing EOS with standard X-ray [film, computed radiography (CR) or digital radiography] in any orthopaedic condition was performed. A narrative synthesis was undertaken. A decision-analytic model was developed to assess the cost-effectiveness of EOS in the relevant indications compared with standard X-ray and incorporated the clinical effectiveness of EOS and the adverse effects of radiation. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the perspective of the NHS. RESULTS: Three studies met the inclusion criteria for the review. Two studies compared EOS with film X-ray and one study compared EOS with CR. The three included studies were small and of limited quality. One study used an earlier version of the technology, the Charpak system. Both studies comparing EOS with film X-ray found image quality to be comparable or better with EOS overall. Radiation dose was considerably lower with EOS: ratio of means for posteroanterior spine was 5.2 (13.1 for the study using the Charpak system); ratio of means for the lateral spine was 6.2 (15.1 for the study using the Charpak system). The study comparing EOS with CR found image quality to be comparable or better with EOS. Radiation dose was considerably lower with EOS than CR; ratio of means for the centre of the back was 5.9 and for the proximal lateral point 8.8. The lowest ratio of means was at the nape of the neck, which was 2.9. No other outcomes were assessed in the included studies, such as implications for patient management from the nature and quality of the image. Patient throughput is the major determinant of the cost-effectiveness of EOS. The average cost per procedure of EOS decreases with utilisation. Using estimates of patient throughput at national level from Hospital Episode Statistics data suggests that EOS is not cost-effective for the indications considered. Throughput in the region of 15,100 to 26,500 (corresponding to a workload of 60 to 106 patient appointments per working day) for EOS compared with a throughput of only 7530 for CR (30 patient appointments per working day) is needed to achieve an incremental cost-effectiveness ratio of £30,000 per QALY. EOS can be shown to be cost-effective only when compared with CR if the utilisation for EOS is about double the utilisation of CR. LIMITATIONS: The main limitation of the systematic review of the clinical effectiveness of EOS was the limited number and quality of the data available. In particular, there were no studies assessing the potential health benefits arising from the quality and nature of the image, over and above those associated with reduced radiation exposure. Uncertainty in the model inputs was not fully explored owing to a lack of reporting of standard deviations or confidence intervals in the published literature for most of the parameters. As a result, uncertainty in the cost-effectiveness results was not presented. CONCLUSIONS: Radiation dose is considerably lower with EOS than standard X-ray, whereas image quality remains comparable or better with EOS. However, the long-term health benefits from reduced radiation exposure with EOS are very small and there was a lack of data on other potential patient health benefits. The implications of any changes in the quality and nature of the EOS image compared with standard X-ray, for patient health outcomes, needs to be assessed. Given the higher cost of an EOS machine, utilisation is the major determinant of cost-effectiveness. Estimates of patient throughput at national level suggest that EOS is not cost-effective. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Growth monitoring for short stature: update of a systematic review and economic model.

OBJECTIVES: The aim of the project was to compare different screening rules and/or referral cut-offs for the identification of children with disorders of short stature. We undertook an update of a previous systematic review and economic model that addressed the same question. DATA SOURCES: Sources searched included MEDLINE, EMBASE, Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index - Science/Social Science & Humanities, Cochrane Library 2009 Issue 4, Office of Health Economics Health Economic Evaluations Database, and the NHS Economic Evaluation Database. REVIEW METHODS: The review was conducted as an update to our previous assessment in 2007. Searching covered January 2005 to November 2009 with no language or publication restrictions. Two reviewers examined full papers for relevance. Data extraction was conducted by one reviewer and independently checked by a second. In addition, searches were conducted to identify quality of life or utility papers to inform the economic evaluation. We developed a probabilistic decision analytic model to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and personal social services. The model was a cohort model, assuming a homogeneous population of 5-year-olds at baseline. RESULTS: One study was included in the systematic review. The study was not UK based, but had been identified in the brief as relevant to the UK setting. The study's authors examined the performance of a number of rules to determine sensitivity and specificity of referral for short stature in four patient groups and three reference groups in the Netherlands. They derived an algorithm for referral based on the optimal rules. No new studies were located that provided appropriate quality of life or utilities data for the economic model. The model was based on the previous assessment which was updated to better reflect current UK clinical practice. We compared two alternative monitoring strategies, one of which was based on the study identified in our systematic review (Grote strategy); the other was based on UK consensus (UK strategy). We identified that the UK strategy was the least effective and least costly, with a mean gain of 0.001 QALYs at a mean cost of £21. The Grote strategy was both more expensive and more effective, with a mean cost of £68 and a mean QALY gain of 0.042. The incremental cost-effectiveness ratio was £1144 per QALY gained. CONCLUSIONS: This assessment contributes further knowledge, but does not provide definitive answers on how to deliver growth monitoring. In particular, we were unable to ascertain current practice in the UK for growth screening. Further, we were unable to evaluate through the use of identified studies and modelling an optimal referral cut-off and age at which to screen. We identified a number of research questions that would further inform referral strategies, which in summary would involve further primary and secondary data collection. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction.

This paper presents a summary of the evidence review group (ERG) report into trastuzumab for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic adenocarcinoma of the stomach (mGC) or gastro-oesophageal junction. HER2 positivity is defined by immunohistochemistry (IHC)3+ or IHC2+/fluorescence in situ hybridisation (FISH)+. The decision problem addressed was the testing of the whole mGC population with IHC and, for IHC2+ patients, also with FISH, followed by treatment of HER2-positive patients with trastuzumab combined with cisplatin and either capecitabine or 5-fluorouracil (5-FU) [HCX (trastuzumab, cisplatin, capecitabine)/fluorouracil (F)] compared with current standard NHS therapy. The manufacturer's submission contained direct evidence from the ToGA trial, a well-conducted, multinational, phase III randomised controlled trial (RCT) that compared HCX/F with cisplatin and a fluoropyrimidine alone [cisplatin, capecitabine (CX)/F]. HCX/F showed statistically significantly better overall survival in the European Medicines Agency-licensed population subgroup (74%) (hazard ratio 0.65, 95% confidence interval 0.51 to 0.83), corresponding to median survival of 16 months versus 11.8 months. No other evidence exists for the efficacy of any therapy in a known HER2-positive mGC population; other comparisons extrapolate from trials in mixed HER2 status populations. The ERG accepted the manufacturer's view that a meaningful network meta-analysis to establish a comparison for HCX/F compared with current standard NHS therapy [epirubicin, cisplatin, capecitabine (ECX)/epirubicin, oxaliplatin, capecitabine (EOX)/epirubicin, cisplatin, 5-FU (ECF)] was not possible, but was unconvinced by arguments advanced in the alternative narrative synthesis. These involved disregarding evidence from a meta-analysis and interpreting non-significant results of small RCTs comparing epirubicin-containing triplets with cisplatin, 5-FU (CF)/capecitabine (X) doublets as evidence of no difference between triplet and doublet regimens. The high CX/F dose in the ToGA trial was an additional basis for the contention of equivalence. An appropriate de novo economic evaluation, including an economic model that separately compared HCX or trastuzumab, cisplatin, 5-FU (HCF) with the triplet regimens ECX, EOX and ECF, based on a simple, three-state cohort model (progression-free, disease, progression and death), was submitted. Utility weights were applied to estimate quality-adjusted life-years (QALYs). Costs were assessed from an NHS perspective, and incorporated the acquisition and monitoring costs of the alternative regimens, HER2 testing, adverse events and other supportive care costs. An 8-year time horizon was used to represent a lifetime analysis. Results from the ToGA trial were combined with a series of assumptions on relative treatment effects and testing strategies. The manufacturer's results produced an incremental cost-effectiveness ratio (ICER) of £ 53,010 per QALY for HCX versus ECX. Although the manufacturer undertook a detailed set of sensitivity analyses, several alternative model assumptions were not evaluated. The ERG undertook a series of alternative base-case analyses. As a result of these analyses, EOX replaced ECX as the appropriate comparator, and the ICER for the comparison of HCX vs EOX increased to between £ 66,982 and £ 71,636 per QALY. The impact of implementation of alternative testing strategies remained unclear. There is also considerable uncertainty surrounding the true estimate of effectiveness for the comparison between triplet regimens containing epirubicin (ECX/ECF/EOX) and doublet CX/F regimens. Consequently, the view of the ERG was that there is insufficient evidence on the efficacy of HCX/F compared with current NHS standard therapy for an ICER to be determined with any degree of certainty.

Effectiveness and cost-effectiveness of height-screening programmes during the primary school years: a systematic review.

OBJECTIVE: To determine the effectiveness and cost-effectiveness of height screening (of children aged 4 to 11) to identify height-related conditions. DESIGN: Systematic review and economic modelling. SETTING AND INTERVENTION: We included published and unpublished screening studies of any design, except case reports, conducted in any setting that measured children's height as part of a population-level assessment. Studies were identified by electronic database searches, contact with experts and from bibliographies of retrieved studies. PARTICIPANTS: Children aged between 4 and 11 years. OUTCOME MEASURES: Diagnostic yield of height-related conditions and change in quality of life, as measured by quality-adjusted life years (QALYs), for early versus late treatment of underlying conditions. RESULTS: Twelve studies described a height-screening programme and provided data on the diagnostic yield of newly diagnosed height-related conditions. Where reported, yield for growth-hormone deficiency (per 1000 children screened) ranged from 0.05 (1 in 20,000) to 0.62 (approximately 1 in 1500) and for Turner syndrome (per 1000 children screened) was between 0.02 (1 in 50,000) and 0.07 (approximately 1 in 14,000). As a secondary gain, children with other potentially treatable conditions were identified; diagnostic yields ranged from 0.22 to 1.84 per 1000 children screened. Three studies did not detect any new cases, but all of these studies had methodological limitations. Economic modelling suggested that height screening is associated with health improvements and is cost effective for a willingness to pay threshold of pound 30,000 per QALY. CONCLUSIONS: This review indicates the utility and acceptable cost-effectiveness of height screening arising from increased detection of height-related disorders and secondary pick-up of other undiagnosed conditions. Further research is needed to obtain more reliable data on quality of life gains and costs associated with early interventions for height-related conditions. The exact role of height-screening programmes in improving child health remains to be determined.

Increased serum sulfate in pregnancy: relationship to gestational age.

Controlled-flow ion chromatography has significantly improved the precision with which inorganic sulfate (SO4) can be measured in serum. In this study, we have shown that serum SO4 is increased in pregnancy. The increase appears to follow gestational age, resulting in a 39% higher value by the middle of the third trimester. We suggest that this increase is a natural physiological process, which enhances SO4 availability to the growing fetus and placenta.

Abnormalities of crystallins in the lens of the CatFraser mouse.

We have analysed, by column chromatography and two-dimensional electrophoresis, the soluble proteins present in the lenses of normal mice and of mice heterozygous (Cat/+) and homozygous (Cat/Cat) for the CatFraser mutation which causes a dominantly inherited cataract. In Cat/+ and Cat/Cat lenses, the gamma-crystallins comprise a smaller fraction, and the alpha-crystallins a greater fraction, of the total crystallins present than found in normal lenses. These changes in composition involve all the subunits of each crystallin class and show a dosage effect, the change being greater in Cat/Cat than Cat/+ lenses. In both Cat/+ and Cat/Cat lenses, the beta H-crystallin aggregate is lost and subunits are present which are not detectable in normal lenses.

Increased inorganic sulfate in mother and fetus at parturition: evidence for a fetal-to-maternal gradient.

Inorganic sulfate is a cosubstrate for numerous sulfoconjugation reactions, including sulfation of estrogen steroids in the fetoplacental unit. It is known that the availability of inorganic sulfate can be the rate-limiting factor in these reactions, but fluxes of inorganic sulfate across the maternal-placental barrier have not been well characterized. Therefore, we measured serum inorganic sulfate in matched samples from 46 mothers and fetuses at parturition to identify any maternal-fetal gradient and explore clinical correlations. The concentration of inorganic sulfate, measured by controlled-flow anion chromatography, was significantly higher (p = 0.006) in fetal cord blood [458 +/- 10 microM; mean +/- SE] than in the maternal circulation [431 +/- 19 microM]. That a gradient was not observed for chloride ion rules out sampling artifact as a source of the difference. Maternal and fetal concentrations of inorganic sulfate were highly correlated (r = 0.84, p less than 0.001). No influence was observed for gestational history, newborn weight, sex, or Apgar scores, but values were significantly higher in those with relatively shorter (less than 36 weeks) or longer (greater than 41 weeks) gestations. We demonstrated that a small but significant fetal-to-maternal inorganic sulfate gradient exists at birth, but the origin of this gradient is not known.

Increased inorganic sulfate concentrations in amniotic fluid.

We assayed inorganic sulfate by ion chromatography in 49 amniotic fluid samples from pregnancies of 14 to 38 weeks gestation. In second trimester samples (14 to 26 weeks gestation), amniotic fluid sulfate concentrations (317 +/- 22 mumol/L, mean +/- SE; n = 32) were not different from previously reported maternal serum values but were significantly lower (p < 0.001) than in the third trimester (693 +/- 42 mumol/L; n = 16). In third trimester samples, sulfate concentrations were significantly correlated with creatinine and uric acid but not chloride, suggesting that renal excretion may be the major source of the amniotic fluid sulfate in the late stages of gestation.